SUSTAINED-RELEASE INJECTABLE ANTIBIOTIC FORMULATION.

Abstract

This description provides injectable antibiotic compositions for veterinary use. The compositions are characterized by forming a gel at physiological animal temperature, and this gel exhibits a stable and repeatable antibiotic release profile. The compositions comprise a high drug load in poloxamer solutions with the addition of a cosolvent, and preferably with the addition of a cellulose derivative at least partially soluble in organic solvents. Methods for treating veterinary infections are also provided.

Description

SUSTAINED-RELEASE INJECTABLE ANTIBIOTIC FORMULATION FIELD AND BACKGROUND OF THE INVENTION The present invention relates to a sustained-release formulation and, more specifically, to a sustained-release formulation that is suitable for poorly soluble antibiotics, for veterinary use. Oral administration of medications, considered the preferred route in human medicine, is, for obvious reasons, often impractical in veterinary medicine, especially when dealing with large domestic animals. Similarly, administering medications that require multiple doses is often difficult or even impractical. Sustained-release drug administration following parenteral administration is generally preferable to oral administration in veterinary medicine and allows for the treatment of large domestic animals (such as cattle), as well as pets and other animals. Reducing the frequency of dosing is known to improve patient safety, decrease the incidence of injection-site complications, and enhance adherence to medication protocols. Sustained-release formulations mitigate the bolus effect at the time of injection and thus have a beneficial influence on drug side effects. For certain uses and prophylactic treatments, single-dose or infrequent administration has become standard practice.For example, monthly administration is available for most heartworm preventive medications, such as Heartguard®, Sentinel®, and Interceptor. Controlled-release parenteral formulations may be in the form of liquids, in situ forming solids, and solids [Medlicott et al., Advanced Drug Delivery Reviews 2004, 56:1345-1365]. Top-selling parenteral controlled-release products include Posilac® milk enhancer (a liquid suspension), Micotil® antibiotic (a liquid solution), Nuflor® antibiotic (a liquid solution), and Revalor® growth enhancer (a solid implant). In recent years, studies have been published involving the use of poloxamers in sustained-release formulations. Poloxamers are nonionic triblock copolymers consisting of relatively hydrophilic poly(ethylene oxide) (PEO) and relatively hydrophobic poly(propylene oxide) (PPO) blocks arranged in a three-block ABA structure: PEO-PPO-PEO. Aqueous poloxamer gels are described, for example, in U.S. Patent No. 3,740,421. Poloxamers are used as emulsifying agents for 1 MA / t / ZUZI / UO1110 intravenous fat emulsions, as solubilizing agents to maintain clarity in elixirs and syrups, and as wetting agents for antibacterials. They can also be used in ointment or suppository bases and as binders or tablet coatings [Sweetman (Ed.), Martindale: The Complete Drug Reference, London: Pharmaceutical Press]. The hydrophobic-lipophilic (HLB) equilibrium of a poloxamer can be characterized by the number of ethylene oxide and propylene oxide units in the copolymer. Due to their amphiphilic nature, poloxamer copolymers exhibit surfactant properties, including the ability to interact with hydrophobic surfaces and biological membranes. In aqueous solutions at concentrations above the critical micelle concentration (CMC), these copolymers self-assemble into micelles. Poloxamer micelles typically range from approximately 10 nm to 100 nm.The core of micelles consists of hydrophobic PPO blocks separated from the aqueous exterior by a hydrated shell of PEO blocks. The core is capable of incorporating various therapeutic or diagnostic reagents [Bartrakova & Kabanov, Journal of Controlled Release 2008, 130:98-106]. Poloxamers are generally designated with the letter P (for “poloxamer”) followed by three digits. The first two digits multiplied by 100 give the approximate molecular mass of the PPO core, and the last digit multiplied by 10 gives the percentage of PEO. For example, P407 is a poloxamer with a PPO molecular mass of 4000 Da and a PEO content of 70%. According to an additional designation system (used, for example, in association with the Pluronic® and Lutrol® trademarks), the copolymer is designated with a letter that defines its physical form at room temperature, L for liquid, P for paste, F for flakes (solid), followed by two or three digits.The first digit (or the first two digits of a three-digit number) multiplied by 300 indicates the approximate molecular weight of the hydrophobic block, and the last digit multiplied by 10 gives the percentage of polyethylene oxide (PEO). For example, L61 is a liquid poloxamer with a PPO molecular weight of 1800 Da and a PEO content of 10%, which would be designated as P181 according to the designation system described above. U.S. Patent Application No. 20090214685 describes a thermoplastic pharmaceutical composition comprising botulinum toxin and a biocompatible poloxamer. The pharmaceutical composition can be administered as a liquid and gels after administration into a sustained-release drug delivery system from which the botulinum toxin is released over a period of several days. U.S. Patent No. 7,008,628 describes a pharmaceutical composition comprising a linear block copolymer 2 ivia / t / zuz i / uo 111 or such as a poloxamer, modified at the ends by a bioadhesive polymer such as polyacrylic acid. The polymer is capable of aggregation in response to an increase in temperature.7,250,177 describes gel-forming poloxamers modified with a crosslinkable group such as acrylate, which can be crosslinked to form a thermosensitive, lipophilic gel useful for drug delivery or tissue coating. Additionally, the prior art includes U.S. Patent No. 5,035,891 and U.S. Patent No. 2004 / 0247672. International patent application WO 2012131678, from some of the inventors, relates to sustained-release formulations comprising poloxamers in the form of a suspension or other form of undissolved active agent, such that the described formulations allow the use of higher amounts of the active agent within a single administration, while maintaining acceptable volumes of the administered dose. Florfenicol is a commonly used broad-spectrum antibiotic, employed for the treatment of porcine respiratory disease (SRD), among other uses. Veterinary approved