[go: up one dir, main page]

WO2024184798A1 - Composition d'obturateurs de trayons et procédé de prévention de la mammite - Google Patents

Composition d'obturateurs de trayons et procédé de prévention de la mammite Download PDF

Info

Publication number
WO2024184798A1
WO2024184798A1 PCT/IB2024/052092 IB2024052092W WO2024184798A1 WO 2024184798 A1 WO2024184798 A1 WO 2024184798A1 IB 2024052092 W IB2024052092 W IB 2024052092W WO 2024184798 A1 WO2024184798 A1 WO 2024184798A1
Authority
WO
WIPO (PCT)
Prior art keywords
teat
composition
solid particles
sealant composition
calcium phosphate
Prior art date
Application number
PCT/IB2024/052092
Other languages
English (en)
Inventor
Ian George Tucker
Sumit DADHWAL
Greg Walker
Richard Gerhardus Martinus OLDE RIEKERINK
Forbes Richard Emslie
Original Assignee
Welfare Concepts Limited
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
Priority claimed from AU2023900582A external-priority patent/AU2023900582A0/en
Application filed by Welfare Concepts Limited filed Critical Welfare Concepts Limited
Publication of WO2024184798A1 publication Critical patent/WO2024184798A1/fr

Links

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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/02—Saturated carboxylic acids or thio analogues thereof; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/10—Carbonates; Bicarbonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0041—Mammary glands, e.g. breasts, udder; Intramammary administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/36—Materials or treatment for tissue regeneration for embolization or occlusion, e.g. vaso-occlusive compositions or devices

