Long-acting injectable formulations and use thereof

Abstract

To provide long-acting, non-aqueous pharmaceutically acceptable compositions of active ingredients for subcutaneous injection.SOLUTION: Provided is an injectable pharmaceutically acceptable composition, comprising: a) a pharmaceutically active agent; b) a polar lipid at about 5.0 to 40.0% w / w; and c) a triglyceride carrier at about 5.0 to 70.0% w / w.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 852,527, filed May 24, 2019, the entire contents of which are incorporated herein by reference in their entirety.

[0002] FIELD OF THE INVENTION The present invention relates generally to long-acting, non-aqueous, subcutaneous injection formulations, and more particularly to long-acting formulations, especially for use in mammals. [Background technology]

[0003] Background information Traditional long-acting injections consist of either a lipophilic drug in an aqueous solvent as a suspension or a lipophilic drug dissolved in vegetable oil. Poorly water-soluble salt formulations can be used to control the dissolution rate of the drug particles and prolong absorption. However, several other factors, such as the injection site, injection volume, the degree of depot diffusion at the injection site, and the absorption and dispersion of the oil vehicle itself, can affect the overall pharmacokinetic profile of the drug.

[0004] Biodegradable microsphere systems can also be used in sustained-release formulations made with suitable biodegradable polymers. The release of drug molecules from biodegradable microspheres is controlled by diffusion through the polymer matrix and polymer degradation. Various biodegradable polymers for controlled drug delivery have been intensively studied over the past few decades. See Pandya et al., International Journal of Biopharmaceutics 5(3):208-213(2014) (Non-Patent Document 1), and Matschke et al., Journal of Controlled Release 85(1-3):1-15(2002) (Non-Patent Document 2).

[0005] As noted, the manufacture of such conventional sustained-release formulations is complex and expensive, requiring additional heat, evaporation steps, application of additional pressure (e.g., via compression or extrusion), and / or the use of significant amounts of organic solvents that can introduce potential toxicity if not completely removed. It is also difficult to adequately control the release of drugs in injectable dosage forms to achieve the desired onset and duration of therapeutic effect in target species. Therefore, it would be desirable to have compositions and less complicated methods that provide long-term therapeutic relief to mammals while minimizing the number of administrations / doses that must be given to the mammal. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Pandya et al., International Journal of Biopharmaceutics 5(3):208-213(2014) [Non-patent document 2] Matschke et al., Journal of Controlled Release 85(1-3):1-15(2002) Summary of the Invention

[0007] Provided herein are long-acting, non-aqueous, injectable, pharmaceutically acceptable compositions.

[0008] In one embodiment, the injectable pharmaceutically acceptable composition comprises: a) a pharmaceutically active agent; and b) about 5.0 to 40.0 w / w% polar lipid, such as glycerol monooleate and / or glycerol monostearate; c) about 5.0 to 70.0 w / w% triglyceride carrier.

[0009] Optionally, the composition further comprises an excipient such as an alcohol (e.g., ethanol and / or benzyl alcohol), which may be present at up to about 10.0-20.0 w / w%, including 10.0, 11.0, 12.0, 13.0, 14.0, 15.0, 16.0, 17.0, 18.0, 19.0 or 20.0 w / w%.

[0010] Optionally, the composition further comprises sucrose acetate isobutyrate (SAIB), which may be present at up to about 5.0-50.0 or 70.0 w / w%.

[0011] In another embodiment, the injectable pharmaceutically acceptable composition comprises: a) a pharmaceutically active agent; and b) about 5.0 to 70.0 w / w% SAIB; c) about 30.0 to 70.0 w / w% of a water-miscible solvent such as triacetin.

[0012] Optionally, the composition further comprises an excipient such as an alcohol (e.g., ethanol and / or benzyl alcohol), which may be present at up to about 10.0-20.0 w / w%, including 10.0, 11.0, 12.0, 13.0, 14.0, 15.0, 16.0, 17.0, 18.0, 19.0 or 20.0 w / w%.

[0013] In another embodiment, the injectable pharmaceutically acceptable composition comprises: a) a pharmaceutically active agent; and b) about 5.0 to 70.0 w / w% sucrose acetate isobutyrate; c) about 5.0 to 70.0 w / w% triglyceride carrier.

[0014] Optionally, the composition further comprises about 30.0-70.0 w / w% of a water-miscible solvent, such as triacetin.

[0015] Optionally, the composition further comprises an excipient such as an alcohol (e.g., ethanol and / or benzyl alcohol), which may be present at up to about 10.0-20.0 w / w%, including 10.0, 11.0, 12.0, 13.0, 14.0, 15.0, 16.0, 17.0, 18.0, 19.0 or 20.0 w / w%.

[0016] In various embodiments, alcohols for use in the pharmaceutically acceptable compositions of the present invention include one or more alcohols and / or glycols. Such alcohols are pharmaceutically acceptable and are generally liquid at room temperature, about 20° C. Illustratively, alcohols or glycols for use in the compositions of the present invention can include one or more of propylene glycol, ethanol, 2-(2-ethoxyethoxy)ethanol (Transcutol®), benzyl alcohol, glycerol, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, and the like.

[0017] In various embodiments, the pharmaceutically acceptable compositions are sterile injectable liquids that increase in viscosity once subcutaneously injected, thereby forming an in situ-forming depot (ISFD) that provides sustained release of the pharmaceutically active agent. The ISFD is formed by a depot-forming agent that precipitates and traps the pharmaceutically active agent upon subcutaneous injection. This precipitate creates a semi-solid, water-insoluble depot that biodegrades and / or diffuses the pharmaceutically active agent over an extended period of time. Notably, the compositions of the present invention, when administered to a mammal via injection, such as subcutaneous or intramuscular injection, provide active agent release of the pharmaceutically active agent for at least up to about 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours or more.

[0018] In certain embodiments, exemplary formulations are as set forth in Table I below, where marbofloxacin may be substituted with any pharmaceutically active agent.

[0019] Table I: Formulations TIFF2025186498000002.tif50128

[0020] In certain embodiments, exemplary formulations are as set forth in Table II below, where marbofloxacin may be substituted with any pharmaceutically active agent.

[0021] Table II: Formulations TIFF2025186498000003.tif36128

[0022] In certain embodiments, exemplary formulations are as set forth in Table III below, where marbofloxacin may be substituted with any pharmaceutically active agent.

[0023] Table III: Formulations TIFF2025186498000004.tif36128

[0024] In certain related embodiments, exemplary formulations are as set forth in Table IV below, where marbofloxacin may be substituted with any pharmaceutically active agent.

[0025] Table IV: Formulations TIFF2025186498000005.tif55128

[0026] In certain related embodiments, exemplary formulations are as set forth in Table V below, where terbinafine can be substituted with any pharmaceutically active agent.

