HK1081457B - Dispersible pharmaceutical compositions - Google Patents

Description

Dispersible pharmaceutical compositions

Technical Field

The present invention relates to a stable pharmaceutical composition containing an antibacterial agent, in particular a composition which is readily dispersible in body fluids. The invention also relates to a method for preparing said composition and to a method for the treatment and/or prevention of diseases caused by bacterial infections of a liquid-containing organ, such as the udder or the ear of a milk-producing animal, said method comprising administering said composition to said liquid-containing organ.

Background

Mastitis is an inflammation of the mammary glands of milk producing animals, such as cows, which is usually caused by a bacterial infection. Bacterial entry into the teat canal of an animal can cause acute, clinical or subclinical mastitis. It is documented that over 135 organisms are considered to be causative pathogens of bovine mastitis. The three major classes of pathogens are gram-positive cocci, gram-negative bacilli and gram-positive bacilli. Hygiene, environmental factors and metabolic disturbances due to high milk production rates combine to create favorable conditions for mastitis to occur. The increase in somatic cell number associated with mastitis is positively correlated with infection and negatively correlated with milk production. It is often necessary to keep infected cows away from the herd and no longer produce milk. Mastitis usually affects one cow throughout its life, and unless the disease is properly treated, one extreme case is that the animal becomes so severely infected that it dies. In a typical herd, the infection rate averages 10% -30% of cows, with a loss per cow of $ 185- $ 250/year. Bovine mastitis is the most economically costly disease for the dairy industry, with losses estimated to be in the billions of dollars per year in the united states alone. Most of these losses are due to a reduction in milk production.

Intramammary administration of antibiotic-containing compositions to prevent and treat mastitis in milk-producing animals is well known. Several compositions suitable for this mode of administration are formulated in aqueous base (aqueous) vehicles (vehicles).

For example, British patent application No. 2,273,655 discloses compositions for intramammary administration containing an insoluble antibiotic in an aqueous suspension, which are useful for treating mastitis.

International patent publication No. WO 95/31180 discloses a composition containing the antibiotic cloxacillin benzathine (cloxacillin benzathine) in an aqueous base, and another teat seal composition, which are placed in a syringe for intramammary use.

European patent application No. 0797988 discloses a veterinary composition in the form of an aqueous gel containing an antibacterial agent for intramammary administration for the prevention and treatment of mastitis.

However, the chemical stability of many antibiotics is severely limited in aqueous base compositions. Thus, in addition, a number of oil-based (oily) formulations have been developed to treat and/or prevent mastitis.

British patent application No. 1,456,349 discloses a composition of an anti-mastitis drug dispersed in a gelled vehicle comprising a mineral oil or a non-drying, semi-drying or drying vegetable oil or a mixture thereof (but not 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 monobasic acid having from 12 to 20 carbon atoms and glycerol, propylene glycol, a mono-or dihydric alcohol having from 1 to 12 carbon atoms, or a polyethylene glycol having a molecular weight of 200-6000. It is believed that such compositions result in short milkout times.

European patent application No. 0058015 discloses an intramammary formulation comprising isoxazolyl penicillin and rifampicin in an acceptable carrier. It is believed that the formulation substantially eliminates intracellular staphylococci.

U.S. Pat. No. 5,342,612 to Daley et al describes a composition containing a synergistic or safe amount of both an aqueous surfactant and tumor necrosis factor, wherein the surfactant is a sterol, n-dodecyl glucoside, decanoyl n-methylglucamide, dodecyl B-D-maltoside, or octanoyl n-methylglucamide. It is believed that this composition is effective in treating mastitis, minimizing milk discard.

U.S. patent No. 4,073,920 to Dowrick discloses an intramammary composition comprising a suspension of a semi-solid synthetic penicillin in an oily vehicle comprising a triglyceride of a fatty acid having from 8 to 10 carbon atoms or a propylene glycol diester. It is believed that such compositions may achieve short milkout times as well as good stability and shelf life.

U.S. Pat. No. 5,064,815 to Szentmiklosi et al relates to a primycin-containing colloidal basic gel containing 5-30% of primycin and 95-70% of N-methyl-2-pyrrolidone.

International patent publication No. WO 88/01504 discloses an infusion solution for intramammary administration comprising a first dosage unit comprising a pharmaceutically acceptable carrier and an anti-mammary infection active substance and optionally a second dosage unit of the active substance, wherein the particles are encapsulated in a degradable membrane.

International patent publication No. WO 87/03876 discloses a veterinary composition for the treatment of mammary gland diseases 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 agent 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 containing an antibiotic in a hydrophobic viscous or gel matrix, said composition additionally containing at least 10% by weight of solids which are finely divided physically non-toxic non-gelling water-soluble compounds having an average particle size of less than 150 microns.

U.S. patent No. 4,011,312 to Reuter & Tsuk discloses a time-release dosage form for treating mastitis consisting of an antimicrobial agent dispersed in a matrix of low molecular weight polyesters of glycolic and lactic acids in the shape of a cylindrical suppository 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. It is believed that high tissue concentrations of the drug can be achieved after administration.

European patent application No. 0271306 discloses a method of treating breast disease comprising administering an antibacterial agent in particulate form suspended in a hydrophobic oil vehicle, wherein at least 65% of the particles have a size of 0-5 microns, the hydrophobic oil vehicle comprising an oil and a gelling agent. It is believed that a delayed release of the drug may be achieved.

U.S. Pat. No. 4,172,138 to Rhodes discloses an infusion of a penicillin salt having limited solubility in a slow release matrix, optionally containing neomycin.

U.S. patent No. 3,636,194 to parizau discloses a composition for treating mastitis by intramammary infusion comprising an antibiotic, a vegetable oil, a soluble fraction in alcohol of a natural lecithin material for promoting dispersion of the oil in milk, said phospholipid being selected from the group consisting of phosphatidylcholine and phosphatidylethanolamine and mixtures thereof, and being present in said oil in an amount of at least 0.25%. It is believed that such compositions can rapidly disperse into milk while also achieving short milkout times.

British patent application 1,181,527 discloses a composition for treating mastitis comprising an active substance and a pharmaceutically acceptable oily base, said composition comprising phospholipid material consisting essentially entirely of alcohol-soluble material for promoting dispersion of said composition in milk.

European patent application No. 0222712 discloses a composition containing one or more antibacterial agents dispersed in an oil consisting of a mixture of triglycerides of palmitic and stearic acids and polyoxyethylenated cetyl and stearyl alcohols, said composition being maintained in a physical vehicle of mineral oil, vegetable oil, synthetic oil or mixed extracts. It is believed that such compositions may accelerate the release of the antimicrobial agent in the udder, increase its bioefficacy and decrease milk production time.