Definitions

  • ITS Internal teat sealants
  • Teat sealants may be used alone or in combination with an intra-mammary antibiotic (dry-cow therapy). Dry cow therapy containing antibiotics has been used for many years to reduce the incidence of mastitis during lactation in dairy cows.
  • a teat sealant composition that does not contain a bismuth salt (ie., it is bismuth-salt-free), for preventing a new intramammary infection or mastitis, or, to provide the public with a useful commercial choice.
  • a bismuth salt ie., it is bismuth-salt-free
  • Composition formulated to occlude a teat canal and/or teat cistern.
  • a teat sealant composition comprising a salt other than a bismuth salt, formulated to occlude a teat canal and/or teat cistern.
  • a teat sealant composition comprising solid particles dispersed within a water-insoluble shear-thinning viscous fluid vehicle, wherein the solid particles are not a bismuth salt.
  • a teat sealant composition comprising solid particles in a gel or in the form of a paste or in the form of a coarse suspension, formulated to occlude a teat canal and/or teat cistern.
  • the composition is free of bismuth salts and bismuth compounds.
  • the composition is formulated for administration to, and retention within, a teat canal and/or teat cistern of a cow.
  • the composition is in the form of a gel, paste or coarse suspension.
  • the composition has an adequately low viscosity so as to allow it to be administered via the teat canal and/or teat cistern by way of injection, preferably using a syringe.
  • the composition is administrable to a teat using a syringe (syringe utilizing a plunger), preferably an intramammary syringe.
  • Any suitable quantity can be administered. Typically, between approximately 2-5 g of composition is administered/injected.
  • the syringeability force for injecting the composition into the teat does not exceed 4500 g at 25°C.
  • the syringeability force for injecting the composition into the teat is between about 1500 g and 3500 g at 25°C, including all numerical values between the upper and lower limits, as well as any subranges falling there within (inclusive of approximately 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, 3000, 3200, 3200, 3300, 3400, 3500). Note this force depends not only on the formulation of the composition but also on the design of the syringe.
  • the syringe is a standard intramammary syringe having a cannular/nozzle inner diameter of 1.5 mm, an outer diameter of 2.5 mm, an inner barrel diameter of 13.5 mm, a cannular/nozzle length of 12 mm, and a barrel length of 49 mm.
  • Hubert De Backer nv Hubert De Backer nv (HDB veterinary intramammary syringe) at https://www.hdb.be/_library/_files/Tabellen/0.5.0/Intramammary_0_5_0.pdf.
  • Hubert De Backer nv Hubert De Backer nv (HDB veterinary intramammary syringe) at https://www.hdb.be/_library/_files/Tabellen/0.5.0/Intramammary_0_5_0.pdf.
  • syringeability studies described herein utilise this HDB veterinary intramammary syring
  • the composition thickens rapidly in the teat so as to be retained and occlude the teat canal and/or teat cistern.
  • the mass of the composition in the teat canal will be very small compared with that in the teat cistern.
  • the composition has a viscosity high enough so as to be retained within the teat canal or teat cistern and occlude the teat canal or teat cistern.
  • the composition has a bounce-back viscosity enabling it to be retained within the teat canal and/or teat cistern as a substantially coherent mass, wherein ‘bounce-back’ means that the viscosity increases fairly rapidly once the sealant is delivered into the teat.
  • the composition has a rheology enabling the composition to be administered to a teat canal and/or teat cistern by way of injection, and to be retained within the teat canal and/or teat cistern and occlude the teat canal and/or teat cistern, or to prevent an intramammary infection.
  • the composition has a density greater than about 1 g/cm 3 , and preferably between about 1.3 g/cm 3 and 1.6 g/cm 3 (inclusive of approximately 1.3, 1.4, 1.5 and 1.6).
  • the phrase ‘formulated to occlude’ means that the composition is capable of forming a physical barrier in the teat canal and/or teat cistern, thereby preventing the entry, or substantially preventing the entry, of pathogenic microbes such as bacteria into the udder.
  • the composition shear-thins at the shearing forces applied during injection and stripping from the teat.
  • the composition has antimicrobial activity, particularly antibacterial activity, particularly against bacteria that cause mastitis.
  • the antibacterial activity can be antibacterial or bacteriocidal.
  • the composition occludes a teat canal and/or teat cistern for a period of at least about 14 days, typically about 42 to about 90 days (including 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, and 90 days and all sub-ranges between 42 and 90), or typically up to about 4 months (including about 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6,
  • occlusion is for the full length of the dry period. [034] In some embodiments, occlusion is for approximately the first 14 days of the dry period until a natural keratin plug develops. [035] The composition is preferably used in a milking cow or heifer. [036] In some embodiments, the composition occludes the teat canal and/or teat cistern or substantially occludes the teat canal and/or teat cistern until a natural keratin plug has formed in the teat canal.
  • the composition occludes the teat canal and/or teat cistern or substantially occludes the teat canal and/or teat cistern for about 4-6 weeks, while allowing the natural keratin plug to develop.
  • the composition is used at dry-off of the cow.
  • the composition is used when environmental pathogens are highest, at the beginning of the dry-off period.
  • the composition is formulated such that no stripping from the teat canal and/or teat cistern is required at the end of the dry-period.
  • All ingredients of the composition can be veterinary-acceptable.
  • the composition is antimicrobial or antibacterial, including inhibiting growth of the microorganism or lethal to the microorganism (eg. bactericidal).
  • one or more ingredients of the composition may provide antimicrobial activity.
  • the solid particles may modify the rheology of the composition as well as provide antimicrobial activity.
  • the composition can have antimicrobial activity against mastitis causing bacteria.
  • the composition can have antimicrobial activity against any one or more of the following bacteria: Streptococcus uberis, Staphylococcus aureus, and Escherichia coli (E.
  • the solid particles can be very soluble, freely soluble, soluble, sparingly soluble, slightly soluble, very slightly soluble, practically insoluble, or insoluble. Guidelines for levels of water-solubility are defined as follows (and are not to be taken as fixed exact figures): [046] Descriptive Level Parts of water (solvent) per 1 part of solute [047] Very Soluble Less than 1 [048] Freely Soluble From 1 to 10 [049] Soluble From 10 to 30 [050] Sparingly Soluble From 30 to 100 [051] Slightly Soluble From 100 to 1000 [052] Very Slightly Soluble From 1000 to 10,000 [053] Practically Insoluble, or Insoluble More than 10,000 [054] Advantages of using water-soluble solid particles include: they can reduce the quantity of residues that are left in the teat canal (and udder) that will need to be stripped or filtered out during milking; and, some water-soluble solid materials can provide
  • any suitable type or types of solid particles can be used, in any suitable quantity or quantities.
  • the solid particles have a solubility in water that exceeds about twice the iso-osmotic concentration.
  • the solid particles comprise at least one type of salt that is not a bismuth salt, such as an organic salt or inorganic salt.
  • the solid particles can comprise at least one type of heavy metal salt provided that it is not a bismuth salt and does not result in toxic or undesirable metal residues in milk or meat of the animal.
  • Acceptable heavy metals may include calcium, magnesium and aluminium, but exclude toxic heavy metals.
  • calcium phosphate as herein defined, context permitting, includes within its scope any compound comprising Ca 2+ combined with PO 3 ⁇ 4, HPO 2 ⁇ 4, or H 2 PO ⁇ 4, including both anhydrous and hydrate forms (salt hydrates), including: monocalcium phosphate; dicalcium phosphate; tricalcium phosphate (which is practically insoluble or insoluble in water); calcium phosphate dibasic anhydrous (which is very slightly soluble) / dicalcium phosphate anhydrous; calcium phosphate dibasic dihydrate (which is very slightly soluble) / dicalcium phosphate dihydrate / dibasic calcium phosphate dihydrate; calcium phosphate monobasic anhydrous / calcium bis(dihydrogenphosphate) anhydrous / calcium dihydrogenphosphate anhydrous; calcium phosphate monobasic monohydrate / calcium bis(dihydrogenphosphate) monohydrate / calcium dihydrogenphosphate monohydrate; and calcium monohydrogen phosphate dihydrate (which is practically
  • the solid particles comprise at least one type of carbohydrate, such as a simple or complex sugar. These include, but are not limited to, sucrose (which is very soluble in water) and mannitol (which is freely soluble in water).
  • the solid particles comprise at least one type of mineral, such as a clay, such as kaolin (which is generally insoluble in water), such as kaolinite, halloysite, dickite or nacrite.
  • the solid particles comprise sodium chloride.
  • the solid particles comprise potassium chloride.
  • the solid particles comprise calcium phosphate as herein defined (such as dicalcium phosphate dihydrate / calcium phosphate dibasic dihydrate). In some embodiments, the solid particles comprise calcium carbonate. In some embodiments, the solid particles comprise magnesium carbonate. [062] In some embodiments, the solid particles comprise sodium chloride or potassium chloride, and calcium phosphate as herein defined (such as dicalcium phosphate dihydrate / calcium phosphate dibasic dihydrate). In some embodiments, the solid particles comprise sodium chloride or potassium chloride, and calcium carbonate. In some embodiments, the solid particles comprise sodium chloride or potassium chloride, and magnesium carbonate.
  • the composition comprises solid particles in the following approximate amount ranges: 10% to 75%, 35% to 70%, 40% to 65%, 50% to 60%, w/w, including all numerical values between 10 and 75, including approximately 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74 and 75.
  • the solid particles comprise approximately 25-60% w/w sodium chloride or potassium chloride (including approximately 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 and 60).
  • the solid particles comprise approximately 10-30% w/w magnesium carbonate (including approximately 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30).
  • the solid particles comprise approximately 10% w/w magnesium carbonate and approximately 25% w/w sodium chloride or potassium chloride.
  • the solid particles comprise approximately 55% w/w sodium chloride or potassium chloride.
  • the solid particles comprise approximately 35-60% w/w calcium phosphate as herein defined (such as dicalcium phosphate dihydrate / calcium phosphate dibasic dihydrate) (including approximately 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 and 60).
  • the solid particles comprise approximately 60% w/w calcium phosphate as herein defined (such as dicalcium phosphate dihydrate / calcium phosphate dibasic dihydrate).
  • the solid particles comprise approximately 10% w/w sodium chloride or potassium chloride and approximately 50% w/w calcium phosphate as herein defined (such as dicalcium phosphate dihydrate / calcium phosphate dibasic dihydrate).
  • the solid particles comprise approximately 25% w/w sodium chloride or potassium chloride and approximately 35% w/w calcium phosphate as herein defined (such as dicalcium phosphate dihydrate / calcium phosphate dibasic dihydrate).