[0027] Table V: Formulations TIFF2025186498000006.tif31128

[0028] In certain related embodiments, exemplary formulations are as set forth in Table VI below, where florfenicol can be substituted with any pharmaceutically active agent.

[0029] Table VI: Formulations TIFF2025186498000007.tif31128

[0030] In certain related embodiments, exemplary formulations are as set forth in Table VII below, where florfenicol can be substituted with any pharmaceutically active agent.

[0031] Table VII: Formulations TIFF2025186498000008.tif41128

[0032] In certain embodiments, the pharmaceutically active agent is present in an amount of about 0.25-25.0 w / w%. In other embodiments, the triglyceride is caprylic / capric triglyceride or caprylic triglyceride. In other embodiments, the triglyceride is present in an amount of up to about 70.0 w / w% ± 10.0 w / w%. In some embodiments, the composition further comprises benzyl alcohol and / or ethanol, and optionally cholesterol, such as milled cholesterol, present in amounts of about 1.0-20.0 w / w%, about 1.0-20.0 w / w%, and about 1.0-2.0 or 3.0 w / w% of the formulation, respectively. In other embodiments, the composition is sterile and formulated for administration by injection.

[0033] Also provided herein are methods for treating a disease or disorder (e.g., an infection, an inflammatory disorder, or pain) in a subject by administering a formulation of the present invention. Surprisingly, a clinically effective amount of a pharmaceutically active agent, when provided in a formulation of the present invention, is present in the subject's bloodstream for about 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours or more after administration. In various embodiments, a single or multiple pharmaceutically active agents are administered in a single formulation. In embodiments, a formulation of the present invention comprising marbofloxacin, terbinafine, or tulathromycin, optionally in combination with buprenorphine or morphine, is delivered to a companion animal, such as a cat or dog.

[0034] In certain embodiments, formulations containing marbofloxacin and / or tulathromycin are particularly suitable for treating dogs for infections such as urinary tract infections or other microbial infections.

[0035] In certain embodiments, formulations containing terbinafine are particularly suitable for treating cats for infections such as ringworm or other microbial infections. [The present invention 1001] A pharmaceutically acceptable composition for injection, comprising: a) a pharmaceutically active agent; and b) about 5.0 to 40.0 w / w% polar lipids; c) about 5.0 to 70.0 w / w% triglyceride carrier; A composition comprising: [The present invention 1002] The composition of claim 1001, further comprising sucrose acetate isobutyrate. [The present invention 1003] 1001. The composition of claim 1001, wherein said sucrose acetate isobutyrate is present at a maximum of about 25.0-70.0 w / w%. [The present invention 1004] A pharmaceutically acceptable composition for injection, comprising: a) a pharmaceutically active agent; and b) about 5.0 to 70.0 w / w% sucrose acetate isobutyrate; c) approximately 30.0 to 60.0 w / w% of a water-miscible solvent; A composition comprising: [The present invention 1005] A pharmaceutically acceptable composition for injection, comprising: a) a pharmaceutically active agent; and b) about 5.0 to 70.0 w / w% sucrose acetate isobutyrate; c) about 5.0 to 70.0 w / w% triglyceride carrier; A composition comprising: [The present invention 1006] Any of the compositions of claims 1001 to 1005, wherein the pharmaceutically active agent is selected from the group consisting of antibacterial agents, anti-inflammatory agents, anthelmintics, analgesics, antiemetics, steroids, sedatives, stimulants, antidepressants, opioids, opiates, nonsteroidal anti-inflammatory drugs (NSAIDs), cannabinoids, and anesthetics. [The present invention 1007] The composition of claim 1006, wherein the antimicrobial agent is an antibiotic, an antiviral, or an antifungal agent. [The present invention 1008] The composition of the present invention 1007, wherein said antibiotic agent is a macrolide antibiotic. [The present invention 1009] The composition of claim 1008, wherein the macrolide antibiotic is doximectin, avimectin, roxithromycin, clarithromycin, tulathromycin, gamithromycin, dirithromycin, fidaxomicin, megalomycin, erythromycin, azithromycin, or a combination thereof. [The present invention 1010] The composition of the present invention 1007, wherein the antifungal agent is a triazole antifungal compound. [The present invention 1011] The composition of the present invention 1007, wherein the antifungal agent is terbinafine. [The present invention 1012] The composition of claim 1006, wherein said anti-inflammatory agent is a corticosteroid or a nonsteroidal anti-inflammatory drug. [The present invention 1013] The composition of claim 1007, wherein said antibiotic agent is a fluoroquinolone. [The present invention 1014] 1013. The composition of claim 1013, wherein the fluoroquinolone is benofloxacin, binfloxacin, cinoxacin, ciprofloxacin, danofloxacin, difloxacin, enoxacin, enrofloxacin, fleroxacin, ibafloxacin, levofloxacin, lomefloxacin, marbofloxacin, moxifloxacin, norfloxacin, ofloxacin, orbifloxacin, pefloxacin, pipemidic acid, temafloxacin, tosufloxacin, sarafloxacin, sparfloxacin, or a combination thereof. [The present invention 1015] The composition of any one of claims 1001 to 1005, further comprising an excipient. [The present invention 1016] The composition of claim 1015, wherein the excipient is benzyl alcohol, ethanol, or a combination thereof. [The present invention 1017] The composition of any one of claims 1001 to 1005, further comprising polyoxyl castor oil. [The present invention 1018] The composition of any one of claims 1001 to 1005, further comprising hydrogenated phosphatidylcholine derived from soybean lecithin. [The present invention 1019] The composition of any one of claims 1001 to 1005, further comprising an antioxidant. [The present invention 1020] 6. The composition of any one of claims 1001 to 1005, wherein the pharmaceutically active agent is present in an amount of 1.0 to 25.0 w / w%. [The present invention 1021] The composition of any one of claims 1001 to 1005, further comprising cholesterol. [The present invention 1022] The composition of any one of claims 1001 and 1002, wherein the polar lipid is selected from the group consisting of glycerol monooleate, glycerol monostearate, glycerol monolinoleate, glycerol monocaprylate, glycerol monocaprate, glycerol monolaurate, glycerol monomyristate, glycerol monopalmitate, glycerol monomyristoleate, glycerol monopalmitoleate, glycerol monosapienate, and any combination thereof. [The present invention 1023] The composition of claim 1022, wherein the polar lipid is glycerol monooleate, glycerol monostearate, or a combination thereof. [The present invention 1024] The composition of claim 1001 or 1002, wherein the polar lipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, glycerophosphocholine, phosphatidic acid, phospholipids derived from egg, soybean, rapeseed, canola, or sunflower oil, synthetic or naturally occurring phospholipids, hydrogenated or unsaturated phospholipids, PEGylated phospholipids, and any combination thereof. [The present invention 1025] 1004. The composition of claim 1004, wherein the water-miscible solvent is a triglyceride, triethyl, or triester. [The present invention 1026] The composition of claim 1025, wherein the triglyceride is triacetin. [The present invention 1027] 1025. The composition of claim 10, wherein said triethyl is triethyl citrate. [The present invention 1028] Any of the compositions of claims 1001 to 1027, wherein at least about 100, 500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 15,000, or 20,000 ng / ml of said pharmaceutically active agent, when administered to a mammal, is present in the bloodstream of the subject for at least about 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours or more. [The present invention 1029] A method for treating a disease or disorder in a subject, comprising administering to the subject an effective amount of any of the compositions of present inventions 1001 to 1028. [The present invention 1030] 1029. The method of claim 1029, wherein the subject is a mammal. [The present invention 1031] The method of claim 1030, wherein the subject is a dog. [The present invention 1032] The method of claim 1029, wherein the subject is a cat. [The present invention 1033] 1029. The method of claim 1029, wherein said disease or disorder is an infectious disease. [The present invention 1034] 1029. The method of claim 1029, wherein said disease or disorder is pain or inflammation. [This invention 1035] 1029. The method of claim 1029, wherein said disease or disorder is an inflammatory disease. [The present invention 1036] 1029. The method of claim 1029, wherein at least about 100, 500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 15,000, or 20,000 ng / ml of said pharmaceutically active agent, upon administration to a mammal, is present in the bloodstream of said subject for at least about 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours or more. [Brief explanation of the drawings]