The Labrafil product manual by Gattefoss é corporation (bulletin OL 0050/5 edition) contains content from a Valette paper (1957) that discusses the properties of Labrafil M-1944CS in the ear canal. The same article describes a test involving injecting LabrafIP M-1944CS mixed with Crystal 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 aerosols for the treatment of mastitis are disclosed in the patents cited separately below.

U.S. patent No. 3,135,658.

U.S. patent No. 3,144,386.

U.S. patent No. 3,347,743.

Canadian patent No. 670,254.

British patent No. 980,282.

In addition, amphipathic oils that are dispersible in water are used in the preparation of many pharmaceutical compositions not specifically intended for intramammary treatment and/or prevention of mastitis.

European patent application No. 0982035 discloses an alcohol-free clear solution comprising cyclosporin in a hydrophilic carrier vehicle comprising propylene glycol, a transesterification product of a triglyceride of a natural vegetable oil 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 polyoxyethylene castor oil, polyoxyethylene alkyl ethers, and polysorbates and transesterified ethoxylated vegetable oils as co-surfactants.

U.S. patent 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 excipient that is soluble in at least one lipophilic pharmaceutically active agent, preparing an oily phase comprising at least one oily component that is partially miscible with the at least one hydrophobic excipient, and then combining the oily phase with the anhydrous hydrophilic phase to form the anhydrous formulation.

European patent No. 035625discloses a pharmaceutical composition for oral, topical or parenteral administration comprising an active agent sparingly soluble in water in an amount of up to 25% and at least one glyceride gelled with at least one cellulose polymer.

International patent publication No. WO 96/06598 describes a pharmaceutical composition for aerosol delivery comprising a drug, a non-chlorofluorocarbon propellant and a polyglycolysed glyceride or derivative thereof.

U.S. Pat. No. 5,614,491 relates to a liquid formulation for oral and parenteral administration comprising a cyclosporin, a polyoxyethylene glycol fatty acid monoester and a monohydric and/or polyhydric alcohol.

International patent publication No. WO 99/61025 discloses microemulsion preconcentrates containing a piperidine substance P antagonist.

U.S. Pat. No. 6,054,136 describes a composition capable of forming a microemulsion containing an active ingredient, a lipophilic phase consisting of a mixture of fatty acid esters and glycerides, a surfactant, a co-surfactant, and a hydrophilic phase.

International patent publication No. WO 99/56727 discloses self-emulsifying microemulsions or emulsion preconcentrates comprising 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 from about 10 to 20, wherein said composition contains little or substantially no hydrophilic solvent system.

European patent application No. 1004294 discloses a substantially anhydrous pharmaceutical composition comprising a nitric oxide donor compound, an adhesion compound, and an emulsifier capable of forming a microemulsion upon addition of water.

European patent application No. 0265044 describes a composition for the treatment of autoimmune diseases (Nva)²-a cyclosporin composition.

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: nonionic esters of triglycerides and polyalkylene polyols, saturated fatty acid triglycerides, and mono-or diglycerides having improved physical and absorption properties.

Two articles "Controlled release of a covalent stereo from bioregradable and injectable gel formulations" by Gao et al in Pharmaceutical Research 12(6), 857-868 (1995): in visualization "and" Controlled release of a conditional stereo and from biocodendable and objectable gel formulations: in vivo evaluation "describes a composition containing levonorgestrel, Labrafil^TMA method for preparing a gel of M-1944CS and glyceryl palmitostearate.

Formulations containing antibacterial and anti-inflammatory agents are believed to be suitable for otic administration to treat otic disorders, as disclosed in the patents and publications cited individually below.

U.S. patent publication No. 2002/142999.

U.S. patent No. 6,395,746 to Cagle et al.

U.S. patent No. 6,440,964 to Cagle et al.

U.S. patent 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. 0592348.

All of the above patents and publications are incorporated herein by reference.

For compositions intended for intramammary administration for the treatment and/or prevention of mastitis in milk producing animals, and for compositions intended for otic administration for the treatment of otic infections, the most common packaging containers and delivery devices therefor are constructed of plastic materials having oxygen permeability, such as polyethylene, polypropylene, and the like, and mixtures thereof. The use of oxygen permeable packaging containers and delivery devices in anti-mastitis formulations and in compositions for the treatment and prevention of ear infections presents serious problems with respect to the long term chemical and/or physical stability of compositions containing ingredients such as active drugs or excipients that are susceptible to oxidative degradation.

Although the various references cited above disclose a number of compositions for treating mastitis and other disease conditions, none of them address the problem of achieving prolonged chemical and/or physical stability of compositions packaged in oxygen permeable containers, wherein the compositions contain a pharmaceutically active substance that is susceptible to oxidative degradation. Despite the above teachings, there remains a need in the art for a class of pharmaceutical compositions that has one or more of the following advantages over existing compositions for treating and preventing mastitis by intramammary infusion: (a) prolonged chemical and/or physical stability even when packaged in hydrogen and delivery devices that are oxygen permeable, particularly when the composition contains a pharmaceutically active substance that is susceptible to oxidative degradation; (b) efficacy against a wide variety of infected organisms; (c) rapid dispersibility in milk and udder fluids, to achieve effective drug concentrations at the site of infection; (d) short milk production time for the dairy cows; (e) slaughter meat at withdrawal period of zero day; (f) short post calving milk withholding time after treatment of a non-lactating cow; and (g) minimal to no irritation following administration.

Summary of The Invention

Pharmaceutical compositions have been developed that exhibit some or all of the advantageous properties previously described. Accordingly, the present invention provides a pharmaceutical composition comprising a vehicle comprising (a) an amphipathic oil that is water dispersible and ethanol insoluble, (b) microcrystalline wax, and (c) a pharmaceutically acceptable non-aqueous carrier; the excipient contains an antibacterial substance stably dispersed therein in an antibacterial effective amount.

In one embodiment, the antimicrobial substance is susceptible to oxidative degradation and exhibits extended chemical and/or physical stability when packaged in an oxygen permeable container or delivery device. Such a composition may be administered, for example, by intramammary infusion to treat and/or prevent mastitis or other diseases in the udder of a milk-producing animal, and it may be effective against a wide variety of infectious organisms.