  • the solid particles comprise approximately 10% w/w sodium chloride or potassium chloride and approximately 50% w/w calcium phosphate as herein defined (such as dicalcium phosphate dihydrate / calcium phosphate dibasic dihydrate).
  • the solid particles can be milled and/or sieved. In some embodiments, the solid particles can be within a particle size range, or of a particular average particle size.
  • the average particle size can be less than approximately 110, 109, 108, 107, 106, 105, 104, 103, 102, 101, 100, 99, 98, 97, 96, 95, 94, 93, 92, 91, 90, 89, 88, 87, 86, 85, 84, 83, 82, 81, 80, 79, 78, 77, 76, 75, 74, 73, 72, 71, 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4 or 3 ⁇ m in size.
  • the average particle size can be less than approximately 106 ⁇ m in size. In some embodiments, the average particle size can be less than approximately 80 ⁇ m in size. In some embodiments, the average particle size can be less than approximately 50 ⁇ m in size. In some embodiments, the average particle size can be less than approximately 30 ⁇ m in size. In some embodiments, the average particle size can be less than approximately 20 ⁇ m in size. In some embodiments, the average particle size can be less than approximately 10, 15, 20, 25, 30, 35 or 40 ⁇ m in size.
  • the average particle size can be approximately 10-40 ⁇ m in size (including approximately 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 and 40). In some embodiments, the average particle size can be approximately 10-50 ⁇ m in size (including approximately 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 and 50). In some embodiments, the average particle size can be approximately 20-30 ⁇ m in size (including approximately 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30).
  • the average particle size can be approximately 1-10 ⁇ m in size (including approximately 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10). In some embodiments, the average particle size can be greater than approximately 3 ⁇ m in size.
  • the D90 particle size distribution parameter of 90%
  • the D90 can be approximately 30-60 ⁇ m (including approximately 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 and 60)
  • the D50 can be approximately 6-12 ⁇ m in size (including approximately 6, 7, 8, 9, 10, 11 and 12); and/or the D10 can be 1-2 ⁇ m.
  • these D90, D50 and D10 particle size distribution parameters are suitable for sodium chloride.
  • these D90, D50 and D10 particle size distribution parameters are suitable for calcium phosphate as defined herein, preferably dicalcium phosphate dihydrate / calcium phosphate dibasic dihydrate.
  • the D90 of calcium phosphate as herein defined can be about 50 ⁇ m.
  • sodium chloride can be milled to an average particle size of approximately ⁇ 10 ⁇ m.
  • sodium chloride can have an average particle size of approximately 20-30 ⁇ m.
  • Any suitable type of vehicle can be used.
  • the vehicle can comprise a water-insoluble carrier and a thickener.
  • the thickener includes the solid particles. That is, the solid particles typically affect the rheology of the composition.
  • the water-insoluble carrier can comprise at least one type of carrier agent.
  • the carrier or carrier agent comprises at least one type of oil or oily liquid. Suitable examples include a vegetable oil, mineral oil, synthetic oil, medium chain triglyceride, and triglyceride. Preferred examples include paraffin oil (light or heavy), liquid paraffin, petrolatum (white or yellow), sesame oil, and miglyol (which is a medium chain triglyceride).
  • Any suitable quantity of carrier or carrier agent can be used.
  • the composition comprises carrier or carrier agents in the following approximate ranges: 20% to 80% w/w (including approximately 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79 and 80), including all subranges and numerical values between 20 and 80%, including approximately 30-65% w/w (including approximately 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64
  • the thickener can comprise at least one type of thickening agent.
  • the at least one type of thickening agent can be water-soluble and/or water- insoluble.
  • at least one thickening agent can function both as a thickener and as an antimicrobial.
  • An example of such an agent is lauric acid.
  • at least one thickening agent can comprise a medium-chain saturated fatty acid, such as lauric acid.
  • lauric acid is used [080]
  • the composition comprises approximately 1% to 10% w/w medium- chain saturated fatty acid, such as lauric acid, including all numerical values between 1 and 10 (including approximately 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10), including approximately 1, 2.5 and 5%.
  • at least one thickening agent can comprise a metal salt of a long chain fatty acid, such as a stearate salt.
  • Suitable salts can include aluminium distearate, aluminium stearate, aluminium tristearate, ammonium stearate, barium stearate, butyl stearate, cadmium stearate, calcium stearate, cobalt stearate, copper stearate, glycol stearate, lithium stearate, magnesium stearate, manganese stearate, methyl stearate, potassium stearate, sodium stearate, strontium stearate, and zinc stearate.
  • the at least one thickening agent comprises aluminium stearate.
  • the composition comprises approximately 1% to 10% w/w metal salt of a long chain fatty acid (including approximately 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10), such as stearate salt, such as aluminium stearate, including all numerical values between 1 and 10 (including approximately 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10), including approximately 4.3 and 5.3%.
  • at least one thickening agent can comprise silicon dioxide, such as hydrophilic or hydrophobic silica. Suitable silicon dioxide agents include fumed silica, such as hydrophilic fumed silica or hydrophobic fumed silica. Hydrophilic fumed silica is sold under the trade mark Aerosil-200.
  • Hydrophobic fumed silica is sold under the trade mark Aerosil R972.
  • the composition comprises approximately 0.1% to 1% w/w silicon dioxide, such as hydrophilic fumed silica, including all numerical values between 0.1 and 1 (including approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 and 1), including approximately 0.7%.
  • at least one thickening agent can comprise a water-soluble fumed silica, such as the one sold under the trade mark Aerosil-200 by Evonik.
  • Any suitable quantity of thickener or thickening agent can be used.
  • the composition comprises thickener or thickening agents in the following approximate ranges: 0.1% to 10%, w/w, including all numerical values between 0.1 and 10 (including approximately 0.1, 0.2...1, 1.1, 1.2...2, 2.1, 2.2...3, 3.1, 3.2...4, 4.1, 4.2...5, 5.1, 5.2...6, 6.1, 6.2...7, 7.1, 7.2...8, 8.1, 8.2...9, 9.1, 9.2...10), including approximately less than 1%.
  • the composition can have antimicrobial activity against mastitis-causing bacteria.
  • the composition can, for example, have antimicrobial activity against any one or more of the following bacteria: Streptococcus uberis, Staphylococcus aureus, and/or Escherichia coli (E. coli).
  • the composition or component, agent or ingredient thereof can provide contact killing.
  • the composition or component, agent or ingredient thereof can provide solution killing.
  • the composition or component, agent or ingredient thereof can provide both contact and solution killing.
  • Contact killing means that the composition’s surface has antimicrobial activity, when surface contact is made by a microbe such as a bacterium.
  • Solution killing means a chemical, ingredient or agent has leached from the composition and has antimicrobial activity when contact is made with a microbe such as a bacterium.
  • the composition comprises at least one type of antimicrobial agent, particularly an antibacterial agent. Suitable agents include chlorhexidine, PVP-iodine, lacticin and lauric acid.
  • the composition does not contain an antibiotic.
  • Antibiotic in this context means a type of antibiotic typically / conventionally used in dry cow therapy. Any suitable quantity of antimicrobial agent can be used.
  • the composition comprises an antimicrobial agent in the following approximate ranges: 0.1% to 10%, w/w, including all numerical values between 0.1 and 10 (including approximately 0.1, 0.2...1, 1.1, 1.2...2, 2.1, 2.2...3, 3.1, 3.2...4, 4.1, 4.2...5, 5.1, 5.2...6, 6.1, 6.2...7, 7.1, 7.2...8, 8.1, 8.2...9, 9.1, 9.2...10), including approximately 1-5% for antimicrobial agents such as lauric acid (including approximately 1, 2, 3, 4 and 5), and approximately 0.2-2% for antimicrobial agents such as chlorohexidine (including approximately 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 and 2).
  • antimicrobial agent in the following approximate ranges: 0.1% to 10%, w/w, including all numerical values between 0.1 and 10 (including approximately 0.1, 0.2...1, 1.1,
  • antimicrobial activity is provided by the vehicle. In some embodiments, antimicrobial activity is provided by the solid particles. In some embodiments, antimicrobial activity is provided by both the vehicle and the solid particles. In some embodiments, antimicrobial activity is provided by an ingredient of the vehicle, such as the carrier or carrier agent thereof and/or the thickener or thickening agent thereof.
  • lauric acid can be both a thickening agent and can provide antibacterial activity.
  • a salt such as sodium chloride can be both a thickening agent and can provide antibacterial activity by way of creating a hypertonic solution around the composition within the teat canal and/or teat cistern.
  • the composition can comprise one or more other ingredients such as at least one antioxidant or preservative. Any suitable quantity or quantities can be added, such as approximately 0.01% w/w to 5% w/w (including approximately 0.01...0.05...0.1...0.5...2...2.5...3...3.5...4...4.5...5).
  • antioxidant or preservative examples include alpha tocopherol, ascorbic acid, ascorbyl palmitate, benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, BHA (butylated hydroxy anisole), BHT (butylated hydroxy toluene), bronopol, butylparaben, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben, fumaric acid, imidurea, malic acid, monothioglycerol, n-propyl gallate, parabens (methylparaben and/or propylparaben), phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium sorbate, sodium ascorbate, sodium benzoate, sodium metabisulfite, sodium propionate,
  • the composition can comprise at least one colourant. Any suitable quantity or quantities can be added, such as approximately 0.01% w/w to 10% w/w (including approximately 0.01...0.1...1...10). Examples of colourants include dyes and pigments, including aluminium lake, caramel, methylene blue and titanium dioxide.
  • a teat sealant composition comprising: [095] an oily carrier; and [096] a thickener that comprises solid particles and lauric acid, [097] wherein the solid particles are not a bismuth metal salt.
  • a teat sealant composition comprising coarse filler material, in the form of solid particles, in a gelling agent, wherein the solid particles are not a bismuth metal salt.
  • a teat sealant composition comprising: [100] liquid paraffin; [101] aluminium stearate; [102] fumed silica; and [103] water-soluble solid particles, [104] wherein said composition is in the form of a paste or suspension.
  • a teat sealant composition comprising: [106] liquid paraffin; [107] aluminium stearate; [108] fumed silica; and [109] water-insoluble solid particles, [110] wherein said composition is in the form of a paste or suspension.
  • the teat sealant composition comprises one of the following formulations shown in the Formulations Table (all ingredients shown are actual or approximate, and all are %w/w). [112] Formulations Table.