[0036] [Figure 1] 1 is a graphical representation depicting data in one embodiment of the present invention. [Figure 2] 1 is a graphical representation depicting data in one embodiment of the present invention. [Figure 3] 1 is a graphical representation depicting data in one embodiment of the present invention. [Figure 4] 1 is a graphical representation depicting data in one embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0037] Detailed Description of the Invention The following terms, definitions, and abbreviations apply: The abbreviations used herein have their conventional meaning within the chemical and biological arts.

[0038] The term "subject" refers to a mammalian organism treated by the methods of the present disclosure. Such organisms include, but are not limited to, companion animals such as domestic dogs and cats. In the context of the present disclosure, the term "subject" generally refers to an individual who will undergo or has undergone a treatment described below (e.g., administration of a composition of the present disclosure).

[0039] As used herein, a "patient" or "subject" refers to either a human or a non-human mammal. Non-human animals also include any non-human mammal. Such non-human animals may include, but are not limited to, rodents, non-human primates (e.g., monkeys and apes), ungulates, sheep, cattle, ruminants, lagomorphs, pigs, goats, horses, dogs, cats, mice, and the like. In certain embodiments of the present invention, the animal is a mammal. In some embodiments, the animal includes, but is not limited to, companion animals such as domestic dogs and cats. In the context of the present disclosure, the term "subject" generally refers to an individual who will undergo or has undergone a treatment described below (e.g., administration of a composition of the present disclosure).

[0040] The term "therapeutically effective amount" means an amount of a compound or pharmaceutical composition that will elicit the biological or medical response in a patient or tissue that a researcher, veterinarian, physician, or other clinician is seeking to obtain.

[0041] By "pharmaceutically acceptable" it is meant that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0042] The terms "administration of" and / or "administering a" compound should be understood to mean providing a compound or pharmaceutical composition of the present disclosure to a subject in need of treatment.

[0043] The term "about" in reference to a numerical value means that the numerical value includes a small range of variation above and below the numerical value, unless otherwise specified; for example, a value of 1 will be understood to include up to 0.5 to 1.5, and all values ​​therebetween.

[0044] In embodiments, the pharmaceutical compositions of the present invention are in the form of a sterile injectable liquid of an active agent such as marbofloxacin, florfenicol, terbinafine, tulathromycin and / or buprenorphine, or other pharmaceutically active agents such as those disclosed below, in a carrier comprising (i) a polar lipid, (ii) a medium chain triglyceride carrier such as caprylic / capric triglyceride, and (iii) optionally SAIB.

[0045] In embodiments, the pharmaceutical compositions of the present invention are in the form of a sterile injectable liquid of an active agent such as marbofloxacin, florfenicol, terbinafine, tulathromycin and / or buprenorphine, or other pharmaceutically active agents such as those disclosed below, in a carrier comprising (i) SAIB, (ii) a medium chain triglyceride carrier such as caprylic / capric triglyceride, and (iii) optionally a polar lipid.

[0046] In one embodiment, the polar lipid is glycerol monooleate, glycerol monostearate, or a combination thereof.

[0047] In certain embodiments, the polar lipid is glycerol monooleate, glycerol monostearate, glycerol monolinoleate, glycerol monocaprylate, glycerol monocaprate, glycerol monolaurate, glycerol monomyristate, glycerol monopalmitate, glycerol monomyristoleate, glycerol monopalmitoleate, glycerol monosapienate, or any combination thereof.

[0048] In certain embodiments, the polar lipid is glycerol monooleate, glycerol monostearate, or a combination thereof.

[0049] In certain embodiments, the polar lipid is a phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, glycerophosphocholine, phosphatidic acid, phospholipids derived from egg, soybean, rapeseed, canola, or sunflower oil, synthetic or naturally occurring phospholipids, hydrogenated or unsaturated phospholipids, PEGylated phospholipids, or any combination thereof.

[0050] In another embodiment, the pharmaceutical composition of the present invention is in the form of a sterile injectable liquid of an active agent such as marbofloxacin, florfenicol, terbinafine, tulathromycin, and / or buprenorphine, or other pharmaceutically active agents such as those disclosed below, in a carrier comprising (i) SAIB and (ii) a water-miscible solvent. In one embodiment, the water-miscible solvent is triacetin.

[0051] In certain aspects, the water-miscible solvent is a triglyceride, a triethyl triester, or a combination thereof. In embodiments, the water-miscible solvent is triacetin, triethyl citrate, or a combination thereof.

[0052] When present, the triglyceride is present in an amount of about 5.0-70.0 w / w%, or 10.0-60.0 w / w%, or 30.0-55.0 w / w%. In some embodiments, the triglyceride is caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, or any combination thereof. For example, the triglyceride is a medium-chain triglyceride such as caprylic / capric (C8 and / or C10) triglyceride or caprylic (C8) triglyceride. In one embodiment, the triglyceride is a mixture of caprylic and capric acids, the mixture comprising about 40.0-85.0% caprylic acid and about 15.0-60.0% caprylic acid, or the mixture comprising about 50.0-80.0% caprylic acid and about 20.0-50.0% caprylic acid, or the mixture comprising about 65.0-80.0% caprylic acid and about 20.0-35.0% caprylic acid, or the mixture comprising about 50.0-65.0% caprylic acid and about 30.0-45.0% caprylic acid. In one embodiment, the triglyceride may be a fatty acid ester emollient, such as a saturated coconut and palm kernel oil-derived caprylic / capric fatty acid mixture with glycerin in solid form, sold under the trade name MIGLYOL™. In another embodiment, the triglyceride may be a fatty acid ester emollient such as a saturated coconut oil and palm kernel oil derived caprylic / capric fatty acid mixture sold under the trade name CAPTEX™, such as CAPTEX™ 8000.