The novel anti-mastitis composition has a low surface tension in aqueous liquids, thereby increasing the dispersibility of the composition in milk and udder liquids relative to conventional oil-based formulations. This allows the composition to be rapidly distributed within the breast, thereby allowing the antimicrobial substance to rapidly reach the infected tissue, providing an effective concentration of the antimicrobial substance at the site of infection. The surface tension of a composition in an aqueous liquid determines the energy required to disperse and spread the composition in the liquid, and the energy necessary for suspended particles in the composition to cross the interfacial boundary of an oil/milk or oil/udder liquid.

Preferably, the composition is a composition capable of producing a suitably short milkout time. The time to milk of a lactating cow is the time from the start of treatment of mastitis until the production of saleable milk is resumed. After administration of the composition, the concentration of the active substance in the milk must be reduced to a level acceptable to healthy tissue before the milk produced is considered suitable for human consumption. A reasonably short milkout time reduces economic losses to dairy farmers due to mastitis outbreaks.

Preferably, the composition is one that provides a short milk withholding time after calving without residual antibiotic in the offspring after treatment of the non-lactating cow.

Preferably, the composition is a composition that provides a zero day withdrawal phase of slaughtered meat. The above-mentioned characteristics are particularly important because they allow the farmer to treat the treated cows at any time when it is economically advantageous, without having to keep or feed them for a certain period of time after their mastitis treatment.

The compositions of the present invention may alternatively or additionally be used for the treatment and/or prevention of ear infections by infusion into the ear canal of humans, companion animals, horses, livestock, and the like. Such compositions are effective against a wide variety of infectious organisms.

Accordingly, the present invention provides a pharmaceutical composition as described above for use in the treatment and/or prevention of an ear infection, said composition having a low surface tension in an aqueous liquid, thereby increasing the dispersibility of said composition in a waxy, moist environment of the ear relative to conventional compositions. This allows for rapid distribution of the composition through the mucosa and the lipid containing the ear canal wax allows the antimicrobial substance to reach the infected tissue quickly, providing an effective concentration of the antimicrobial substance at the site of infection. The pharmaceutical composition also forms a protective layer for inflamed mucous membranes of the ear.

Preferably, such a composition helps to dissolve the wax deposited in the ear, thereby providing better penetration of the antibacterial substance.

The compositions of the present invention preferably have improved physical stability, for example by virtue of improved resuspension of the composition, when compared to conventional oily and aqueous compositions. It has been shown that the compositions of the present invention can cause flocculation of certain drugs, thereby improving resuspension capacity and eliminating the problem of suspension clumping and possible delivery of a reduced or non-effective dose.

Preferably, the compositions of the present invention produce minimal to no irritation after administration.

The present invention provides a process for preparing the pharmaceutical composition of the present invention. The method comprises the following steps: the amphipathic oil, microcrystalline wax, pharmaceutically acceptable non-aqueous carrier, and antimicrobial substance, which are both dispersible in water and soluble in ethanol, are combined in any suitable order to provide a composition having extended chemical and/or physical stability as described herein.

The invention also provides a method of treating or preventing a bacterial infection in a patient, said method comprising administering a composition as described herein to a fluid-containing organ of said patient through a natural exterior orifice of said organ, wherein upon administration said composition is dispersed in a fluid. For example, the organ may be the udder of a milk producing animal, in which case administration is by infusion or injection via a teat canal. Alternatively, the organ may be the ear, in which case administration is by infusion or injection through the external auditory canal of the ear.

Accordingly, in one embodiment there is provided a method of treating and/or preventing an infectious disease of the udder, such as mastitis, in a milk producing animal, the method comprising intramammary infusion of a composition as provided herein.

More specifically, a method for the effective, targeted delivery of an antibacterial substance to a site of mastitis infection in a milk-producing animal is provided, said method comprising administering to the udder of the animal, for example by means of elm injection or injection, a composition as provided herein.

In another embodiment, a method of treating and/or preventing an infectious disease in an ear of a patient is provided, the method comprising infusing or injecting into the ear a composition provided herein.

More specifically, a method for the effective, targeted delivery of an antibacterial substance to an ear infection site in a patient is provided, the method comprising infusing or injecting a composition provided herein into the ear of the subject.

The present invention provides a solution to several problems long-standing in the art and has one or more advantages over prior art compositions. Other features, advantages and benefits of the present invention will be apparent from the description below.

Detailed Description

The present invention provides a pharmaceutical composition comprising an excipient comprising an amphipathic oil that is water dispersible and ethanol insoluble, microcrystalline wax, and a pharmaceutically acceptable non-aqueous carrier; the excipient contains an antibacterial substance stably dispersed therein in an antibacterial effective amount. The term "ethanol-insoluble" means that the amphipathic oil is substantially insoluble in ethanol at 20 ℃.

In one embodiment of the invention, the antimicrobial substance is susceptible to oxidative degradation. According to the described embodiments, the compositions have extended chemical and/or physical stability when packaged in oxygen permeable containers or delivery devices. The term "extended chemical and/or physical stability" means herein that the compositions of the present invention have a higher chemical and/or physical stability than a reference composition of the same antimicrobial substance at the same concentration. A "reference composition" in the context of the present invention refers to a composition lacking one or both of the amphipathic oil and the microcrystalline wax, but otherwise similar to the composition of the present invention.

The oxygen permeable container or delivery device may be made of any suitable thermoplastic material including, but not limited to, polymers and copolymers of polystyrene, polyacrylonitrile, polyvinyl chloride, and particularly polyolefins. Polyolefins include, for example, polyethylene, polypropylene, polybutylene, polyisoprene, polypentene, copolymers thereof and the like, as well as mixtures thereof.

Compositions for intramammary administration are typically packaged in syringes with cannula nozzles for insertion into the nipple to allow direct expression into the mammary gland via a striped catheter. Intramammary suspensions are often prepared in thick excipients to prevent drug particles from settling into the cannula nozzle, which can cause nozzle clogging leading to incomplete extrusion of the composition.

Cephalosporins are a class of antibacterial substances, many of which have a broad spectrum of activity against both gram-positive and gram-negative bacteria.

In the early practice of developing suspensions for intramammary administration of the cephalosporin ceftiofur, 12.5mg/ml ceftiofur hydrochloride was suspended in a thick vehicle comprising 20mg/ml glyceryl monostearate in peanut oil. Despite its clinical efficacy, the efficacy of the composition decreased to below 90% of the label when packaged in polyethylene syringes after less than 18 months storage at room temperature. Oxidative degradation of ceftiofur hydrochloride was determined to be the main cause of the decrease in potency. For intramammary suspension, it is desirable to achieve a room temperature shelf life of at least 90% label potency for at least 24 months.

