Mastitis is an inflammation of the mammary gland of milk producing animals, for example dairy cows, most often caused by bacterial infection. Bacteria enter through the teat canal of the animal and can cause acute, clinical, or sub-clinical mastitis. Over 135 organisms have been documented as causative pathogens for bovine mastitis. Three of the major groups of pathogens are gram-positive cocci, gram-negative bacilli, and gram-positive bacilli. Hygiene, environmental factors, and metabolic disturbances deriving from high milk yield combine to create conditions favorable to the onset of mastitis. An increased somatic cell count, associated with mastitis, is positively correlated with infection and negatively correlated with milk production. Frequently, an infected cow must be removed from the herd and dried up. Mastitis often affects a cow during its entire life unless the disease is properly treated, and in extreme cases an animal may become so severely infected that she dies. Infection rates average from 10% to 30% of the cows in a typical herd, with losses per cow ranging from $185 to $250 per cow per year. Bovine mastitis is the most economically costly disease to the dairy industry, with losses estimated at two billion dollars annually in the United States alone. The majority of these losses are due to reduced milk production.
Intramammary administration of compositions comprising an antibiotic for prevention and treatment of mastitis in milk producing animals is well known. Several compositions suitable for such administration are formulated in aqueous based vehicles.
For example, British Patent Application No. 2,273,655 discloses compositions for intramammary use comprising an insoluble antibiotic in an aqueous suspension for treatment of mastitis.
International Patent Publication No. WO 95/31180 discloses a composition comprising the antibiotic cloxacillin benzathine in an aqueous base, and additionally a teat seal composition, in injectors for intramammary application.
European Patent Application No. 0 797 988 discloses a veterinary composition in the form of an aqueous gel containing an antibacterial agent, useful for intramammary administration for prevention and treatment of mastitis.
The chemical stability of many antibiotics is, however, severely limited in aqueous based compositions. Hence, a number of oil based formulations for treatment and/or prevention of mastitis have also been developed.
British Patent Application No. 1,456,349 discloses a composition of an anti-mastitis medicament dispersed in a gelled vehicle comprising a mineral oil or non-drying, semi-drying, or drying vegetable oil or a mixture thereof, other than a mixture of drying and semi-drying vegetable oils, and from 0.5% to 5% by weight of a fatty acid ester derived from a saturated or unsaturated monocarboxylic acid having from 12 to 20 carbon atoms, and glycerin, propylene glycol, a mono- or dihydric alcohol having from 1 to 12 carbon atoms, or a polyethylene glycol having a molecular weight of 200 to 6000. Such a composition is said to provide short milkout times.
European Patent Application No. 0 058 015 discloses an intramammary formulation comprising isoxazolyl penicillin and rifampicin in an acceptable carrier. This formulation is said to substantially eliminate intracellular staphylococci.
U.S. Pat. No. 5,342,612 to Daley et al. describes a composition comprising a potentiating or safening amount of an aqueous surfactant in combination with a tumor necrosis factor, wherein the surfactant is sterol, n-dodecylglucosid, decanoyl n-methylglucamid, dodecyl B-D-maltosid or octanoyl n-methylglucamid. Such a composition is said to provide an efficacious treatment for mastitis with minimal milk discard.
U.S. Pat. No. 4,073,920 to Dowrick discloses an intramammary composition comprising a suspension of a semi-solid synthetic penicillin in an oily vehicle that comprises triglycerides or propylene glycol diesters of fatty acids containing 8-10 carbon atoms. Such a composition is said to provide short milkout times and good stability and shelf life.
U.S. Pat. No. 5,064,815 to Szentmiklosi et al. relates to a primycin-containing colloidal basic gel comprising 5-30% of primycin and 95-70% of N-methyl-2-pyrrolidone.
International Patent Publication No. WO 88/01504 discloses an intramammary infusion comprising a first dosage unit comprising a pharmaceutically acceptable vehicle and a substance active against mammary infection, and a second, optional, dosage unit of active substance, the particles of which are microencapsulated within a membrane capable of degrading.
International Patent Publication No. WO 87/03876 discloses a veterinary composition for treatment of mammary disorders and keratoconjunctivitis comprising benzathine cephalothin and a veterinarily acceptable carrier.
British Patent Application No. 2,273,443 discloses a composition for treating mastitis, comprising an antibacterial and a seal comprising a polyethylene gel.
British Patent Application No. 2,273,441 discloses a composition for treating mastitis, comprising an antibacterial and a seal comprising a gel base containing a heavy metal salt.