[0053] It will be understood that the triglycerides used in the compositions may be fully replaced or supplemented with monoglycerides or diglycerides, the fatty acid moieties of which may be saturated or unsaturated, preferably saturated, and contain from 6 to 30 carbon atoms. In some embodiments, the fatty acid moieties of the glycerides contain from 18 to 24 carbon atoms, more preferably from 20 to 22 carbon atoms.

[0054] As used herein, the term "saturated" refers to a fatty acid moiety that contains only carbon-carbon single bonds, e.g., an alkyl group. As used herein, the term "unsaturated" refers to a fatty acid moiety that contains at least one carbon-carbon double or triple bond (e.g., an alkenyl group, -CH=CH-, or an alkynyl group, -CH≡CH-). Any alkenyl groups that may be present can be in either the cis or trans configuration. In some embodiments, the fatty acid moiety of the fat is either saturated or unsaturated with one or more alkenyl groups.

[0055] The composition may also contain a polar lipid such as glycerol monooleate and / or glycerol monostearate in an amount of about 5.0-40.0 w / w%, or 10.0-40.0 w / w%, or 15.0-30.0 w / w%, or 17.0-25.0 w / w%, or 19.0-21.0 w / w%, for example, about 20.0 w / w% of the composition.

[0056] The composition may also contain SAIB in an amount of about 5.0 to 70.0 w / w%, or 5.0 to 65.0 w / w%, or 10.0 to 55.0 w / w%, or 10.0 to 45.0 w / w%, or 15.0 to 40.0 w / w%, for example, about 35.0 to 40.0 w / w% of the composition.

[0057] The composition may also contain a water-miscible solvent such as a triglyceride (e.g., triacetin), triethyl and / or triester in an amount of about 30.0-60.0 w / w%, or 30.0-55.0 w / w%, or 35.0-50.0 w / w%, or 35.0-45.0 w / w%, or 37.0-45.0 w / w%, for example, about 40.0-45.0 w / w% of the composition.

[0058] The composition may also contain cholesterol particles, such as milled cholesterol, in an amount of about 1.0-10.0 w / w%, or 1.0-7.0 w / w%, or 1.0-5.0 w / w%, or 1.0-4.0 w / w%, or 2.0-4.0 w / w%, for example, about 3.0 w / w% of the composition.

[0059] The composition may also contain an excipient. In certain aspects, the excipient is ethanol or benzyl alcohol. In certain such embodiments, the excipient is present in an amount of about 1-20%, 5-20%, or 10-20 w / w%, e.g., about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 w / w%. Other suitable excipients include ethanol, 2-ethoxyethanol, ethyl oleate, ethyl acetate, ethyl benzoate, benzyl alcohol, glycerol, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, benzyl benzoate, isopropyl myristate, isopropyl alcohol, 2-pyrrolidone, DMSO, polyvinylpyrrolidone (e.g., PVP K17), propylene carbonate, glycofurol, N-methylpyrrolidone, propylene glycol, acetone, methyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, decyl methyl sulfoxide, tetrahydrofuran, caprolactam, decyl methyl sulfoxide, and oleic acid, 1-dodecylazacycloheptanon-2-one. In certain embodiments, benzyl alcohol and / or ethanol are present in an amount of about 1-25%, 1-20%, 5-20%, 5-15%, e.g., about 5-15 w / w%. In embodiments, benzyl alcohol is present in an amount of about 5-20%, 10-20%, 10-15%, or 15-20 w / w%, and ethanol is present in an amount of about 1-10%, 2-10%, 3-8%, 4-7%, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 w / w%.

[0060] Furthermore, the pharmaceutically active agent may be in its hydrated form, but water is not added to the composition during or after mixing.Therefore, the compositions described herein are substantially non-aqueous, for example, the compositions have less than about 3.0, 2.5, 2.0, 1.5, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.5, or 0.1 w / w% aqueous material, for example, water.

[0061] Any or all of the components of the composition may be included in their dehydrated form or in their anhydrous form.

[0062] Exemplary formulations are as set forth below in Table VIII, where marbofloxacin may be substituted with any pharmaceutically active agent.

[0063] Table VIII: Formulations TIFF2025186498000009.tif55128

[0064] Exemplary formulations are as set forth below in Table IX, where marbofloxacin may be substituted with any pharmaceutically active agent.

[0065] Table IX: Formulations TIFF2025186498000010.tif40128

[0066] Exemplary formulations are as set forth below in Table X, where marbofloxacin may be substituted with any pharmaceutically active agent.

[0067] (Table X) Formulations TIFF2025186498000011.tif40128

[0068] Exemplary formulations are set forth below in Table XI, where marbofloxacin may be substituted with any pharmaceutically active agent.

[0069] Table XI: Formulations TIFF2025186498000012.tif60128

[0070] Exemplary formulations are set forth below in Table XII, where terbinafine can be substituted with any pharmaceutically active agent.

[0071] Table XII: Formulations TIFF2025186498000013.tif30128

[0072] Other exemplary formulations according to embodiments of the present invention are set forth in Table XIII, in which the pharmaceutically active agent may be substituted with any active agent.

[0073] Table XIII: Formulations TIFF2025186498000014.tif156128TIFF2025186498000015.tif228121TIFF2025186498000016.tif203121 TIFF2025186498000017.tif213121TIFF2025186498000018.tif209121TIFF2025186498000019.tif150128

[0074] Other exemplary formulations according to embodiments of the present invention are set forth in Table XIV, in which the pharmaceutically active agent may be substituted with any active agent.

[0075] Table XIV: Formulations TIFF2025186498000020.tif232122

[0076] Other exemplary formulations according to embodiments of the present invention are set forth in Table XV, where the pharmaceutically active agent may be substituted with any active agent.

[0077] Table XV: Formulations TIFF2025186498000021.tif223114

[0078] Another exemplary formulation is set forth below in Table XVI, where florfenicol can be substituted with any pharmaceutically active agent.

[0079] Table XVI: Formulations TIFF2025186498000022.tif45128

[0080] Another exemplary formulation is set forth below in Table XVII, where florfenicol can be substituted with any pharmaceutically active agent.

[0081] Table XVII: Formulations TIFF2025186498000023.tif45128

[0082] Exemplary formulations are set forth below in Table XVIII, where terbinafine may be substituted with any pharmaceutically active agent.