A number of suspension compositions of ceftiofur hydrochloride were subsequently prepared in various thickened vehicles and packaged in oxygen permeable polyethylene syringes. Ceftiofur hydrochloride formulations were prepared at a concentration of 12.5 mg/ml. All excipients were based on cottonseed oil and contained the following other components:

(1)50mg/ml microcrystalline wax.

(2)70mg/ml microcrystalline wax +1.0mg/ml propyl gallate.

(3)100mg/ml microcrystalline wax +50mg/ml Labrafil^TM M-1944CS。

(4)40mg/ml Gelucire^TM 62/05+10mg/ml Gelucire^TM 33/01。

(5)70mg/ml Lexemul^TM AR。

(6)2.5mg/ml Coagulan^TM GP-1。

(7)10mg/ml microcrystalline wax +5mg/ml Hydrofol Glycerides^TM T 57L。

(8)30mg/ml Drewpol^TM 10-10-S。

(9)15mg/ml beeswax blend.

(10)60mg/ml Drewpol^TM 10-10-S。

(11)10mg/ml beeswax blend +50mg/ml Labrafil^TM M-1944CS。

(12)100mg/ml microcrystalline wax +1.0mg/ml propyl gallate.

(13)70mg/ml microcrystalline wax +100mg/ml Labrafil^TM M-1944CS。

(14)70mg/ml microcrystalline wax +100mg/ml Labrafil^TMM-1944CS +0.2mg/ml butylated hydroxytoluene.

(15)70mg/ml microcrystalline wax +50mg/ml Labrafil^TMM-1944CS +1.0mg/ml propyl gallate.

(16)70mg/ml microcrystalline wax +50mg/ml Labrafil^TMM-1944CS +0.2mg/ml butylated hydroxytoluene.

(17)50mg/ml microcrystalline wax +1.0mg/ml propyl gallate.

(18)100mg/ml microcrystalline wax +100mg/ml Labrafil^TMM-1944CS +1.0mg/ml propyl gallate.

(19)100mg/ml microcrystalline wax +100mg/ml Labrafil^TMM-1944CS +0.2mg/ml butylated hydroxytoluene.

(20)100mg/ml microcrystalline wax +50mg/ml Labrafil^TMM-1944CS +1.0mg/ml propyl gallate.

(21)100mg/ml microcrystalline wax +50mg/ml Labrafil^TMM-1944CS +0.2mg/ml butylated hydroxytoluene.

(22)50mg/ml microcrystalline wax +100mg/ml Labrafil^TMM-1944CS +0.2mg/ml butylated hydroxytoluene.

Labrafil ^TMM-1944CS is an amphipathic oil that is both dispersible in water and substantially insoluble in ethanol at 20 ℃. Gelucire^TM62/05 and Gelucire^TM33/01 are substantially inert excipients derived from naturally hydrogenated food grade fats and oils. Lexemul^TMAR is an acid stable cationic, self emulsifying glyceryl monostearate. "beeswax blend" means a blend containing white beeswax, camauba wax and candelilla wax. Coagulan (Coagulan)^TMGP-1 is N-Acyl glutamic acid diamide, an amino acid gelling agent for oils. Drewpol^TMIs modified glyceride.

Most surprisingly, it was found that after 24 months of storage in oxygen permeable polyethylene syringes at room temperature, only those containing Labrafil at the same time^TMThe ceftiofur hydrochloride composition of M-1944CS and microcrystalline wax provides a formulation that maintains at least 90% of the potency of the label. Contains Labrafil in cotton seed oil^TMM-1944CS and microcrystalline wax ceftiofur hydrochloride formulations estimated Room temperature shelf-Life ratio without Labrafil^TMThe estimated room temperature shelf life of the reference formulation of M-1944CS was 2.4-3.7 times higher. In addition, despite the Labrafil contained in the cottonseed oil^TMThe ceftiofur hydrochloride composition of M-1944CS and beeswax mixture has a potency of less than 90% after 24 months storage in an oxygen permeable polyethylene syringe at room temperature, but contains Labrafil in cottonseed oil^TMThe potency of a comparably viscous ceftiofur hydrochloride formulation of M-1944CS and microcrystalline wax after 24 months storage under the same storage conditions was higher than 90% of the label.

Compositions comprising a cephalosporin, an amphipathic oil that is both water dispersible and ethanol insoluble, microcrystalline wax and a non-aqueous carrier provide, in addition to prolonged chemical and/or physical stability, efficacy against a wide variety of infectious organisms, rapid dispersion of the composition in milk and udder fluids to achieve effective drug concentrations at the site of infection, short milkout times for lactating cows, zero day slaughter meat withdrawal, short milk withholding times after calving for non-lactating cows, and minimal to no irritation after administration.

Antibacterial substances that may be used in the present invention include any substance that is effective in the treatment and/or prevention of breast disease and/or ear infection. Suitable antibacterial substances include, but are not limited to, beta-lactam antibacterials such as penicillins, synthetic penicillins, cephalosporins, macrolides (e.g., tylosin, tilmicosin, aivlosin, erythromycin, azithromycin, spiramycin, josamycin, kitasamycin, etc.), lincosamides (e.g., lincomycin, clindamycin, priomycin, etc.), pleuromutilins (e.g., thiocolin, valnemulin, etc.), penam penicillins (e.g., benzylpenicillin, phenoxymethylpenicillin, coxillin, nafcillin, methicillin, oxacillin, amoxicillin, temocillin, ticarcillin, etc.), polypeptides, penicillinase-stable penicillins, acylamino and carocillin (e.g., piperacillin, azlocillin, mezlocillin, carbenicillin, temocillin, ticarcillin, etc.), broad spectrum penicillins (e.g., streptomycin, neomycin), Neomycin B, gentamicin, apramycin, amikacin, spectinomycin, amoxicillin, ampicillin, and the like), polymyxins (e.g., polymyxin B, polymyxin E, and the like), sulfonamides (e.g., sulfamethazine, sulfadiazine, sulfamethoxazole, sulfatozazole, and the like, alone or in combination with trimethoprim), chloramphenicol, thiamphenicol, florfenicol, tetracycline and derivatives thereof (e.g., tetracycline, chlortetracycline, oxytetracycline, doxycycline, minocycline, and the like), quinolones, fluoroquinolones, thiamethoxam, ciprofloxacin, polymyxin E, domeclocycline, mafenide, metacycline, norfloxacin, ofloxacin, pyrimethamine, silver sulfadiazine, sulfacetamide, sulfisoxazole, tobramycin, vanemulin, oxazolidinones (e.g., (S) -N- ((3- (3-fluoro-4- (4- (hydroxyacetyl) -1-piperazinyl ) Phenyl) -2-oxo-5-oxazolidinyl) methyl) acetamide (eperezolid), (S) -N- ((3- (3-fluoro-4- (4- (morpholinyl) phenyl) -2-oxo-5-oxazolidinyl) methyl) acetamide (linezolid), N- ((5S) -3- (3-fluoro-4- (4- (2-fluoroethyl) -3-oxo-1-piperazinyl) phenyl) -2-oxo-5-oxazolidinyl) methyl) acetamide, (S) -N- ((3- (5- (3-pyridyl) thiophen-2-yl) -2-oxo-5-oxazolidinyl) methyl) acetamide, (S) -N- ((3- (5- (4-pyridyl) pyridin-2-yl) -2-oxy-5-oxazolidinyl) methyl) acetamide hydrochloride, and the like), aminoglycosides and aminocyclopolyols, dapipridone, ansamycin, carbaphenem, cephamycin, vancomycin, monobactam, oxacephem, synthetic antibiotics (e.g., 2, 4-diaminopyrimidine), nitrofuransulfones, marbofloxacin, and the like, and combinations thereof.