British Patent Application No. 1,089,523 discloses a composition comprising an antibiotic in a hydrophobic viscous or gel base, and comprising in addition at least 10% by weight of a solid, finely divided physiologically innocuous non-gelling water soluble compound of average particle size below 150 microns.
U.S. Pat. No. 4,011,312 to Reuter & Tsuk discloses a prolonged release dosage form for treatment of mastitis consisting of an antimicrobial agent dispersed in a matrix of low molecular weight polyesters of glycolic and lactic acids, and shaped as a cylindrical bougie for insertion into the teat canal.
British Patent No. 1,589,917 discloses a composition comprising a crystalline sodium salt of clavulanic acid methyl ether and a pharmaceutically acceptable carrier. High tissue levels of medicament are said to be produced after administration.
European Patent Application No. 0 271 306 discloses a method of treating mammary disorders comprising administering an antibacterial in the form of particles, at least 65% of which have a size in the range 0-5 microns, suspended in a hydrophobic oily vehicle which comprises an oil and a gelling agent. Prolonged release of medicament is said to be achieved.
U.S. Pat. No. 4,172,138 to Rhodes discloses an infusion of a limited solubility penicillin salt in a slow release base, optionally with neomycin.
U.S. Pat. No. 3,636,194 to Parizeau discloses a composition for treating mastitis by intramammary infusion, comprising an antibiotic, a vegetable oil, an alcohol-soluble fraction of natural lecithin phospholipid material for promoting dispersion of the oil in milk, the phospholipid being selected from the group consisting of phosphatidyl choline and phosphatidyl ethanolamine and mixtures thereof and present in amount of at least 0.25% in said oil. Such compositions are said to provide rapid dispersion into milk and short milkout times.
British Patent Application 1,181,527 discloses a composition for treating mastitis comprising an active substance and a pharmaceutically acceptable oil base, said composition containing phospholipid material consisting substantially entirely of alcohol-soluble material for promoting dispersion of the composition in milk.
European Patent Application No. 0 222 712 discloses a composition which contains one or more antimicrobial agents dispersed in an oil consisting of a mixture of triglycerides of palmitic and stearic acid together with polyoxyethylenated cetyl alcohol and stearyl alcohol, and held in an oily medium of mineral, vegetable, synthetic or mixed extraction. Such compositions are said to speed up release of the antimicrobial agent in the udder, enhancing its biological potential, and reducing milkout time.
A Labrafil product brochure (Notice OL 0050/5th edition) from Gattefossé Corporation contains an extract from a thesis by Valette (1957), discussing characteristics of Labrafil™ M-1944CS in the ear canal. The same thesis describes an experiment involving injecting Labrafil™ M-1944CS mixed with gentian violet into a cow teat. It was shown that Labrafil™ wetted the entire surface of the mammary parenchyma section and reached the retromammary ganglion.
Non-aqueous aerosol mastitis formulations are disclosed in the patents cited individually below.
U.S. Pat. No. 3,135,658.
U.S. Pat. No. 3,144,386.
U.S. Pat. No. 3,347,743.
Canadian Patent No. 670,254.
British Patent No. 980,282.
In addition, amphipathic oils that are dispersible in water have been utilized in preparation of a number of pharmaceutical compositions not specifically developed for intramammary treatment and/or prevention of mastitis.
European Patent Application No. 0 982 035 discloses an alcohol free transparent solution which comprises a cyclosporin in a hydrophilic carrier medium comprising propylene glycol, a transesterification product of a natural vegetable oil triglyceride and a polyalkylene polyol, a polyoxyethylene hydrogenated castor oil product and triacetin.
International Patent Publication No. WO 00/48571 discloses a spontaneously dispersible composition for oral administration comprising N-benzoyl-staurosporine, a surfactant selected from the group consisting of a polyoxyethylene castor oil, a polyoxyethylene alkyl ether and a polysorbate and a transesterified ethoxylated vegetable oil as a co-surfactant.
U.S. Pat. No. 5,314,685 to Tyle et al. discloses a method of making an anhydrous formulation by preparing an anhydrous hydrophilic phase comprising at least one hydrophilic vehicle which is solubilizing at least one lipophilic pharmaceutically active agent, preparing an oily phase comprising at least one oily component which is partially miscible with the at least one hydrophobic vehicle and combining the oily phase with the anhydrous hydrophilic phase to form the anhydrous formulation.