  • a teat sealant composition comprising solid particles dispersed within a water-insoluble shear-thinning viscous fluid vehicle, said method comprising the steps of: [115] (1) forming a water-insoluble gel by mixing at least one type of water-insoluble carrier agent with at least one
  • a method of preparing a teat sealant composition comprising the steps of: [123] (1) forming a water-insoluble gel by mixing at least one type of oily carrier with at least one type of thickening agent; [124] (2) adding solid particles to the gel to form a paste; and, [125] (3) adding lauric acid as a thickening agent to the gel or paste, wherein: [126] the solid particles are not a bismuth metal salt.
  • teat sealant composition when prepared by the method according to the ninth or tenth aspect of the present invention.
  • a teat sealant composition for preventing a new intramammary infection or mastitis in a cow, said composition being as described in respect of the first to eighth and eleventh aspects of the present invention.
  • a teat sealant composition for use or when used for preventing a new intramammary infection or mastitis in a cow, said composition being as described in respect of the first to eighth and eleventh aspects of the present invention.
  • a teat sealant composition in the manufacture of a medicament for preventing a new intramammary infection or mastitis in a cow, said composition being as described in respect of the first to eighth and eleventh aspects of the present invention.
  • a method of preventing a new intramammary infection or mastitis in a cow comprising the step of administering to at least one teat canal and/or teat cistern of the cow the composition as described in respect of the first to eighth and eleventh aspects of the present invention.
  • compositions as described in respect of the first to eighth and eleventh aspects of the present invention for preventing a new intramammary infection or mastitis in a cow.
  • a syringe containing the composition as described in respect of the first to eighth and eleventh aspects of the present invention there is provided.
  • kitsset for use or when used in a method of preventing a new intramammary infection or mastitis in a cow, wherein the kitset comprises: a syringe capable of administering to at least one teat canal and/or teat cistern of a cow the composition as described in respect of the first to eighth and eleventh aspects of the present invention.
  • the composition is preferably used in a milking cow or heifer.
  • the composition prevents a new intramammary infection or mastitis for a period of at least about 14 days, typically about 42 to about 90 days (including 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, and 90 days and all sub-ranges between 42 and 90), or typically up to about 4 months (including about 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, and 16 weeks).
  • occlusion by the composition is for approximately the first 14 days of the dry period until a natural keratin plug develops.
  • the composition occludes the teat canal and/or teat cistern or substantially occludes the teat canal and/or teat cistern until a natural keratin plug has formed in the teat canal.
  • the composition protects the teat or teats of the cow from bacterial infection during an entire dry period.
  • the composition is administered per quarter at the end of lactation.
  • the composition is administered per quarter in maiden heifers approximately 4 weeks prior to calving.
  • a bismuth-salt-free teat sealant composition formulated to occlude a teat canal and/or teat cistern.
  • a teat sealant composition comprising a salt other than a bismuth salt, formulated to occlude a teat canal and/or teat cistern.
  • a teat sealant composition formulated for administration to, and retention within, a teat canal and/or teat cistern of a cow.
  • the teat sealant composition of any one of the preceding paragraphs wherein: [150] - the teat sealant composition has an adequately low viscosity so as to allow it to be administered via a teat canal and/or teat cistern by way of injection; [151] - approximately 2-5 g of the teat sealant composition is administered/injected into a teat canal and/or teat cistern; [152] - a syringeability force for injecting the teat sealant composition into a teat does not exceed 4500 g at 25°C, and preferably the syringeability force for injecting the teat sealant composition into a teat is between about 1500 g and 3500 g at 25°C; [153] - the teat sealant composition thickens rapidly in a teat so as to be retained and occlude a teat canal and/or teat cistern; [154] - once located within a teat canal and/or teat cistern, the teat seal
  • a teat sealant composition comprising solid particles dispersed within a water-insoluble shear-thinning viscous fluid vehicle, wherein the solid particles are not a bismuth salt.
  • antimicrobial activity is provided by the vehicle; antimicrobial activity is provided by the solid particles; antimicrobial activity is provided by both the vehicle and the solid particles; antimicrobial activity is provided by an ingredient of the vehicle; or, the composition further comprises at least one type of antimicrobial agent, preferably an antibacterial agent.
  • the vehicle comprises a water-insoluble carrier and a thickener, and preferably the thickener includes the solid particles.
  • the teat sealant composition of paragraph 8 wherein the water-insoluble carrier comprises at least one type of carrier agent, and the carrier agent comprises at least one type of oil or oily liquid.
  • the at least one type of oil or oily liquid comprises a vegetable oil, mineral oil, synthetic oil, medium chain triglyceride, or triglyceride, preferably paraffin oil, liquid paraffin, petrolatum, sesame oil, or a medium chain triglyceride.
  • the teat sealant composition of paragraph 9 or 10 wherein the composition comprises approximately 20% to 80% w/w or 30-65% w/w of the at least one type of carrier agent.
  • the thickener comprises at least one type of thickening agent which is water-soluble and/or water-insoluble, preferably in an amount of approximately 0.1% to 10%, w/w.
  • the at least one thickening agent functions both as a thickener and as an antimicrobial.
  • the metal salt of the long chain fatty acid comprises aluminium distearate, aluminium stearate, aluminium tristearate, ammonium stearate, barium stearate, butyl stearate, cadmium stearate, calcium stearate, cobalt stearate, copper stearate, glycol stearate, lithium stearate, magnesium stearate, manganese stearate, methyl stearate, potassium stearate, sodium stearate, strontium stearate, or zinc stearate, preferably aluminium stearate.
  • the teat sealant composition of paragraph 17 wherein the composition comprises approximately 1% to 10% w/w of the metal salt of the long chain fatty acid.
  • the composition comprises approximately 0.1% to 1% w/w silicon dioxide, preferably hydrophilic fumed silica.
  • a teat sealant composition comprising solid particles in a gel or in the form of a paste or in the form of a course suspension, formulated to occlude a teat canal and/or teat cistern.
  • a teat sealant composition comprising: [211] an oily carrier; and [212] a thickener that comprises solid particles and lauric acid, [213] wherein the solid particles are not a bismuth salt.
  • a teat sealant composition comprising coarse filler material, in the form of solid particles, in a gelling agent, wherein the solid particles are not a bismuth salt.
  • a teat sealant composition comprising: [216] liquid paraffin; [217] aluminium stearate; [218] fumed silica; and [219] water-soluble solid particles, [220] wherein said composition is in the form of a paste or suspension.
  • a teat sealant composition comprising: [222] liquid paraffin; [223] aluminium stearate; [224] fumed silica; and [225] water-insoluble solid particles, [226] wherein said composition is in the form of a paste or suspension. [227] 28.
  • a teat sealant composition comprising one of the following formulations, wherein all ingredients shown are actual or approximate: [257] NaCl or KCl 55% w/w; [258] Aluminium stearate 4.3% w/w; [259] Fumed silica 0.7% w/w; [260] Lauric acid 5% w/w; and [261] Paraffin oil 35% w/w; [262] or [263] NaCl or KCl 60% w/w; [264] Aluminium stearate 4.3% w/w; [265] Fumed silica 0.7% w/w; [266] Lauric acid 5% w/w; and [267] Paraffin oil 30% w/w; [268] or [269] NaCl or KCl 55% w/w; [270] Aluminium stearate 4.3% w/w; [271] Fumed silica 0.7% w/w; [272] Lauric acid 2.5% w/
  • a method of preparing a teat sealant composition comprising solid particles dispersed within a water-insoluble shear-thinning viscous fluid vehicle, said method comprising the steps of: [323] (1) forming a water-insoluble gel by mixing at least one type of water-insoluble carrier agent with at least one type of thickening agent; [324] (2) adding solid particles to the gel to form a paste; and, optionally, [325] (3) adding at least a further type of thickening agent to the gel or paste, wherein: [326] a teat sealant composition comprising solid particles dispersed within a water-insoluble shear- thinning viscous fluid vehicle is prepared; [327] the solid particles are not a bismuth metal salt; [328] step (3) is optional; and [329] steps (2) and (3) need not be carried out in the stated order.
  • a method of preparing a teat sealant composition comprising the steps of: [331] (1) forming a water-insoluble gel by mixing at least one type of oily carrier with at least one type of thickening agent; [332] (2) adding solid particles to the gel to form a paste; and, [333] (3) adding lauric acid as a thickening agent to the gel or paste, wherein: [334] the solid particles are not a bismuth metal salt. [335] 33.
  • a teat sealant composition when prepared by the method according to paragraph 31 or paragraph 32. [336] 34.
  • a teat sealant composition for preventing a new intramammary infection or mastitis in a cow wherein the composition is as described in any one of paragraphs 1 to 30 and 33.
  • 35 A teat sealant composition for use or when used for preventing a new intramammary infection or mastitis in a cow, wherein the composition is as described in any one of paragraphs 1 to 30 and 33.
  • 36 Use of a teat sealant composition in the manufacture of a medicament for preventing a new intramammary infection or mastitis in a cow, wherein the composition is as described in any one of paragraphs 1 to 30 and 33.
  • 37 37.
  • a method of preventing a new intramammary infection or mastitis in a cow comprising the step of administering to at least one teat of the cow the composition as described in any one of paragraphs 1 to 30 and 33.
  • 38. Use of the composition as described in any one of paragraphs 1 to 30 and 33 for preventing a new intramammary infection or mastitis in a cow.
  • 39. A syringe containing the composition as described in any one of paragraphs 1 to 30 and 33.
  • kitset for use or when used in a method of preventing a new intramammary infection or mastitis in a cow, wherein the kitset comprises: a syringe capable of administering to at least one teat of a cow the composition as described in any one of paragraphs 1 to 30 and 33.
  • kitset comprises: a syringe capable of administering to at least one teat of a cow the composition as described in any one of paragraphs 1 to 30 and 33.
  • 42 The teat sealant composition of paragraph 34 or 35, the use of paragraph 36 or 38, the method of paragraph 37, or the kitset of paragraph 40, wherein the composition is used in a milking cow or heifer.
  • compositions/formulations/medicaments may also relate to methods/uses and vice-versa, context permitting. It is to be understood that the terms ‘formulation’, ‘medicament’ and ‘composition’ may be used interchangeably, context permitting.
  • [361] Having broadly described the invention in its various embodiments, non-limiting examples of preferred embodiments will now be described. [362] Brief Description of the Figures [363] Figures of Example 1 [364] Figure 1. Syringeability of F1 at various times of storage at 4, 25 and 40°C. [365] Figure 2. Syringeability of F2 at various times of storage at 25 and 40 °C. [366] Figure 3.