It is to be understood that any reference herein to any one particular pharmaceutical compound includes tautomers, stereoisomers, enantiomers, salts, hydrates, and prodrugs of said compound, and is not specifically limited to a particular solid form of said drug.

Preferred antibacterial agents of the invention are cephalosporins including, but not limited to, ceftiofur hydrochloride, ceftiofur crystalline free acid, ceftiofur sodium, other ceftiofur salts, cephalexin, cephradine, cefquinome, cephaloacetonitrile, cefalonine, cefuroxime, cefazidime, cefoperazone, crystalline sodium cephemocarboxylate, crystalline cephem heptahydrate, crystalline cephalosporin di-or trihydrate, cefadroxil monohydrate, cefazolin sodium monohydrate, cefixime, ceftizoxime, ceftriaxone, crystalline o-formylcefamandole, salts of 3-acetoxymethyl-7- (acetamido) -cephalosporanic acid derivatives, crystalline monohydrate of 7- (D-alpha-amino-alpha- (p-hydroxyphenyl) acetamido) -3-methyl-3-cephem-1-carboxylic acid, Hydrochloride of cis-7- ((2-amino-1-thiazolyl) (methoxyimino) acetyl) amino-3-methyl-3-cephem-4-carboxylic acid, crystalline cephem acid addition salt, crystalline pivaloyloxy) methyl-7-beta- (2- (2-amino-4-thiazolyl) acetamido) -3- (((1- (2- (dimethylamino) ethyl) -1H-tetrazol-5-yl) thio) methyl) 3-cephem-4-carboxylate, cephalexin crystal, cephalexin crystal monohydrate, 7- (D-2-naphthylglycylamino) -3-methyl-3-cephem-4-carboxylic acid tetrahydrate crystal and the like. Examples of cephalosporin antibiotic compounds are disclosed in the patents and publications listed below, each of which is incorporated herein by reference in its entirety.

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U.S. patent No. 5,079,007 to Putman.

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Chemical abstracts 84: 184895j (1976).

Chemical abstracts 97: 38761q (1982).

Chemical abstracts 110: 212490z (1989).

The most preferred cephalosporins according to the invention are ceftiofur and pharmaceutically acceptable salts thereof.

If the antibiotic is ceftiofur or a pharmaceutically acceptable salt thereof, the preferred concentration range in the composition of the present invention is from about 1 to about 1000mg/ml, more preferably from about 5 to about 750mg/ml, and still more preferably from about 10 to about 100 mg/ml. For other antibiotics than ceftiofur, suitable concentration ranges equivalent to the described antibacterial can be determined by one skilled in the art based on the information already disclosed.

The term "amphipathic oil" is defined as a material having distinct polar regions and distinct non-polar regions. Structurally the two regions of the amphipathic oil are far enough apart that the two regions have distinct properties that are quite different.

Amphipathic oils useful in the present invention include all amphipathic oils that are both water dispersible and ethanol insoluble.

Preferred such amphipathic oils are polyglycolized glycerides prepared by an alcoholization reaction of natural triglycerides and polyethylene glycols, examples of which include, but are not limited to, the following gattefosse oil or substantially equivalent oils thereof from other manufacturers: labrafil^TM M-1944CS、Labrafil ^TM M-1966CS、Labrafil^TM M-1969CS、Labrafil^TM M-1980CS、Labrafil ^TM-2125CS、Labrafil^TM WL-2609BS、Labrafil^TMISO and combinations thereof.

Even more preferred amphiphilic oils are polyglycolysed glycerides prepared according to the above process and containing the main fatty acid component of oleic or linoleic acid, examples of which include but are not limited to the following gattefosse oils or substantially equivalent oils thereof from other manufacturers: labrafil^TM M-1944CS、Labrafil^TM M-1966CS、Labrafil^TMM-1969CS、Labrafil^TM M-1980CS、Labrafil^TM M-2125CS、Labrafil^TMWL-2609BS and combinations thereof.

Even more preferred amphiphilic oils are the polyglycolysed glycerides obtained according to the above process and containing the main fatty acid component of oleic acid, examples of which include but are not limited to the following gattefosse oils or the substantially equivalent oils thereof from other manufacturers: labrafil^TM M-1944CS、Labrafil^TM M-1966CS、Labrafil^TMM-1980CS and combinations thereof.

The most preferred amphipathic oil is pegicol 5-oleate, such as Labrafil from Gattefoss é, Inc^TM M-1944CS。

Preferred concentrations of the amphipathic oil in the present composition range from about 0.01% to about 99% weight/volume, more preferably from about 1% to about 80% weight/volume, and even more preferably from about 3% to about 25% weight/volume.

Microcrystalline waxes are defined, for example, in Handbook of Pharmaceutical Excipients3 rd edition or inNational FormularyIn NF 19, 19 th edition, it is available from many manufacturers including Witco.

Preferred concentrations of microcrystalline wax in the compositions of the present invention range from about 0.01% to about 50% weight/volume, more preferably from about 1% to about 40% weight/volume, and even more preferably from about 3% to about 15% weight/volume.