European Patent No. 0 356 325 discloses a pharmaceutical composition for oral, topical, or parenteral administration containing a sparingly water-soluble active agent in an amount as high as 25% and at least one glyceride gelled with at least one cellulose polymer.
International Patent Publication No. WO 96/06598 describes pharmaceutical compositions for aerosol delivery comprising a medicament, a non-chlorofluorocarbon propellant, and a polyglycolized glyceride or derivative thereof.
U.S. Pat. No. 5,614,491 relates to a liquid preparation for oral and parenteral administration comprising a cyclosporin, a polyoxyethylene glycol fatty acid monoester, and a monohydric and/or polyhydric alcohol(s).
International Patent Publication No. WO 99/61025 discloses microemulsion proconcentrates with a piperidine substance P antagonist.
U.S. Pat. No. 6,054,136 describes compositions capable of forming a microemulsion, comprising an active principle, a lipophilic phase consisting of a mixture of fatty acid esters and glycerides, a surfactant, a cosurfactant, and a hydrophilic phase.
International Patent Publication No. WO 99/56727 discloses self-emulsifying microemulsion or emulsion preconcentrate compositions containing a poorly water soluble active agent, an effective amount of a low HLB oil component, and a surfactant system consisting essentially of at least one surfactant having an HLB of about 10 to 20, wherein the composition contains minor amounts or is substantially free of a hydrophilic solvent system.
European Patent Application No. 1 004 294 discloses a substantially anhydrous pharmaceutical composition comprising a nitric oxide donating compound, a mucoadhesive compound, and an emulsifier capable of forming a microemulsion on addition of water.
European Patent Application No. 0 265 044 describes (Nva)2-cyclosporin compositions for treatment of autoimmune diseases.
U.S. Pat. No. 4,388,307 to Cavanak discloses a pharmaceutical composition comprising an active monocyclic peptide and at least one of the following: a nonionic ester of a triglyceride and a polyalkylene polyol, a saturated fatty acid triglyceride, and a mono- or diglyceride having improved physical and absorption properties.
Two articles by Gao et al. (1995) in Pharmaceutical Research 12(6), 857-868, “Controlled release of a contraceptive steroid from biodegradable and injectable gel formulations: in vitro evaluation” and “Controlled release of a contraceptive steroid from biodegradable and injectable gel formulations: in vivo evaluation”, describe preparation of gels containing levonorgestrel, Labrafil™ M-1944CS, and glyceryl palmitostearate.
Formulations comprising an antibacterial agent and an anti-inflammatory agent, said to be suitable for otic administration to treat otic conditions, are disclosed in the patents and publications cited individually below.
U.S. Patent Publication No. 2002/142999.
U.S. Pat. No. 6,395,746 to Cagle et al.
U.S. Pat. No. 6,440,964 to Cagle et al.
U.S. Pat. No. 6,509,327 to Cagle et al.
International Patent Application No. WO 01/89495.
International Patent Application No. WO 01/89496.
European Patent No. 0 592 348.
All of the above patents and articles are incorporated herein by reference.
The most commonly used packaging containers and delivery devices for compositions intended for intramammary administration to treat and/or prevent mastitis in milk producing animals as well as for compositions for otic administration to treat ear infections are constructed of oxygen permeable plastic materials, for example polyethylene, polypropylene, etc. and mixtures thereof. The use of oxygen permeable packaging containers and delivery devices for anti-mastitis formulations and for compositions for treatment and prevention of ear infections, poses serious problems for long term chemical and/or physical stability of compositions comprising an ingredient, for example an active medicament or an excipient, that is prone to oxidative degradation.
Although the references cited above disclose a number of compositions for treatment of mastitis and other disease conditions, none addresses the problem of providing extended chemical and/or physical stability of compositions packaged in oxygen permeable containers, where the composition comprises a pharmaceutically active substance that is prone to oxidative degradation. Despite the above teachings, there still exists a need in the art for pharmaceutical compositions having one or more of the following advantages over prior art compositions used in treatment and prevention of mastitis by intramammary infusion: (a) extended chemical and/or physical stability even when packaged in oxygen permeable containers and delivery devices, particularly where the composition comprises a pharmaceutically active substance that is prone to oxidative degradation, (b) efficacy against a wide variety of infectious organisms, (c) rapid dispersibility in milk and in udder fluids to achieve efficacious medicament levels at sites of infection, (d) short milkout times for lactating cows, (e) zero day slaughter meat withdrawal period, (f) short milk withholding times post calving after dry cow treatment, and (g) minimal to no irritation after administration.