  • Figure 10 Effect of storage at 25 °C on syringeability (injection force).
  • Figure 11 Effect of storage at 25 °C on syringeability (injection force).
  • Figure 12. Effect of temperature cycling (4 and 25 °C) on the syringeability of calcium phosphate and sodium chloride formulations.
  • Figure 13 Storage stability of calcium phosphate and sodium chloride formulations at 25 °C.
  • Figure 14 Flow behaviour of NaCl and KCl formulations.
  • Figure 15 Injection simulation behaviour of NaCl and KCl formulations.
  • Figures of Example 2 [380] Figure 16. Flow behavior of commercial TeatsealTM. [381] Figure 17.
  • Figure 22 Effect of lauric acid addition into room temperature formulation vs warm formulation on the rheology during an injection simulation test.
  • Figure 23 Flow behaviour of various test teat sealant formulations versus TeastsealTM and BioblocTM.
  • Figure 24 Injection simulation for various test teat sealant formulations versus TeastsealTM and BioblocTM.
  • Figure 25 Flow behaviour of various test teat sealant formulations versus TeastsealTM and BioblocTM.
  • Figure 26 Injection simulation for various test teat sealant formulations versus TeastsealTM and BioblocTM.
  • Figure 27 Figure 27.
  • FIG. 33 Syringeability for a test teat sealant formulation versus BioblocTM delivered from a BioBloc syringe or white HDB syringe.
  • Figure 34 Syringeability of BioblocTM using its own syringe.
  • Figure 35 Syringeability of BioblocTM using a white HDB syringe.
  • Figure 36 Syringeability of a test teat sealant formulation delivered using a white HDB syringe.
  • Figure 37 Syringeability of a test teat sealant formulation delivered using a white HDB syringe.
  • FIG. 41 Streptococcus uberis cell counts over time exposed to teat sealant formulations.
  • FIG. 1 Figures of Example 6
  • Figure 44 Ultrasound image of Cow 302 front left teat, 1 hr (F2).
  • Figure 45 Ultrasound images of Cow 302 front right teat, 1 hr (F3).
  • Figure 46 Ultrasound images of Cow 302 rear right teat, 1 hr (TeatsealTM).
  • Figure 47 Ultrasound image of Cow 302 rear left teat, 1 hr (F1).
  • Figure 48 Cow mammary glands at 28 days post-treatment (dry-off) showing udders with some milk present and have not completed involution (top row) and some udders that have undergo complete involution (bottom row).
  • FIG. 49 Diagrammatic representation of teat sealant scoring. Teat sealant is depicted by the red shaded areas.
  • Figure 60 Percentage of solids in milk samples grouped by treatment assigned to each teat. The bars represent median values, which are also depicted at the bottom within each bar.
  • Figure 63 Estimated recovery from the teat.
  • Figure 64 Scatterplot of teat length and percentage recovery from the teat with linear regression line (solid line) and 95% confidence intervals (broken lines).
  • Figure 65 Proportion of front (A) and rear (B) teats with recoveries from the teat greater than or equal to TeatsealTM ( ⁇ 95.81% in front teats and ⁇ 84.64% in rear teats).
  • Figure 66 Shows the cut open teats with the remaining formulation after stripping and before scraping.
  • Figures of Example 8 [437] Figure 67.
  • Teat sealants are used at dry-off of the milking cow, and in heifers, to ‘seal’ the teat canal and thereby prevent, or at least reduce, the entry of environmental pathogenic microorganisms from entering the udder.
  • Formulation of a teat sealant presents the following challenges: [444] - It must be sufficiently liquid such that 2-5g can be infused from a syringe (no needle) though the single teat canal. [445] - It should flow into the epithelial folds of the mucosal lining of the teat to seal most effectively.
  • TeatsealTM is a commercial product known to have high efficacy. The present inventors’ aim was to understand the rheological properties of TeatsealTM (see Example 2), and then to use this information to guide the development of formulations using soluble and insoluble solid particles / fillers, instead of bismuth subnitrate. [461] Initial research attempted to make suitable viscoelastic systems using ethylcellulose, castor wax, chitosan, and alginate zein, to match the properties of TeatsealTM but this was unsuccessful.
  • NaCl was milled in a planetary ball mill (Retsch PM-100, balls size 9 mm) for 1 h (Speed-600 rpm) and sieved for 30 mins (90 ⁇ m).
  • Preparation method (beaker method) for lab tests
  • Weighed amounts of paraffin oil and aluminium stearate were added into a beaker and heated at 120°C for 30 mins. After melting/heating the mixture, the beaker was removed from the heat source and mixed with spatula until a gel like mixture was formed. The gel was cooled at room temperature followed by addition of solid particles/filler and mixed well with spatula. After mixing filler, Aerosil- 200 was added and mixed well with a spatula.
  • Lauric acid was melted at 45°C and added to above mixture and mixed well with a spatula. Formulations were rested for 24 h in a beaker at room temperature before testing.
  • Preparation method for retention studies [471] Syringes, aluminium stearate, Aerosil-200, Aerosil-R972, lauric acid, kaolin and paraffin oil were sterilised by gamma irradiation. Heat sterilisation (160°C, 3 h) was used to sterilise magnesium carbonate, sodium chloride and glassware. 100 g of each formulation batch was prepared using the beaker method.
  • the plunger of the syringe was advanced at a constant speed of 2 mm/s over a distance of 25 mm to expel the formulation in 12.5 s.
  • the analyser continuously measured the force, providing a graph of force versus time.
  • Rheometry [476] A Discovery Hybrid Rheometer HR-3 (TA instruments) was used to test the rheology of the formulations. Sample (4-5 g) was placed on the plate of the rheometer. Cone/plate geometry was: 2°, 60 mm and a gap of 500 ⁇ m. Temperature was fixed at 32°C. [477] Shear thinning was tested by applying shear from 0 to 100 (1/s). Soak time and duration was 300 s.
  • formulations were added into scintillation vials and 20 mL distilled water was added. Vials and tubes were shaken in a rotary shaker (150 rpm) at 37°C. In another experiment, 20 mL of milk was added instead of water. [482] The weight of remaining formulation was determined at various times by decanting the water, drying the vials with remaining formulation at 60°C for 24 h and weighing. In this case vials with milk, after decanting the milk the remaining formulation was gently rinsed three times with 10 mL of water to remove milk solids before drying as above. [483] In another screening test for swelling and dispersion, a formulation (3-4g) was added to a Falcon tube followed by the addition of water.
  • ICPMS analysis was done to check the dissolution of fillers/solid particles in water. The levels of bismuth ion from TeatsealTM and magnesium was low compared with Na + ions indicating some dissolution of the sodium chloride formulation. The dissolution of NaCl depended on the aluminium stearate percentage indicating that the dispersion of the sodium chloride formulation might be tuned by varying the percentage of aluminium stearate. Water (Milli Q) was used as control in this study and showed presence of magnesium and sodium ions in it which is why the TeatsealTM sample also showed these ions at low concentrations. [504] Table 1B. ICPMS analysis of the water from the dispersion tests.
  • Formulation Bi Mg Na (ng/mL) (ng/mL) (ng/mL) TeatsealTM 6.9 27 1400 25% MgCO 3 +4.3% Aluminum stearate 0.013 25000 1800 50% NaCl+5.3%Aluminum stearate ⁇ 0.1 170 2100000 50% NaCl+6.3%Aluminum stearate ⁇ 0.1 240 1300000 Detection limit 0.005 5 5 [505] All the formulations contained 5% LA and 0.7% Aerosil. [506] Formulations for retention study in cows (see Example 6) [507] After this screening work, magnesium carbonate, sodium chloride and Kaolin were selected as fillers /solid particles in formulations for assessment in cows.
  • Formulation Density (g/cm 3 ) TeatsealTM 1.92 25%MgCO 3 +4.3% Aluminum stearate+0.7% Aerosil+5% LA (F1) 1.0 50% NaCl +5.3% Aluminium stearate+0.7% Aerosil-200+5% 1.2 Lauric acid (F2) 60% Calcium Phosphate+2.5% MgCO 3 +2% Aluminum 1.4 stearate+0.35% Aerosil+5% LA 55% Calcium Phosphate+5% MgCO 3 +2% Aluminum 1.35 stearate+0.35% Aerosil+5% LA 55% Calcium Phosphate+2.5% MgCO 3 +2% Aluminum 1.30 stearate+0.35% Aerosil+5% LA 55% Calcium Carbonate+3.0% Aluminum stearate+0.35% 1.34 Aerosil+5% LA 50% Calcium Phosphate+10% NaCl+3.0% Aluminum 1.37 stearate+0.35% Aerosil+5% LA 55% Calcium Phosphate+5% NaCl+3.0% Aluminum 1.41 stearate+
  • the syringe was used to add 3-4 g of the formulation into the vial. After adding formulations, vials were shaken in an orbital shaker at 37°C and 150 rpm. At predetermined times, vials were removed and the water layer was decanted. The vials were dried at 60°C for 24 h. After drying the weight of dry vial with remaining formulation was recorded. [572] Stability studies [573] Stability on storage [574] Formulations were prepared and rested at room temperature for 24 h before filling into HDB (white plunger and barrel) syringes. The syringes were stored tip side up in an incubator at 25°C for various time.
  • HDB white plunger and barrel
  • the idea of using soluble fillers /solid particles is truly novel and opens the possibility of designing slowly eroding teat sealants overcoming the need for stripping at the end of the dry-cow period.
  • the rheological properties (shear thinning, bounce back) of such formulations can be manipulated by varying the percentages of the sodium chloride and/or calcium phosphate and the concentration of aluminium stearate and Aerosil-200.
  • the formulations can be adjusted to vary the dispersion rate in water indicating that it should be possible to design formulations to erode/disperse at tailored rates in the teat.
  • TeatsealTM (1 g) was added into a falcon tube (15 mL) followed by addition of hexanes (10 mL) to remove paraffin oil. TeatsealTM was mixed with hexanes using spatula and shaken (with hand) and centrifuged at 3000 rpm at 25°C for 30 mins. After centrifugation, supernatant was removed, and this step was repeated three times. Extracted bismuth subnitrate was dried at room temperature overnight. Scanning Electron Microscopy (SEM) was used to analyse the particle size and shape of bismuth subnitrate. Commercially available bismuth subnitrate (Sigma-Aldrich) was used as reference.
  • the formulation should be viscous when undisturbed but when a shearing force is applied the formulation should thin and flow like a liquid to make expulsion from the syringe easy. In another words when a shearing force is applied the sample shows shear-thinning. Aerosil-200 and aluminium stearate without bismuth subnitrate showed poor initial viscosity (Table A2). Bismuth subnitrate alone in paraffin oil showed higher but still poor initial viscosity. Addition of bismuth subnitrate in oil with aerosol showed improved viscosity (84 Pa.s).
  • In-house teat sealant formulation showed good initial viscosity (Table A2) which was comparable with commercial TeatsealTM: 180 Pa.s compared to commercial TeatsealTM (143 Pa.s). This difference is within the inter-batch variability in TeatsealTM and could be due to various factors: method of preparation, storage time, particle properties of bismuth subnitrate.
  • Injection simulation [661] This test is to mimic the injection of formulation into the teat. In this test, a high shear rate (550 (1/s)) was applied initially for a few seconds followed by low shear rate (10 (1/s)) after a few seconds to mimic the conditions in the teat in the period shortly after administration.
  • the formulation should thicken quickly (so-called ‘bounce back’) in order to be retained in the teat.
  • the bounce-back should not be immediate but should allow time for the formulation to spread into crevices in the teat cistern. If the formulation does not bounce back it will drip from the teat.