The pharmaceutically acceptable non-aqueous carrier of the present invention may be fully saturated, or partially or fully unsaturated. Examples of non-aqueous carriers include, but are not limited to, vegetable oils (e.g., cottonseed oil, corn oil, sesame oil, soybean oil, olive oil, fractionated coconut oil, peanut oil, sunflower oil, safflower oil, almond oil, avocado oil, palm kernel oil, babassu oil, beech nut oil, linseed oil, rape oil, and the like), mineral oils, synthetic oils, and combinations thereof. Examples of fully saturated non-aqueous carriers include, but are not limited to, esters of medium to long chain fatty acids (e.g., having about C)₆To about C₂₄Fatty acid triglycerides of chain length). The fatty acids are obtained by splitting natural oils (e.g., coconut oil, palm kernel oil, babassu oil, etc.), and then refining. In some embodiments, about C is used₆To about C₁₂Triglycerides of medium-chain fatty acids. Exemplary saturated non-aqueous carriers include capric acid (about 20% to about 45% by weight of the carrier) and caprylic acid (about 45% to about 80% by weight of the carrier). Other fully saturated non-aqueous carriers include, but are not limited to, saturated coconut oil (which typically includes a mixture of lauric, myristic, palmitic, capric and caprylic acids), including those from Huls under the trademark Miglyol^TMCoconut oil is sold under the trade names 810, 812, 829 and 840. Other well known are NeoBee sold by Drew Chemicals^TMAnd (5) producing the product. Isopropyl myristate is another example of a non-aqueous carrier that may be used in the compositions of the invention. Examples of synthetic oils include saturated or unsaturated fatty acids having 6 to 24 carbon atoms such as hexanoic acid, octanoic acidTriglycerides and propylene glycol diesters of (caprylic acid), pelargonic acid (pelargonic acid), capric acid (capric acid), undecanoic acid, dodecanoic acid, tridecanoic acid, tetradecanoic acid (myristic acid), pentadecanoic acid, hexadecanoic acid (palmitic acid), heptadecanoic acid, octadecanoic acid (stearic acid), nonadecanoic acid, heptadecanoic acid, eicosanoic acid, heneicosanoic acid, docosanoic acid, tricosanoic acid, and tetracosanoic acid, and the like. Examples of unsaturated carboxylic acids include oleic acid, linoleic acid, linolenic acid, and the like. It is to be understood that the non-aqueous carrier may contain mono-, di-, and triglyceryl esters of fatty acids or mixed glycerides and/or propylene glycol diesters in which at least one molecule of glycerol is esterified with fatty acids of variable carbon atom length. A non-limiting example of a "non-oil" of the present invention is polyethylene glycol.

Preferred non-aqueous carriers are selected from the group consisting of cottonseed oil, corn oil, peanut oil, sesame oil, soybean oil, olive oil, sunflower oil, safflower oil, almond oil, avocado oil, palm kernel oil, babassu oil, beechnut oil, linseed oil, rape oil and fractionated coconut oil.

The most preferred non-aqueous carrier is cottonseed oil. By way of example, cottonseed oil may be obtained from a 70% unsaturated fatty acid formulation from Sigma Chemical co.

Preferred concentrations of the non-aqueous carrier in the compositions of the present invention range from about 0.5% to about 99% weight/volume, more preferably from about 10% to about 95% weight/volume, and even more preferably from about 40% to about 90% weight/volume.

The compositions of the present invention may be mixed with any conventional pharmaceutical additives that do not have a toxic effect on the composition, including, but not limited to, antioxidants, preservatives, stabilizers, wetting agents, lubricants, emulsifiers, salts for adjusting osmotic pressure, colorants, alcohols, buffers, other conventional pharmaceutical additives, and combinations thereof. Examples include, but are not limited to, vitamin E, ascorbyl palmitate, butyl hydroxyanisole, butyl hydroxytoluene, benzoic acid derivatives, ethylenediamine, sodium bisulfite, sulfur dioxide, maleic acid, propyl gallate, magnesium stearate, talc, silicic acid, carbohydrates (e.g., lactose, amylose, and starch), and combinations thereof.

Methods of administering the compositions of the present invention are described herein as comprising an "infusion" or "infusion" step. "infusion" and "injection" refer herein to the delivery of a liquid composition directly into a fluid-containing organ, including, for example, injection using a syringe, which is accomplished in a very short time interval and is more capable of delayed delivery.

The composition of the invention can be administered for the treatment or prevention of mastitis by inserting the cannula nozzle of a mastitis syringe into the external orifice of a streak canal of an udder of a milk producing animal and then injecting the composition into the udder.

The compositions of the present invention can be administered for or to prevent an ear infection by inserting the nozzle of an ear syringe, ear drop dispenser (disperser), or other suitable ear delivery device into the external auditory canal of the ear of a subject and then injecting the composition into the ear.

It is to be understood that the preferred amount of the composition administered in a particular situation will vary depending upon the particular composition used, the mode of administration, the particular situation and organism being treated, and other factors. The dosage to achieve a given purpose may be determined by means of conventional considerations, such as a conventional comparison of the different activities of the administered composition and a known drug by an appropriate conventional pharmaceutical protocol.

An exemplary suspension of the invention containing ceftiofur hydrochloride as the antibacterial substance has the following composition:

antibacterial substance 1-1000mg/ml

Labrafil^TM-1944CS 0.01-99％

Microcrystalline wax 0.01-50%

Cottonseed oil 0.5-99%

(all percentages are weight/volume).

Examples

The following examples illustrate aspects of the invention and should not be construed as limiting.

Example 1

A suspension having the following composition for the treatment and/or prevention of mastitis in a lactating cow by intramammary infusion is prepared.

Ceftiofur hydrochloride (micronized) 12.5mg/ml

Labrafil^TM M-1944CS 50mg/ml

Microcrystalline wax NF 70mg/ml

Cottonseed oil NF q.s.

The microcrystalline wax and approximately 27% of the total cottonseed oil were heated to 85-98 c with mixing in a kettle. The remaining cottonseed oil was heated to 85-98 c with mixing in the manufacturing tank. After the microcrystalline wax is completely melted, the microcrystalline wax/cottonseed oil mixture in the kettle is transferred to a manufacturing tank containing cottonseed oil and mixed thoroughly. The resulting mixture was cooled to 38-45 deg.C and Labrafil was added to the manufacturing tank with mixing^TMM-1944CS, forming an excipient. Ceftiofur hydrochloride is then added to the vehicle and the resulting composition is mixed to form a homogeneous suspension. The suspension was sieved and loaded into a 12ml high density polyethylene mastitis syringe. Finally, the dosage of the packaged product is 25-Gamma irradiation sterilization at 40 kGy.

The surface tension of the above suspension was determined by drop volume method and mixed with 70mg/ml microcrystalline wax in cottonseed oil but without Labrafil^TM1944 surface tension of the reference suspension made with CS. Simultaneously contains Labrafil^TMThe surface tension of the suspension of M-1944CS and microcrystalline wax in cottonseed oil was 3.4 times lower than that of the reference suspension.