[0083] Table XVIII: Formulations TIFF2025186498000024.tif31128

[0084] Other exemplary formulations according to embodiments of the present invention are set forth in Table XIX, in which the pharmaceutically active agent may be substituted with any active agent.

[0085] Table XIX: Formulations TIFF2025186498000025.tif54128

[0086] In certain related embodiments, exemplary formulations are as set forth in Table XX below, where terbinafine can be substituted with any pharmaceutically active agent.

[0087] Table XX: Formulations TIFF2025186498000026.tif31128

[0088] Other exemplary formulations according to embodiments of the present invention are set forth in Table XXI, in which the pharmaceutically active agent may be substituted with any active agent.

[0089] Table XXI: Formulations TIFF2025186498000027.tif229134TIFF2025186498000028.tif141134

[0090] In some embodiments, the composition includes a surfactant, such as castor oil, hydrogenated castor oil, or polyoxyl castor oil, e.g., KOLLIPHOR® ELP, KOLIPHOR® HS15, KOLIPHOR® RH40, or tocopherol polyethylene glycol succinate (TPGS), polysorbate (e.g., 20 and 80), or lecithin. In embodiments, the surfactant is present in an amount of about 0.01-10%, 0.05-10%, 0.5-5.0%, or 1.5-4.5%. For example, in embodiments, the composition comprises polyoxyl castor oil in an amount of up to or about 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 w / w%.

[0091] The formulation may also contain other inactive ingredients, such as antioxidants or preservatives. Antioxidants such as propyl gallate, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), MTG (monothioglycerol), triethyl citrate, citric acid, and TBHQ (tert-butylhydroquinone) may be added to the formulation. Antioxidants are generally added to the formulation in amounts of about 0.01 to about 2.0% (w / w). In certain embodiments, the antioxidant is present in an amount of about 0.01 to 2.0%, 0.05 to 2.0%, 0.5 to 2.0%, or 0.5 to 1.5%. For example, in embodiments, the composition comprises MTG and / or citric acid in an amount of up to or about 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 w / w%. For example, in embodiments, the composition comprises BHT and / or propyl gallate in an amount of up to or about 0.01, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 w / w%.

[0092] Preservatives such as parabens (methylparaben and / or propylparaben) are suitably used in the formulation in an amount ranging from about 0.01 to about 2.0 w / w.

[0093] The formulations of the present invention can be prepared without adding water to the mixture during any step of the process.

[0094] The present disclosure provides pharmaceutical compositions, comprising at least one pharmaceutically active agent in an amount effective for treating disease or disorder, and a pharmaceutically acceptable vehicle.It should be noted that the pharmaceutically active agent described in any of the formulations herein can be replaced or enhanced with a variety of pharmaceutically active agents, including but not limited to antibacterial agents, anti-inflammatory agents, and analgesics.The pharmaceutically active agent can be hydrated, for example, in the monohydrate or dihydrate form of the molecule.

[0095] Suitable pharmaceutically active agents for use in the formulations described herein are active pharmaceutical ingredients or combinations of active ingredients, including, by way of example only, anthelmintics, analgesics, antiemetics, anti-inflammatory agents, steroids, sedatives, antibacterial agents, stimulants, antidepressants, opioids, opiates, NSAIDs, cannabinoids, and anesthetics.

[0096] In embodiments, the active agent is an antimicrobial agent, such as an antiviral, antibiotic, or antifungal agent.

[0097] Thus, the present disclosure provides compositions comprising at least one antiviral, antibacterial, or antifungal agent in an amount effective to treat a disease or disorder, such as a microbial infection, and a pharmaceutically acceptable vehicle.

[0098] In some embodiments, the antiviral agent for use in the formulations described herein is an integrase inhibitor. Examples of integrase inhibitors include cabotegravir, elvitegravir, curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, quinolinic acid ... These include benzodiazepine, dolutegravir, JTK-351, bictegravir, AVX-15567, diketoquinoline-4-one derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, and stilbene disulfonic acid, T-169.

[0099] In some embodiments, the antiviral agent for use in the formulations described herein is a nucleoside analog such as, but not limited to, remdesivir, abacavir, acyclovir, adefovir, brivudine, cidofovir, clevudine, didanosine, edoxudine, emtricitabine, entecavir, famciclovir, floxuridine, ganciclovir, idoxuridine, inosine pranobex, lamivudine, penciclovir, sorivudine, stavudine, ribavirin, terbivivudine, tenofovir, trifluridine, valacyclovir, valganciclovir, vidarabine, zalcitabine, and zidovudine. In certain embodiments, the antiviral agent is one effective in treating or preventing an infectious disease caused by Ebola virus, Zika virus, influenza, or a coronavirus, e.g., coronavirus disease 2019 (COVID-19), SARS-related coronavirus (SARS-CoV), or Middle East respiratory syndrome coronavirus (MERS-CoV).

[0100] In some embodiments, the antibacterial agent for use in the formulations described herein is a fluoroquinolone antibiotic. Fluoroquinolones are disclosed, inter alia, in the following documents: U.S. Pat. No. 4,670,444 (Bayer AG); U.S. Pat. No. 4,472,405 (Riker); No. 4,704,459 (Toyama), and specific examples that may be used include benofloxacin, binfloxacin, cinoxacin, ciprofloxacin, danofloxacin, difloxacin, enoxacin, enrofloxacin, fleroxacin, ibafloxacin, levofloxacin, lomefloxacin, marbofloxacin, moxifloxacin, norfloxacin, ofloxacin, orbifloxacin, pefloxacin, pipemidic acid, temafloxacin, tosufloxacin, sarafloxacin, and sparfloxacin.

[0101] In some embodiments, the antibacterial agent for use in the formulations described herein is an amphenicol antibiotic, which may include, but is not limited to, chloramphenicol, thiamphenicol, azidanphenicol, and florfenicol.

[0102] In some embodiments, the antibacterial agent for use in the formulations described herein is tetracycline, clindamycin, or lincomycin.

[0103] In some embodiments, the antibacterial agent for use in the formulations described herein is a macrolide antibiotic. Macrolide antibiotics can include, but are not limited to, mectins (including, but not limited to, doximectin and avimectin), mycins (including, but not limited to, roxithromycin, clarithromycin, tulathromycin, gamithromycin, dirithromycin, fidaxomicin, megalomycin, erythromycin, etc.), and azilides such as azithromycin. The active agent is typically hydrated, for example, a monohydrate or dehydrated form of the molecule.

[0104] In some embodiments, the antifungal agent for use in the formulations described herein is a triazole antifungal agent, which may include, but is not limited to, clotrimazole, ketoconazole, itraconazole, fluconazole, miconazole, econazole, butoconazole, oxiconazole, sulconazole, terconazole, posaconazole, and voriconazole.