  • Samples without bismuth subnitrate and aluminium stearate showed poor bounce back (Table A2). This test indicated that the combination of aluminium stearate and bismuth subnitrate is important for the bounce back property.
  • Example 3 Preparation of experimental teat sealant formulations containing lauric acid
  • the inventors describe the general preparation of bismuth-salt-free teat sealant compositions/formulations, but otherwise with functional characteristics similar to TeatsealTM.
  • the inventors discovered that bismuth metal-free teat sealant formulations could be formulated by way of the following steps: [665] - Forming a water-insoluble gel by mixing an oily carrier, such as paraffin oil, with a thickener (gelling agent), such as aluminium stearate.
  • an oily carrier such as paraffin oil
  • a thickener such as aluminium stearate
  • [666] Adding a further thickener to the gel, such as fumed silica (Aerosil-200) to modify the flow behaviour of the gel.
  • a further thickener such as fumed silica (Aerosil-200) to modify the flow behaviour of the gel.
  • [667] Adding solid particles (filler) to the gel, to obtain a paste containing coarse solid particles / filler.
  • the particles can be water-soluble or water-insoluble.
  • solid particle types can be used, including sodium chloride (which is water-soluble), potassium chloride (which is water-soluble), sucrose (which is very soluble in water), mannitol (which is freely soluble in water), dicalcium phosphate dihydrate (calcium phosphate dibasic dihydrate) (which is practically insoluble in water), magnesium carbonate (which is sparingly soluble in water), calcium carbonate (which is practically insoluble in water), and others.
  • the solid particles may be milled to a particular average particle size.
  • the particles modify the rheology of the formulation and may also provide antimicrobial properties. [668] - Adding a further thickener, such as lauric acid (which is practically insoluble in water), which provides antibacterial properties to the paste.
  • the rheological properties (shear thinning, bounce back) of such formulations can be manipulated by varying the percentages of the sodium chloride and/or calcium phosphate and the concentration of aluminium stearate and fumed silica (Aerosil-200).
  • the formulations can be adjusted to vary the dispersion rate in water indicating that it is possible to design formulations to erode/disperse at tailored rates in the teat.
  • the teat sealant formulations were generally prepared as described below. [671] An oven was preheated to 120°C. Paraffin oil (Sigma-Aldrich) and aluminium stearate (Strem Chemicals, Inc.) were added to a beaker and mixed.
  • the mixture was heated at 120°C for 40 mins to melt the aluminium stearate.
  • the beaker was removed from the oven and mixed with a spatula to form a gel.
  • the gel was cooled to room temperature over 30-40 mins.
  • Aerosil-200 (Chemiplas (NZ) Ltd) was weighed and put onto a glass slab.
  • the gel and Aerosil-200 were mixed with a spatula on the glass plate.
  • Solid particles/fillers were added and mixed well with a spatula to obtain a smooth suspension/paste containing coarse filler/solid particles.
  • the suspension was added to a beaker and melted lauric acid (45 °C) was added and stirred in.
  • the size of milled NaCl particles was determined by electron microscope and was found to be ⁇ 10 ⁇ m (average size).
  • the method and timing of addition of lauric acid was found to affect the rheological properties of the formulation. For this reason, various methods for adding lauric acid were investigated, as described below.
  • Method 1-Lauric acid was added into the oil with aluminium stearate and heated at 120°C. After melting lauric acid and aluminium stearate, the mixture was cooled to room temperature. The mixture was mixed with the filler on a glass plate and spatulated until a smooth formulation was obtained.
  • teat sealant is applied to the teat of a dairy cow at dry-off to prevent new mastitis infections.
  • Internal teat sealants are typically composed of 65% w/w bismuth subnitrate, aluminium stearate (4.3% w/w), and AerosilTM fumed silica (0.7% w/w) dispersed in a mineral oil vehicle, in the form of a paste.
  • This antibiotic-free teat sealant paste is applied to the teat canal using a disposable syringe and functions by preventing bacteria from entering the udder.
  • coli ATCC 10536, S. uberis ATCC 19436, S. aureus ATCC 6538 were kept in glycerol stocks (500 ⁇ l culture mixed with 500 ⁇ l of 87.5% glycerol) stored at -80 ⁇ C.
  • Methods Bacteria culture [721] S. aureus cultures were grown in TSB (tryptic soy broth), S. uberis cultures were grown in Todd-Hewitt broth (THB) and E. coli cultures was grown in Lysogeny broth (LB).
  • Antibacterial activity of the solution was measured either by spotting the solution onto bacterial cell lawns of either S. uberis, or E. coli, or transferred to a new universal medium and was inoculated with 1x10 6 CFU/ml of either E. coli or S. uberis. Samples of the bacterial medium were taken at day 0, 1 and 3 after inoculation for cell survival calculations.
  • Contact killing [727] A sterile bismuth subnitrate-free teat sealant composition (1.0 g) was added aseptically into a 24-well plate, then 1 ml of medium inoculated with bacteria was added to each well and incubated at 32 ⁇ C, and mixed at 100 rpm.
  • a sample 50 ⁇ l was removed from each well and serially diluted in PBS in a 96-well plate to 10 7 cells/ml (time zero). Then 20 ⁇ l of dilutions 10 to 10 7 cells/ml were plated onto TSA plates and grown overnight at 37 ⁇ C to calculate CFU/ml for each sample.
  • Kaolin (heavy) is used in pharmaceuticals including topical and oral formulations. Kaolin is a layered silicate mineral, with an approximate chemical formula of H 2 Al 2 Si 2 O 8 (H 2 O) and is supplied as a fine powder. The antimicrobial activity of kaolin-based formulations against S. uberis was assessed without LA and with LA at either 1, 2.5 or 5% w/w. Kaolin based paste without LA showed a similar bacteria count to the control group, whereas all LA containing formulations showed antimicrobial activity against S. uberis (Figure 41H).
  • S. aureus is a gram-positive bacterium which was completely inhibited by gentamycin on day 0, as seen in Figure 43. Paraffin oil had no impact on the growth of S. aureus (Figure 43A).
  • Commercial teat sealant TeatsealTM and prototype teat sealant formulation pastes which contained NaCl 50, 55 or 60 % w/w only or MgCO 3 25 % w/w with LA 5 % w/w showed no inhibitory activity against S. aureus ( Figure 43A and B).
  • Example 6 Retention of novel teat sealant formulations administered at dry-off in dairy cattle [763] Summary [764] The objective of this retention study was to determine the mass and proportion of six teat sealant formulations F1-F6 recovered from the teats of four groups of cows scheduled for dry-off and compare recovery with the pioneer bismuth-containing product, TeatSealTM. This study was conducted in dairy cattle during autumn in Waikato, New Zealand. [765] A single application of six test formulations of teat sealant and one commercial product (TeatsealTM; Zoetis (TS)) were administered via intra-mammary infusion at 1 tube per quarter. Animals were fed as per normal farm practice for dry-off (i.e.
  • Cows were selected from a mob of approximately 20 cows presented for dry-off. Cows underwent udder health checks (rapid mastitis test to check for mastitis, udder palpation to check for inflammation and poor udder health and teat- end scoring to ensure healthy teat ends) and the first 16 to have negative RMT, and ⁇ 1 with udder palpation and teat-end scores were enrolled. Cows were randomly allocated to Treatment Groups 1 (F1-F3 + TS; 1 hrs), 2 (F1-3 + TS; 48 hrs), 3 (F1-F3 + TS; 672 hrs) or 4 (F4-F6 + TS; 672 hrs).
  • Treatment Groups 1 F1-F3 + TS; 1 hrs
  • 2 F1-3 + TS; 48 hrs
  • 3 F1-F3 + TS; 672 hrs
  • 4 F4-F6 + TS; 672 hrs
  • Cows were milked by the farmer and drafted out from the main mob for treatment. Cows were treated in the following order: Treatment Group 3, 4, 2, 1. Treatment Group 3 was treated and observed for approximately 1 hour prior to infusion of formulations in Treatment Group 4 cows. Approximately 1 hr after treatment, Group 1 was brought into the shed again, and teats were stripped individually after teats were examined by ultrasound. While the base of the teat was occluded, the infused formulations were carefully stripped out from the teats until no further excretions (milk and/or teat sealant) could be recovered. A second stripping was collected from Treatment Group 1 where the milk from the gland cistern was collected.
  • cows being brought into the shed shortly after dry-off meant a let-down response was triggered. This would result in more milk in the teat canal and may have resulted in product ‘leaking’ with the pressure of the milk on top of the formulation. It was also relatively difficult to occlude the teat canal, hold the collection vessel and strip the teat. Physical measures (eg. a suitable clamp at the base of the teat) could be used to aid in the collection of formulation this way, and this would also aid in the stripping of the teat. Ultrasound examination revealed little about the amount of teat sealant within each treated cistern/canal.
  • TeatsealTM had the highest proportion of product recovered at 1 hr and 28 days (both Treatment Group 3 and 4). On Day 2, the highest proportion of product recovered was F1 with 37.82%, then TeatsealTM with 24.30%). [824] The mean mass of formulation recovered in an individual cow compared with TeatsealTM in that cow was variable with values from 15.57% (F4) to 844% (F1, Day 2). Generally, recovery was higher for F1-F3 compared with F4-F6. [825] For the second stripping, the variation was also large and in all cases more than product was ‘recovered’ (>114%) than was administered (>114% of data not shown).
  • a score of 2 represents a small amount of teat sealant sitting at the opening of the teat (i.e. over the inside of the teat canal, at the bottom of the teat cistern.
  • a teat sealant score of 3 is ideal and provides >25% of the teat canal filled and sitting at the bottom of the teat cistern, covering the teat canal.
  • Cows underwent ultrasound scanning in the milking shed. Teat sealant scores were recorded for each teat of each animal that was to be stripped (e.g. Treatment Group 2 at 48 hrs, Treatment Group 3 and 4 at 28 days). Scores were averaged for each formulation (1- 6), and compared to each other and the control product. Data was presented as arithmetic and/or geometric means, and suitable statistical analysis was conducted.
  • Cows were ‘dried-off’, i.e. treated, approximately 6.5 hrs after milking. Usually, cows are dried off in mobs to allow a shorter time between the end of milking and the drying-off treatment. Also, it is unusual for cows to be brought into the shed shortly (e.g. less than an hour or days) after drying off – normal practice is to put them in a paddock with little grass (and possibly hay) to reduce their energy consumption to aid in dry-off.
  • Cows have a psychological response to various noises, smells or events associated with milking. These vary amongst the cows and therefore vary with the time between let-down and milking. Some cows will see the shed and drop their milk, while others may be triggered by the sound of the milking machine. Without careful behavioural observations over a period of time, the triggers for individual cows cannot be ascertained with any great certainty. Stripping in yards could be considered, rather than bringing cows into the cow shed where their let- down trigger is activated.
  • cows in the photos on the top row could have leaked milk as they had milk sitting in the teat canal and gland cistern.