Example 2

A suspension having the following composition for the treatment and/or prevention of mastitis in a lactating cow by intramammary infusion is prepared.

Ceftiofur hydrochloride (micronized) 12.5mg/ml

Labrafil^TM M-1944CS 50mg/ml

Microcrystalline wax NF 100mg/ml

Cottonseed oil NF q.s.

The microcrystalline wax and cottonseed oil were heated to 85-98 c with mixing in the production tank. After the microcrystalline wax was completely melted, the mixture was cooled to 38-45 deg.C and Labrafil was added to the manufacturing tank with mixing^TMM-1944 CS. Ceftiofur hydrochloride was then added to the resulting vehicle and mixed to form a homogeneous suspension. The suspension was sieved and loaded into a 12ml high density polyethylene mastitis syringe. Finally sterilizing the packaged product by gamma irradiation with a dose of 25-40 kGy.

The surface tension of the above suspension was determined by drop volume method and mixed with 100mg/ml microcrystalline wax in cottonseed oil but without Labrafil^TMThe surface tension of the reference suspension made with M-1944CS was compared. Simultaneously contains Labrafil^TMSurface tension of suspension of M-1944CS and microcrystalline wax in cottonseed oil versus reference suspensionThe surface tension was 4.0 times lower.

Example 3

A suspension having the following composition for the treatment and/or prevention of mastitis in a lactating cow by intramammary infusion is prepared.

Ceftiofur hydrochloride (micronized) 12.5mg/ml

Labrafil^TM M-1944CS 200mg/ml

Microcrystalline wax NF 100mg/ml

Cottonseed oil NF q.s.

The microcrystalline wax and cottonseed oil were heated to 85-98 c with mixing in the production tank. After the microcrystalline wax was completely melted, the mixture was cooled to 38-45 deg.C and Labrafil was added to the manufacturing tank with mixing^TMM-1944 CS. Ceftiofur hydrochloride was then added to the resulting vehicle and mixed to form a homogeneous suspension. The suspension was sieved and loaded into a 12ml high density polyethylene mastitis syringe. Finally sterilizing the packaged product by gamma irradiation with a dose of 25-40 kGy.

The surface tension of the above suspension was determined by drop volume method and mixed with 100mg/ml microcrystalline wax in cottonseed oil but without Labrafil^TMThe surface tension of the reference suspension made with M-1944CS was compared. Simultaneously contains Labrafil^TMThe surface tension of the suspension of M-1944CS and microcrystalline wax in cottonseed oil was more than 28 times lower than that of the reference suspension.

Example 4

A suspension having the following composition for treatment and/or prevention of milk production and mastitis in cows by intramammary infusion is prepared.

Ceftiofur crystalline free acid (micronized) 25.0mg/ml

Labrafil^TM M-1966CS 100mg/ml

Microcrystalline wax NF 50mg/ml

Corn oil NF q.s.

The microcrystalline wax and corn oil are mixed and heated to 85-98 deg.C in the production tank. After the microcrystalline wax was completely melted, the mixture was cooled to 38-45 deg.C and Labrafil was added to the manufacturing tank with mixing^TMM-1966 CS. Ceftiofur crystalline free acid is then added to the vehicle and mixed to form a homogeneous suspension. The suspension was sieved and loaded into a 12ml high density polyethylene mastitis syringe. Finally sterilizing the packaged product by gamma irradiation with a dose of 25-40 kGy.

Example 5

A suspension having the following composition for treating and/or preventing canine otitis externa by otic infusion was prepared.

Ceftiofur hydrochloride (micronized) 25mg/ml

Labrafil^TM-1980CS 500mg/ml

Microcrystalline wax NF 1.0mg/ml

Propyl gallate 1.0mg/ml

Mineral oil q.s.

The microcrystalline wax and approximately 27% of the total mineral oil were heated to 85-98 c with mixing in a kettle. Mixing the rest mineral oil in the production tankTo 85-98 ℃. After the microcrystalline wax is completely melted, the microcrystalline wax/mineral oil mixture in the kettle is transferred to a production tank containing mineral oil and mixed thoroughly. The resulting mixture was cooled to 38-45 deg.C and Labrafil was added to the manufacturing tank with mixing^TMM-1980 CS. Ceftiofur hydrochloride was then added to the resulting vehicle and mixed to form a homogeneous suspension. The suspension was sieved and filled into 20ml polypropylene containers.

Example 6

A suspension having the following composition for the treatment and/or prevention of mastitis in a non-dairy cow by intramammary infusion is prepared.

Ceftiofur hydrochloride (micronized) 50mg/ml

Labrafil^TM M-1944CS 50mg/ml

Microcrystalline wax NF 70mg/ml

Cottonseed oil NF q.s.

The microcrystalline wax and approximately 27% of the total cottonseed oil were heated to 85-98 c with mixing in a kettle. The remaining cottonseed oil was heated to 85-98 c with mixing in the manufacturing tank. After the microcrystalline wax is completely melted, the microcrystalline wax/cottonseed oil mixture in the kettle is transferred to a manufacturing tank containing cottonseed oil and mixed thoroughly. The resulting mixture was cooled to 38-45 deg.C and Labrafil was added to the manufacturing tank with mixing^TMM-1944 CS. Ceftiofur hydrochloride was then added to the resulting vehicle and mixed to form a homogeneous suspension. The suspension was sieved and loaded into a 12ml high density polyethylene mastitis syringe. Finally sterilizing the packaged product by gamma irradiation with a dose of 25-40 kGy.

Example 7

A suspension having the following composition for the treatment and/or prevention of mastitis in a lactating cow by intramammary infusion is prepared.

Ceftiofur sodium (micronized) 20mg/ml

Labrafil^TM WL-2609BS 75mg/ml

Microcrystalline wax NF 100mg/ml

Miglyol^TM 812 q.s.

Mixing microcrystalline wax and Miglyol at about 30% of the total^TM812 were heated to 85-98 c with mixing in the autoclave. The rest of Miglyol^TM812 was heated to 85-98 c with mixing in the production tank. After the microcrystalline wax is completely melted, the microcrystalline wax/Miglyol in the reaction kettle is added^TM812 the mixture was transferred to a container containing Miglyol^TM812, mixed well. The resulting mixture was cooled to 38-45 deg.C and Labrafil was added to the manufacturing tank with mixing^TMWL-2609 BS. Ceftiofur sodium is then added to the resulting vehicle and mixed to form a homogeneous suspension. The suspension was sieved and loaded into a 12ml high density polyethylene mastitis syringe. Finally sterilizing the packaged product by gamma irradiation with a dose of 25-40 kGy.