[0105] In some embodiments, the antifungal agent for use in the formulations described herein is a thiocarbamate antifungal agent, which may include, but is not limited to, tolnaftate.

[0106] In some embodiments, the antifungal agent for use in the formulations described herein is a polyene antifungal agent, which may include, but is not limited to, nystatin.

[0107] In one embodiment, the antifungal agent for use in the formulations described herein is terbinafine.

[0108] The present disclosure provides compositions comprising at least one anti-inflammatory agent in an amount effective to treat a disease or disorder, such as pain or inflammation, and a pharmaceutically acceptable vehicle.

[0109] In some embodiments, the anti-inflammatory agent for use in the formulations described herein is an H1 or H2 blocker. Examples of H1 blockers include, but are not limited to, clemastine and terfenadine. Examples of H2 blockers include, but are not limited to, cimetidine, famotidine, nizatidine, and ranitidine.

[0110] In some embodiments, the anti-inflammatory agent for use in the formulations described herein is an NSAID. As used herein, the term "NSAID" refers to a class of therapeutic compounds with analgesic, anti-inflammatory, and antipyretic properties. NSAIDs reduce inflammation by blocking cyclooxygenase. NSAIDs can be classified based on their chemical structure or mechanism of action. Non-limiting examples of NSAIDs include salicylate-derived NSAIDs, p-aminophenol-derived NSAIDs, propionic acid-derived NSAIDs, acetic acid-derived NSAIDs, enolic acid-derived NSAIDs, fenamic acid-derived NSAIDs, non-selective cyclooxygenase (COX) inhibitors, selective cyclooxygenase 1 (COX-1) inhibitors, and selective cyclooxygenase 2 (COX-2) inhibitors. The NSAID can be a profen. Examples of suitable salicylate-derived NSAIDs include, but are not limited to, acetylsalicylic acid (aspirin), diflunisal, hydroxylethyl salicylate, and salsalate. Examples of suitable p-aminophenol derivative NSAIDs include, but are not limited to, paracetamol and phenacetin. Examples of suitable propionic acid derivative NSAIDs include, but are not limited to, aluminoprofen, benoxaprofen, dexketoprofen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, pranoprofen, and suprofen.Examples of suitable acetic acid derivative NSAIDs include Aceclofenac, Acemetacin, Actarit, Aclofenac, Aloxipirin, Amfenac, Aminophenazone, Antraphenine, Azapropazone, Benorilate, Benzydamine, Butibufen, Chlorthenoxacine, Choline Salicylate, Clometacin, acin, diclofenac, emorfazone, epirizole, etodolac, feclobuzone, felbinac, fenbufen, fenclofenac, glafenine, indomethacin, ketoprofen, lactylphenetidine, metamizole, metiazinic acid, mofebutazone, mofezolac, nabumetone, nifenazone, niflumic acid, oxametacin, pipebuzone, propyphenazone, proquazone, protozinic acid, salicylamide, sulindac, tiaramide, tinoridine, and zomepirac. Examples of suitable enolic acid (oxicam) derivative NSAIDs include, but are not limited to, droxicam, isoxicam, lornoxicam, meloxicam, piroxicam, and tenoxicam. Examples of suitable fenamic acid derivative NSAIDs include, but are not limited to, flufenamic acid, mefenamic acid, meclofenamic acid, and tolfenamic acid. Examples of suitable selective COX-2 inhibitors include, but are not limited to, celecoxib, etoricoxib, firocoxib, lumiracoxib, meloxicam, parecoxib, rofecoxib, and valdecoxib.

[0111] A particular NSAID for use in the formulations described herein is a coxib. As used herein, the term "coxib" refers to a selective cyclooxygenase-2 (COX-2) inhibitor or "COX-2 inhibitor."

[0112] In embodiments, the coxib may be any coxib known in the art, such as, but not limited to, mavacoxib, rofecoxib, celecoxib, cimicoxib, deracoxib, firocoxib, robenacoxib, valdecoxib, parecoxib, etoricoxib, or any combination thereof.

[0113] In some embodiments, the coxib is mavacoxib (ATCvet code QM01AH92), a nonsteroidal anti-inflammatory drug (NSAID) of the coxib class. Mavacoxib-4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide is used in the treatment of chronic pain and inflammation associated with osteoarthritis in dogs.

[0114] In some embodiments, the coxib is a "chromencoxib," a member of the structural class of COX-2 selective inhibitors of formula (I): TIFF2025186498000029.tif44128 or an isomer or a pharmaceutically acceptable salt thereof, or a compound of formula (II): TIFF2025186498000030.tif32128 or an isomer or a pharmaceutically acceptable salt thereof.

[0115] Particular isomers or pharmaceutically acceptable salts of the compounds of Formula (I) and (II) for use in the compositions of the present invention include tris(hydroxymethyl)aminomethane (±)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate, (±)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, tris(hydroxymethyl)aminomethane (R)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate, (R)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, tris(hydroxymethyl)aminomethane (S)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate, and (S)-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid.

[0116] The compositions of the present invention may include analgesics other than anti-inflammatory agents, such as buprenorphine, opiates including morphine, or local anesthetics such as lidocaine, mepivacaine, prilocaine, procaine, pentazocine, benzocaine, syntocaine, tetracaine, zingicaine, articaine, bupivacaine, butanilicaine, chloroprocaine, or, for example, polidocanol.

[0117] Additionally, the compositions may also include anti-inflammatory agents that may have a secondary effect as an analgesic other than those listed above, which may have a partial anti-inflammatory effect, such as corticosteroids or hormones, particularly cortisone and corticoids, e.g., glucocorticoids (e.g., cortisone, cloprednol, prednisone, prednisolone, methylprednisolone, deflazacort, fluocortolone, triamcinolone, dexamethasone, betamethasone) and mineralocorticoids (e.g., aldosterone, desoxycorticosterone, fludrocortisone).

[0118] In one embodiment, the composition comprises a corticosteroid selected from amcinonide, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clocortolone pivalate, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, diflorasone acetate, fluocinonide, fluocinolone acetonide, flandrenolide, fluticasone propionate, halcinonide, halobetasol propionate, hydrocortisone, hydrocortisone butyrate, hydrocortisone valerate, mometasone furoate, prednisolone acetate, triamcinolone acetonide, and combinations thereof.

[0119] The pharmaceutically active compounds of the present disclosure may be formulated into compositions in their natural or salt form. Pharmaceutically acceptable non-toxic salts include base addition salts (formed with free carboxyl or other anionic groups) that can be derived from inorganic bases such as sodium, potassium, ammonium, calcium, or ferric hydroxide, and organic bases such as isopropylamine, trimethylamine, 2-ethylamino-ethanol, histidine, procaine, and the like. Such salts may also be formed as acid addition salts with any free cationic group, typically formed with inorganic acids such as hydrochloric acid, sulfuric acid, or phosphoric acid, or organic acids such as acetic acid, citric acid, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, tartaric acid, mandelic acid, and the like. Salts of the present disclosure include amine salts formed by protonation of an amino group with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like. Salts of the present disclosure may also include amine salts formed by protonation of an amino group with suitable organic acids such as p-toluenesulfonic acid, acetic acid, and the like.