  • Typical milk solid proportion is around 8-12% with larger differences between breeds (e.g. Jersey cows have higher milk fat and protein compared with Friesian cows (Holmes et. al 2003). Cows differ in their milk composition. Calculations were done assuming 10% milk solids and repeated assuming 13% milk solids. This made little difference to the results and this is because the milk volumes in the samples from the first stripping were not too large.
  • the variation may also be attributed to the difficulty involved in stripping the contents of the teat while occluding the base of the teat and holding the sampling pottle.
  • a device e.g. band
  • this may help to prevent milk being dropped into the teat canal and will aid in the process of removing the content of the teat canal while avoiding the collection of milk from the gland cistern.
  • This requires careful thought as the band/device cannot be too tight so-as to irritate the cow, nor can it be too loose to allow milk from the gland cistern to drop into the teat canal.
  • Example 7 Acute retention and recovery of teat sealant formulations in an ex vivo udder model (suspended udder study) [849]
  • Objective [850] The objective of this study was to determine the retention and recovery of teat sealant formulations at approximately 60 minutes after intramammary infusion into excised cow udders.
  • Materials and methods [852] This study was conducted on two experimental days, separated by a week. On each day, udders from recently slaughtered dairy cows were retrieved from a nearby abattoir and transported to a necropsy room. This was a controlled temperature room set at 18 ⁇ 1 o C.
  • udders were selected each day (18 udders in total) on the basis of having four functional quarters with no gross evidence of mastitis.
  • the udders were suspended from a frame in a close-to-natural position by penetrating them with a baling needle, threading synthetic string through the tissue and tying it to the frame.
  • the length of each teat was then measured to the nearest millimetre from the base of the teat, at the insertion to the udder, to the teat meatus.
  • approximately 10 mL of milk was collected from each teat into individual plastic containers, and stripping of the remaining milk out from each gland cistern was attempted.
  • Injection syringes were weighed before and after infusion into the quarters to determine the mass of product infused.
  • the composition of the trialled treatments is depicted in Table 7B.
  • Individual plastic containers were positioned underneath each teat to collect any secretion/formulation that dripped spontaneously during approximately the first hour post-infusion. At approximately 60 minutes after being infused, treatments were stripped from the teats as follows. The base of the teat was held with the non-dominant hand between the thumb and the index finger and then stripped repeatedly with the dominant hand until no further product was recovered; the recovered product was collected in individual plastic containers. [855] After stripping each teat, the base of each teat was closed off with a Kelly forceps.
  • each teat cistern was visually inspected and photographed. A representative image of the longitudinal cross-section of each teat was taken and filed, but not analysed in this study. Immediately after obtaining photographs of the open teats, each teat was scraped and any recovered contents put into individual plastic containers. [856] The milk and any formulation flushed out by the rush of milk from the gland and gland cistern when cutting the teat was collected in two-litre plastic containers. Any visible formulation was placed into individual plastic containers and the milk discarded. [857] All the containers were properly identified, and weighed before and after collection of the samples.
  • Results were expressed as percentage values in relationship to mass of infused treatment for samples collected by dripping, by stripping, by scraping, and by flushing, and for total treatment accounted for according to the following equations: [869] [870] [871] Statistical analysis [872] Data were analysed using the D’Agostino and Pearson normality test and, as appropriate, were presented as mean ⁇ SD and/or median (range). Differences between treatments for teat length, milk solids in milk samples, mass of infused formulation, recovery by dripping, stripping, scraping, and flushing, and total treatment retrieved were analysed using a Kruskal-Wallis test followed by a Dunn’s multiple comparisons test.
  • the cut-off benchmark may be considered as arbitrary and, thus, the results comparing the recovery rates from the teat to those for TeatsealTM should be interpreted in light of this limitation.
  • Some of the infused formulation entered the gland cistern. However, recovery by flushing was smaller in the current study (from 0.3% to 51.84%) than in the previous suspended udder study (from 23.4% to 87.87%). This may be due to partial tip insertion and apparently longer teats used in the current study as opposed to full tip insertion and apparently shorter teats in the previous study. Although it seems that syringe tip length insertion has an effect on the recovery rate of the infused formulation from the gland cistern, further studies are needed to test this hypothesis.
  • Cow I 363 developed a severe clinical mastitis in the hind right udder quarter on SD 2, which required concomitant treatment. A relation to Staph. aureus, which was determined in the corresponding milk sample after arrival cannot be ruled out, even if the quarter was treated with Synulox LC PlusTM before inclusion. Cow I 366 developed a clinical mastitis in the front left quarter on SD 4. Both affected quarters were sealed with OrbesealTM on SD 0. Besides milk dripping in three cows after drying-off no further findings were observed during local tolerance assessments.
  • Teat Sealant 1 (TS 1) formulation.
  • Teat Sealant 2 (TS 2) formulation Ingredient TS2 MgCO 3 NaCl 50% Kaolin Aluminium stearate 5.3% Aerosil 0.7% Lauric acid 5% Liquid paraffin 39% [913]
  • Application [914] The intramammary application of the IVP and the reference item was conducted according to study outline. The complete dose was applied without any losses in every case. Teat Sealant 1 (TS 1) was difficult to apply and both hands were needed to push the complete content into the teat.
  • Application of Teat Sealant 2 (TS 2) was comparable to the application of OrbeSealTM.
  • SD 4 in the morning and in the evening: milking out the respective quarter, treatment with Orbenin ExtraTM (1 applicator intramammary), SeptomamminTM locally.
  • SD 5 in the morning and in the evening: milking out the respective quarter, treatment with Orbenin ExtraTM (1 applicator intramammary), SeptomamminTM locally.
  • SD 6 general appearance reduced, ears dropped, animal lying a lot, rumen poorly filled, inappetence, udder quarter swollen, hard, no increased heat, painful during palpation, heart rate elevated, rectal examination: no feces, rumen moderately filled, treatment with infusion (1L of G40TM, 60mL CatosalTM, 13mL MetacamTM i.v.), drench (40L water + 2 bags of RumentinolTM orally), milking out respective quarter (small amount of yellowish fluid and remnants of teat sealant), Orbenin ExtraTM (1 applicator intramammary).
  • SD 7 rectal temperature: 37.8°C, drench (40L + 2 bags of RumentinolTM), swelling of quarter still severe, swelling moving towards front right quarter, feed intake after drenching.
  • SD 8 right hind quarter still hard and swollen, swelling moving towards front right quarter, animal fitter, rumen moderately filled, mucous nasal discharge, treatment with infusion (1.5L NaCl, 0.5L G40TM, 30mL CatosalTM, 250mL CalciumborogluconatTM, 13mL MetacamTM, 5mL MederantilTM i.v.), after infusion shaking gait, but good feed intake.
  • SD 9 general appearance improved, good feed intake and rumination.
  • Necropsy revealed areas in the left udder in one cow of the TS 1 group. Change-in-contents and consistency change was observed in the right and left udder of single animals in the TS 2 group. Swelling of the mammary gland occurred in one cow of the TS 1 group. Udder lymph nodes were swollen in 2 cows of the TS 1 group and in one cow of the TS 2 group.
  • Histopathology [945] No treatment-related local toxic effect was found for TS 1, TS 2 or OrbesealTM. Three cows revealed chronic active suppurative or subacute abscessing mastitis.
  • I 363 group 01:TS 1 or OrbesealTM revealed multiple subacute abscesses at marked degree with moderate bacteria in the right hind quarter (treated with OrbesealTM). The teat was affected by moderate inflammation. The right udder lymph node showed slightly increased cellularity.
  • I 366 group 02:TS 2 or OrbesealTM was affected by chronic active suppurative inflammation of gland and teat at slight to moderate degree in the left front (treated with OrbesealTM) and hind quarter (treated with TS 2) with focal glandular fibroses. The associated left lymph node showed slightly increased cellularity and lymphoid hyperplasia.
  • Cow I 363 revealed subacute abscesses in one quarter corresponding to clinical findings during the treatment period. Without major histopathological findings, many cows had increased granulocytes and/or mononuclear cells or debris in mammary alveoli which might be responsible for clinically increased cell counts in the milk. [956] Conclusion [957] The two occurred adverse events of clinical mastitis after drying-off were unlikely to be related to the IVP (ie. TS 1 and TS 2). Both affected quarters were sealed with OrbesealTM on SD 0. Besides milk dripping in three cows after drying-off no further findings were observed during local tolerance assessments. Histopathological examination did not reveal any IVP-related local toxic effects.
  • teat sealant formulation is bismuth-salt-free and has antimicrobial activity (but is ‘antibiotic-free’ in the sense that it does not include an antibiotic as used in dry-cow therapy); [961] - the teat sealant formulation is easy to administer; [962] - the teat sealant formulation can be infused from a syringe; [963] - the teat sealant formulation will remain with the teat throughout a large part of the dry period; [964] - the teat sealant formulation is easily removeable without concern for remaining heavy metal residues, like bismuth residues; [965] - at the end of the dry-period, the teat sealant formulation can be stripped out; [966] - the teat sealant formulation
  • the word ‘comprising’ and its derivatives including ‘comprises’ and ‘comprise’ include each of the stated integers but does not exclude the inclusion of one or more further integers.
  • the terms “about” and “approximately” denote an interval of accuracy that a person skilled in the art will understand to still ensure the technical effect of the feature in question. The term typically indicates a deviation from the indicated numerical value of ⁇ 10 %, preferably ⁇ 5 %, more preferably ⁇ 2 %, and even more preferably ⁇ 1 %.
  • Reference in this specification to any number range includes all possible numbers/numerical values falling within that range, and further includes all possible subranges falling within that range, context permitting.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Wood Science & Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Zoology (AREA)
  • Organic Chemistry (AREA)
  • Plant Pathology (AREA)
  • Pest Control & Pesticides (AREA)
  • Environmental Sciences (AREA)
  • Dermatology (AREA)
  • Agronomy & Crop Science (AREA)
  • Dentistry (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dispersion Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une composition d'obturateurs de trayons qui ne contient pas de sel de bismuth, son procédé de préparation, et un procédé de prévention d'une nouvelle infection intramammaire ou de la mammite.
PCT/IB2024/052092 2023-03-06 2024-03-04 Composition d'obturateurs de trayons et procédé de prévention de la mammite WO2024184798A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AU2023900582 2023-03-06
AU2023900582A AU2023900582A0 (en) 2023-03-06 Teat Sealant Composition and Method of Preventing Mastitis