Having described the invention in detail and by reference to preferred embodiments thereof, it will be apparent that modifications and variations are possible without departing from the scope of the appended claims.

Claims (21)

1. A pharmaceutical composition comprising an excipient comprising (a) an amphipathic oil which is a polyglycolized glyceride prepared by an alcoholysis reaction of natural triglycerides and polyethylene glycols, (b) microcrystalline wax, and (c) a pharmaceutically acceptable non-aqueous carrier; the excipient contains an antibacterial substance stably dispersed therein in an antibacterial effective amount, wherein the antibacterial substance is selected from penicillin, synthetic penicillin, cephalosporin, tylosin, tilmicosin, aivlosin, erythromycin, azithromycin, spiramycin, josamycin, kitasamycin, lincomycin, clindamycin, policomycin, thiomycin, valnemulin, benzylpenicillin, phenoxymethylpenicillin, cloxacillin, nafcillin, methicillin, oxacillin, amoxicillin, temocillin, ticarcillin, polypeptide, piperalin, azlocillin, mezlocillin, carbenicillin, streptomycin, neomycin B, damycin, apramycin, amikacin, spectinomycin, ampicillin, polymyxin B, polymyxin E, sulfamethazine, sulfadiazine, sulfamethoxazole, trimethoprim, and the like, Chloramphenicol, thiamphenicol, florfenicol, tetracycline, chlortetracycline, oxytetracycline, doxycycline, minocycline, quinolones, fluoroquinolones, ciprofloxacin, domeclycine, mafenide, methacycline, norfloxacin, ofloxacin, pyrimethamine, silver sulfadiazine, sulfacetamide, sulfisoxazole, tobramycin, vanemulin, oxazolidinones, glucosamides, aminocyclopolyols, amtopyridinone, ansamycin, carbaphenem, cephamycin, vancomycin, monocarboxamide, oxacephem, 2, 4-diaminopyrimidine, nitrofuransulfones, marbofloxacin, and combinations thereof.

2. The composition of claim 1, wherein said oxazolidinone is selected from the group consisting of eperezolid, linezolid, n- ((5S) -3- (3-fluoro-4- (4- (2-fluoroethyl) -3-oxy-1-piperazinyl) phenyl-2-oxy-5-oxazolidinyl) methyl) acetamide, (S) -N- ((3- (5- (3-pyridinyl) thiophen-2-yl) -2-oxy-5-oxazolidinyl) methyl) acetamide and (S) -N- ((3- (5- (4-pyridinyl) pyridin-2-yl) -2-oxy-5-oxazolidinyl) methyl) acetamide hydrochloride.

3. The composition of claim 1, wherein the cephalosporin is selected from the group consisting of ceftiofur and salts thereof, cephalexin, cephradine, cefquinome, cephaloacetonitrile, ceftaroline, cefuroxime, ceftazidime, cefoperazone, sodium cephemate, cephem heptahydrate, cephalosporin di-or trihydrate, cefadroxil monohydrate, ceftazolin sodium monohydrate, cefixime, cefotaxime, ceftizoxime, ceftriaxone, o-formyl cefamandole, salts of 3-acetoxymethyl-7- (iminoacetamido) -cephalosporanic acid derivatives, monohydrate of 7- (D- α -amino- α - (p-hydroxyphenyl) acetamido) -3-methyl-3-cephem-1-carboxylic acid, cis-7- ((2-amino-1-thiazolyl) (methoxyiminoctadine) Amino) acetyl) amino-3-methyl-3-cephem-4-carboxylic acid hydrochloride, crystalline cephem acid addition salt, (pivaloyloxy) methyl-7-beta- (2- (2-amino-4-thiazolyl) acetamido) -3- (((1- (2- (dimethylamino) ethyl) -1H-tetrazol-5-yl) thio) methyl) 3-cephem-4-carboxylic acid ester, cephalexin monohydrate, 7- (D-2-naphthylglycylamino) -3-methyl-3-cephem-4-carboxylic acid tetrahydrate, tautomers, stereoisomers, solvates of said cephalosporins, Enantiomers, salts, hydrates, and prodrugs, and combinations thereof.

4. The composition of claim 1 wherein the antibacterial substance is selected from the group consisting of ceftiofur and pharmaceutically acceptable salts thereof, and combinations thereof.

5. The composition of claim 4, wherein said polyglycolized glyceride contains a major fatty acid component of oleic or linoleic acid.

6. The composition of any of claims 1-5, wherein the non-aqueous carrier is selected from the group consisting of vegetable oils, mineral oils, medium to long chain fatty acids and alkyl esters thereof, propylene glycol diesters of medium to long chain fatty acids, mono-, di-, and triglyceryl esters of fatty acids, polyethylene glycols, and combinations thereof.

7. The composition of any of claims 1-5, wherein the amphipathic oil comprises 0.01% to 99% weight/volume of the composition.

8. The composition of claim 7, wherein the amphipathic oil comprises 1% to 80% weight/volume of the composition.

9. The composition of claim 8, wherein the amphipathic oil comprises 3% to 25% weight/volume of the composition.

10. The composition of any of claims 1-5, wherein the microcrystalline wax comprises 0.01% to 50% weight/volume of the composition.

11. The composition of claim 10 wherein the microcrystalline wax comprises 1% to 40% weight/volume of the composition.

12. The composition of claim 11 wherein the microcrystalline wax comprises 3% to 15% weight/volume of the composition.

13. The composition of any of claims 1-5, wherein the non-aqueous carrier comprises from 0.5% to 99% weight/volume of the composition.

14. The composition of claim 13, wherein the non-aqueous carrier comprises 10% to 95% w/v of the composition.

15. The composition of claim 14, wherein the non-aqueous carrier comprises from 40% to 90% w/v of the composition.

16. An article of manufacture comprising a container or delivery device having an oxygen permeable wall and further comprising the composition of any of claims 1-15 contained therein.

17. The product of claim 16, wherein said composition has extended chemical and/or physical stability by comparison to an otherwise similar reference composition lacking one or both of the amphipathic oil and the microcrystalline wax.

18. Use of the composition of any one of claims 1-15 for the manufacture of a medicament for treating or preventing a bacterial infection in a subject.

19. The use of claim 18, wherein the bacterial infection is present in the udder of a milk producing animal, and wherein the medicament is administered by intramammary infusion.

20. The use of claim 19, wherein the bacterial infection is manifested as mastitis.

21. The use of claim 19, wherein the bacterial infection is present in an ear, and wherein the medicament is administered by otic infusion or injection.