[0120] Additional excipients contemplated for use in the practice of the present disclosure are available to those skilled in the art, and can be found, for example, in the United States Pharmacopeia, Volume XXII and the National Formulary, Volume XVII, US Pharmacopeia Convention, Inc., Rockville, Md. (1989), the relevant contents of which are incorporated herein by reference. In addition, polymorphs, hydrates, and solvates of compounds are included in the present disclosure. It should be noted that hydrate molecules provide moisture to pharmaceutical compositions, but other water sources are not expected to be included.

[0121] This composition can be conveniently presented in dosage unit form and can be prepared by any method well known in the pharmaceutical field.All methods include the step of associating the active ingredient with the carrier that constitutes one or more accessory ingredients.Generally, pharmaceutical compositions are prepared by uniformly and essentially associating the active ingredient with the carrier that is suitable for intended route, specifically via injection, for administration.In pharmaceutical compositions, the active compound is contained in an amount sufficient to produce the desired effect in disease process or condition.

[0122] For the compositions of the present invention, the pharmaceutically active agent only needs to be administered by a single subcutaneous injection (allowing the use of higher doses), which is once during the entire course of treatment to clinically resolve the disease or disorder.However, the pharmaceutically active agent may also be administered by a series of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more subcutaneous injections over the period required to clinically resolve the disease or disorder.In this regard, "clinical resolution" can be measured by referring to the presence of clinically significant measurable activity in the bloodstream of animals (at least about 1.0 ng / ml) for the required time, for example, at least about 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours or more. However, it will be understood that the specific dosage level and frequency of dosage for any particular patient may vary and will depend on a variety of factors including the activity of the particular compound employed, the metabolic stability and length of action of the compound, age, body weight, general health, sex, daily diet, mode and frequency of administration, excretion rate, drug combination, and the severity of the particular condition.

[0123] Similarly, the formulations of the present disclosure are expected to achieve a disease or disorder cure rate of at least 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% upon a single injection. Patients administered the formulation are expected to exhibit at least 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% cure within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days of administration.

[0124] As used herein, "cure rate" refers to clinical effectiveness in eliminating a disease or disorder, such as infection, pain, or inflammation. In embodiments, the disease or disorder is eliminated with greater than about 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or up to 100% effectiveness within a period of less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days after a single administration.

[0125] In embodiments, suitable active agent concentration levels are generally from about 0.01 to about 500.0 mg / ml, or from about 0.1 to about 250.0 mg / ml, such as about 0.25 to 500.0 mg / ml, 1.0 to 400.0 mg / ml, 5.0 to 250.0 mg / ml, 1.0 to 100.0 mg / ml, 5.0 to 150.0 mg / ml, 10.0 to 250.0 mg / ml, 10.0 to 200.0 mg / ml, 15.0 to 250.0 mg / ml, or 15.0 to 200.0 mg / ml (including all intermediate dosages), all in single injection form.

[0126] In embodiments, suitable active agent concentration levels are generally from about 0.1 to about 30.0 mg / ml or from about 0.1 to about 25.0 mg / ml, such as about 0.25 to 30.0 mg / ml, 1.0 to 25.0 mg / ml, 1.0 to 10.0 mg / ml, 5.0 to 15.0 mg / ml, 10.0 to 25.0 mg / ml, 10.0 to 20.0 mg / ml, 15.0 to 25.0 mg / ml, or 15.0 to 20.0 mg / ml (including all intermediate dosages) for all single injection forms.

[0127] In embodiments, upon administration of a composition of the invention to a subject, at least about 10, 50, 100, 500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 15,000, 20,000, 25,000, 30,000, 35,000, 40,000, 45,000, or 50,000 ng / ml of the pharmaceutically active agent is present in the bloodstream of the subject for at least about 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours or more upon administration to a mammal. In various embodiments, upon administration of a composition of the present invention to a subject, at least about 10, 50, 100, 500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 15,000, 20,000, 25,000, 30,000, 35,000, 40,000, 45,000, or 50,000 ng / ml of the pharmaceutically active agent is present in the bloodstream of the subject for at least about 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours or more upon administration of a single dose to a mammalian subject.

[0128] The formulations of the present invention are particularly useful in mammals, particularly companion animals, and especially cats and dogs.

[0129] The following examples are provided to further illustrate embodiments of the present invention, but are not intended to limit the scope of the invention. While they are examples that are typical of those that might be used, other procedures, methodologies, or techniques known to those skilled in the art may alternatively be used. [Example]

[0130] Example I formulation The following marbofloxacin-containing formulations were prepared for subcutaneous injection into dogs to treat urinary tract infections (UTIs).

[0131] Table XXII: Formulations TIFF2025186498000031.tif83128

[0132] Example II Pharmacokinetics of the formulations of the present invention The formulation in Table XXII (Formulation 22) was administered to dogs by subcutaneous injection at a dosage level of approximately 20 mg / kg. As shown in Figure 1 (dotted line), blood concentrations of marbofloxacin maintained clinically significant levels (greater than approximately 1 ng / ml) for more than 160 hours after administration of this composition.

[0133] Example III Pharmacokinetics of the formulations of the present invention The formulation in Table XXII (Formulation 23) was administered to dogs by subcutaneous injection at a dosage level of approximately 20 mg / kg. As shown in Figure 1 (solid line), after administration of this composition, blood concentrations of marbofloxacin maintained clinically significant levels (greater than approximately 1 ng / ml) for more than 160 hours.

[0134] Example IV formulation The following florfenicol-containing formulations were prepared:

[0135] Table XXIII: Formulations TIFF2025186498000032.tif59128

[0136] Example V In vitro kinetics of the formulations of the present invention The formulations in Table XXIII were analyzed for in vitro release rate.

[0137] The formulations were compounded. The containers were filled with 600 mL of phosphate buffer and allowed to equilibrate. Using a 1 mL syringe with a 6-inch stainless steel needle, 1.0 mL of the formulation was introduced into each container to form a depot. Approximately 2 mL of medium was withdrawn from each container at time intervals (T0 (3 hours), T1 (24 hours), T2 (48 hours), T3 (72 hours), T5 (120 hours), and infinity), and UV absorbance was measured in a spectrophotometer to determine the percent active agent released from the depot.

[0138] The results are shown in Figure 2. For both formulations 59 and 60, 100% release was demonstrated over 150 hours.