Publications (1)

Publication Number Publication Date
WO2024184798A1 true WO2024184798A1 (fr) 2024-09-12

Family

ID=92674316

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2024/052092 WO2024184798A1 (fr) 2023-03-06 2024-03-04 Composition d'obturateurs de trayons et procédé de prévention de la mammite

Country Status (1)

Country Link
WO (1) WO2024184798A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010065747A2 (fr) * 2008-12-04 2010-06-10 Merial Limited Obturateur intramammaire de mamelle
AU2014202666A1 (en) * 2009-04-08 2014-06-12 Wisconsin Alumni Research Foundation Intra-mammary teat sealant formulation and method of using same to reduce or eliminate visual defects in aged cheeses
WO2017071998A1 (fr) * 2015-10-29 2017-05-04 Bimeda Finance S.A.R.L. Formulation d'étanchéité de trayon
AU2022204326A1 (en) * 2008-09-17 2022-07-14 Elanco New Zealand Anti-infection formulation and methods of use

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2022204326A1 (en) * 2008-09-17 2022-07-14 Elanco New Zealand Anti-infection formulation and methods of use
WO2010065747A2 (fr) * 2008-12-04 2010-06-10 Merial Limited Obturateur intramammaire de mamelle
AU2014202666A1 (en) * 2009-04-08 2014-06-12 Wisconsin Alumni Research Foundation Intra-mammary teat sealant formulation and method of using same to reduce or eliminate visual defects in aged cheeses
WO2017071998A1 (fr) * 2015-10-29 2017-05-04 Bimeda Finance S.A.R.L. Formulation d'étanchéité de trayon

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANONYMOUS: "Orbeseal Dry Cow Intramammary Suspension ", UK/V/0172/001/E/001 ZOETIS UK LTD APPLICATION FOR MUTUAL RECOGNITION PROCEDURE PUBLICLY AVAILABLE ASSESSMENT REPORT, 30 June 2014 (2014-06-30), XP093211952 *

Similar Documents

Publication Publication Date Title
US20060198814A1 (en) Anti-infectious hydrogel compositions
JP5318770B2 (ja) 乳房内乳首シーラント製剤、およびこれを用いて、熟成チーズの視覚的欠陥を抑制または除去する方法
US20070093421A1 (en) Bio-security system
CN105492005A (zh) 治疗包括乳房炎的微生物感染的方法
JP2010501484A (ja) 乳腺炎の発症を減少する方法
AU2009304000B2 (en) Anti-infective formulation and methods of use
WO2024184798A1 (fr) Composition d'obturateurs de trayons et procédé de prévention de la mammite
US20230057782A1 (en) Compositions and methods of use thereof for treatment of mastitis
AU2022204326B2 (en) Anti-infection formulation and methods of use
JP5322649B2 (ja) セフキノム組成物およびその使用方法
US20120022038A1 (en) Animal treatment formulation and methods of use
AU2015218447B2 (en) Animal Treatment Formulation and Methods of Use
AU2025201973A1 (en) Anti-infection formulation and methods of use
Alany et al. Intramammary delivery technologies for cattle mastitis treatment
NZ573297A (en) Animal treatment formulation and methods of use
WO2022136622A1 (fr) Méthodes de traitement de la mammite à l'aide d'un composé antimicrobien d'orthosomycine
GB2608701A (en) Sol-gel compositions for veterinary use
JP2021511113A (ja) 乾乳牛のウシ乳房炎予防における内部ティートシールおよびその使用
Alany et al. Intramammary Delivery Technologies

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24766601

Country of ref document: EP

Kind code of ref document: A1