[0139] Example VI Pharmacokinetics of the formulations of the present invention Formulation 37 from Table VIII containing marbofloxacin was prepared for subcutaneous injection in dogs to treat UTI. Dogs were dosed by subcutaneous injection with Formulation 37 at dosage levels of about 15 mg / kg and about 20 mg / kg. Figure 3 shows the PK curves compared to Zeniquin®. The potential bladder concentration of marbofloxacin was determined for Formulation 37 administered at a dosage level of about 20 mg / kg, demonstrating that a higher amount of marbofloxacin is released into the bladder over a longer period of time compared to Zeniquin®.

[0140] Example VII Pharmacokinetics of the formulations of the present invention The formulations in Table XX containing terbinafine were prepared for subcutaneous injection into dogs. The formulations were administered to the dogs by subcutaneous injection at a dosage level of approximately 30 mg / kg. Figure 4 shows the concentrations of terbinafine in plasma and tissues (by skin punch analysis) at the time of administration.

[0141] Although the scope of the present disclosure has been described with reference to the above examples, it will be understood that modifications and variations are encompassed within the spirit and scope of the disclosure. Accordingly, the disclosure is limited only by the appended claims.

Claims

1. A pharmaceutically acceptable composition for injection, comprising: a) a pharmaceutically active agent; and b) about 5.0 to 40.0 w / w% polar lipids; c) about 5.0 to 70.0 w / w % of a triglyceride carrier; A composition comprising:

2. 10. The composition of claim 1, further comprising sucrose acetate isobutyrate.

3. 10. The composition of claim 1, wherein the sucrose acetate isobutyrate is present at a maximum of about 25.0-70.0 w / w%.

4. A pharmaceutically acceptable composition for injection, comprising: a) a pharmaceutically active agent; and b) about 5.0-70.0 w / w% sucrose acetate isobutyrate; c) about 30.0 to 60.0 w / w % of a water-miscible solvent; A composition comprising:

5. A pharmaceutically acceptable composition for injection, comprising: a) a pharmaceutically active agent; and b) about 5.0-70.0 w / w% sucrose acetate isobutyrate; c) about 5.0 to 70.0 w / w % of a triglyceride carrier; A composition comprising:

6. 6. The composition of any one of claims 1 to 5, wherein the pharmaceutically active agent is selected from the group consisting of antibacterial agents, anti-inflammatory agents, anthelmintics, analgesics, antiemetics, steroids, sedatives, stimulants, antidepressants, opioids, opiates, nonsteroidal anti-inflammatory drugs (NSAIDs), cannabinoids, and anesthetics.

7. The composition of claim 6 , wherein the antimicrobial agent is an antibiotic, an antiviral, or an antifungal agent.

8. 8. The composition of claim 7, wherein the antibiotic agent is a macrolide antibiotic.

9. 9. The composition of claim 8, wherein the macrolide antibiotic is doximectin, avimectin, roxithromycin, clarithromycin, tulathromycin, gamithromycin, dirithromycin, fidaxomicin, megalomycin, erythromycin, azithromycin, or a combination thereof.

10. The composition of claim 7 , wherein the antifungal agent is a triazole antifungal compound.

11. 8. The composition of claim 7, wherein the antifungal agent is terbinafine.

12. 7. The composition of claim 6, wherein the anti-inflammatory agent is a corticosteroid or a nonsteroidal anti-inflammatory drug.

13. 8. The composition of claim 7, wherein the antibiotic agent is a fluoroquinolone.

14. 14. The composition of claim 13, wherein the fluoroquinolone is benofloxacin, binfloxacin, cinoxacin, ciprofloxacin, danofloxacin, difloxacin, enoxacin, enrofloxacin, fleroxacin, ibafloxacin, levofloxacin, lomefloxacin, marbofloxacin, moxifloxacin, norfloxacin, ofloxacin, orbifloxacin, pefloxacin, pipemidic acid, temafloxacin, tosufloxacin, sarafloxacin, sparfloxacin, or a combination thereof.

15. The composition of any one of claims 1 to 5, further comprising an excipient.

16. 16. The composition of claim 15, wherein the excipient is benzyl alcohol, ethanol, or a combination thereof.

17. The composition of any one of claims 1 to 5, further comprising polyoxyl castor oil.

18. The composition according to any one of claims 1 to 5, further comprising hydrogenated phosphatidylcholine derived from soybean lecithin.

19. The composition of any one of claims 1 to 5, further comprising an antioxidant.

20. The composition of any one of claims 1 to 5, wherein the pharmaceutically active agent is present in an amount of 1.0 to 25.0 w / w%.

21. The composition according to any one of claims 1 to 5, further comprising cholesterol.

22. 3. The composition of claim 1, wherein the polar lipid is selected from the group consisting of glycerol monooleate, glycerol monostearate, glycerol monolinoleate, glycerol monocaprylate, glycerol monocaprate, glycerol monolaurate, glycerol monomyristate, glycerol monopalmitate, glycerol monomyristoleate, glycerol monopalmitoleate, glycerol monosapienate, and any combination thereof.

23. 23. The composition of claim 22, wherein the polar lipid is glycerol monooleate, glycerol monostearate, or a combination thereof.

24. 3. The composition of claim 1, wherein the polar lipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, glycerophosphocholine, phosphatidic acid, phospholipids derived from egg, soybean, rapeseed, canola, or sunflower oil, synthetic or naturally occurring phospholipids, hydrogenated or unsaturated phospholipids, PEGylated phospholipids, and any combination thereof.

25. 5. The composition of claim 4, wherein the water-miscible solvent is a triglyceride, triethyl, or triester.

26. 26. The composition of claim 25, wherein the triglyceride is triacetin.

27. 26. The composition of claim 25, wherein the triethyl is triethyl citrate.

28. 28. The composition of any one of claims 1-27, wherein at least about 100, 500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 15,000, or 20,000 ng / ml of the pharmaceutically active agent, upon administration to a mammal, is present in the bloodstream of a subject for at least about 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or more.

29. 29. A method of treating a disease or disorder in a subject, comprising administering to the subject an effective amount of a composition according to any one of claims 1 to 28.

30. 30. The method of claim 29, wherein the subject is a mammal.

31. 31. The method of claim 30, wherein the subject is a dog.

32. 30. The method of claim 29, wherein the subject is a cat.

33. 30. The method of claim 29, wherein the disease or disorder is an infectious disease.

34. 30. The method of claim 29, wherein the disease or disorder is pain or inflammation.

35. 30. The method of claim 29, wherein the disease or disorder is an inflammatory disease.

36. 30. The method of claim 29, wherein at least about 100, 500, 1,000, 2,000, 3,000, 4,000, 5,000, 10,000, 15,000, or 20,000 ng / ml of the pharmaceutically active agent, upon administration to a mammal, is present in the bloodstream of the subject for at least about 48, 60, 72, 84, 96, 108, 120, 132, 144, 156, 168 hours, or more.

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