florfenicol products include injectable formulations typically containing 300 mg / ml. One such approved injectable formulation for veterinary use is dissolved in the organic solvent N-methylpyrrolidone (NMP). Several formulations for sustained release of florfenicol have been previously described, including Chinese patent application CN103202802, which addresses sustained-release formulations incorporating poloxamers and polysaccharides. The description refers to various polysaccharides and varying loadings of the active agent florfenicol in these formulations. A pharmacokinetic study of an in situ forming gel for controlled delivery of florfenicol in pigs was described in Geng et al. [J. vet. Pharmacol. Therap.38, 596-600], and demonstrated the increase in the half-life of florfenicol in animal plasma after administration of 20% loading gels based on poloxamers and cellulose-based polysaccharide. There is a need in the art for injectable antibiotic formulations that can release drugs in a controlled manner over extended periods. There is an additional need for formulations that successfully maintain minimum inhibitory concentrations for a variety of veterinary pathogens. There is an even greater need for antibiotic formulations with a high drug load, for example, above 25% to approximately 50%, that can still be injected using standard syringes. MA / / UO1110 SUMMARY OF THE INVENTION The stability of a sustained-release formulation and the effect that this stability has on the release profile of the active agent in the target organism over time is a crucial factor, which in many cases has proven to be a delicate balance between the different components of the formulation. Surprisingly, it was found that using a combination of a poloxamer, an organic solvent, and optionally a cellulose derivative that is at least partially soluble in organic solvents, in a sustained-release formulation of an antimicrobial agent results in a stable injectable dispersion formulation with a consistent and reproducible release profile, both in vitro and in vivo.Thus, in one aspect, the present invention provides a composition comprising a sparingly soluble antimicrobial agent, at least one poloxamer, an organic solvent, and a cellulose derivative that is at least partially soluble in organic solvents, and an aqueous medium, wherein said composition is injectable. Furthermore, it was surprisingly found that with a very high loading of the active material, for example, above 35% or 40% by weight, the combination of poloxamer and organic solvent in water can be sufficient to provide an injectable formulation having a consistent and reproducible release profile. Therefore, in another aspect, the present invention provides a composition comprising an antimicrobial agent, at least one poloxamer, an organic solvent, and an aqueous medium, wherein the concentration of said antimicrobial is greater than 35% by weight up to and above 40% by weight, and wherein said composition is injectable. Therefore, the present description provides a pharmaceutical composition comprising a biologically active agent, poloxamer, an aqueous carrier, and an organic cosolvent, wherein said composition is an injectable composition at room temperature, provided that where said concentration of active agent is less than 35% by weight, the composition further comprises a cellulose-based material that is at least partially soluble in organic solvents. In one embodiment, when the drug concentration is greater than 35% by weight, for example, from 35% by weight up to 50 or 55% by weight, the cellulose-based material is included. In other embodiments, when the drug concentration is greater than 35% by weight, for example, from 35% by weight up to 50 or 55% by weight, the composition is devoid of cellulose-based material, for example, between 40% and 50% by weight, or between 42.5% by weight and 50% by weight, or between 45% by weight and 50% by weight. A pharmaceutical composition comprising a biologically active agent, poloxamer, an aqueous carrier, an organic cosolvent, and a cellulose-based material that is at least partially soluble in organic solvents is also provided herein, wherein said composition is an injectable composition at room temperature and wherein the concentration of said biologically active agent is greater than 10% by weight and up to 35% by weight. The biologically active agent may be selected from florfenicol, lincomycin, tylosin, metronidazole, tilmicosin, spiramycin, erythromycin, tulathromycin, tiamulin, ampicillin, amoxicillin, clavulanic acid, penicillin, streptomycin, trimethoprim, sulfonamide, sulfamethoxazole, pleuromotulin, avilosin, tilvasoline, doxycycline, and oxytetracycline. Preferably, the biologically active agent is florfenicol.In addition, florfenicol may preferably be present in the composition in a loading of from approximately 25% to approximately 50% by weight. The organic cosolvent may be present in an amount of from approximately 5% to approximately 15% by weight. The cellulose-based material that is at least partially soluble in organic solvents may be hydroxypropylcellulose. The organic solvent may be selected from the group consisting of N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), PEG 400, propylene glycol, and ethanol. Preferably, the organic solvent is N-methylpyrrolidone. In some preferred embodiments, the pharmaceutical composition comprises the organic solvent being N-methylpyrrolidone, the cellulose-based material that is at least partially soluble in organic solvents being hydroxypropylcellulose, and the biologically active agent being florfenicol at a concentration of from 25% to 50% by weight.In some other preferred embodiments, the pharmaceutical composition comprises the organic solvent N-methylpyrrolidone and florfenicol in a concentration of between 35% and 50% by weight. This description also provides a pharmaceutical composition as defined herein for use in the treatment of a veterinary infection in a non-human animal by administering to that animal a pharmacologically effective dose of an antibiotic in that composition. Preferably, the composition is administered once to that non-human animal during the course of treatment. Furthermore, the administration preferably comprises intramuscular or subcutaneous injection. In some embodiments, the infection may be caused by a porcine pathogen. BRIEF DESCRIPTION OF THE FIGURES Figure 1 schematically represents the florfenicol release profiles of selected compositions. IVIA / t / ZUZ I / UO III or Figure 2 schematically represents the florfenicol release profiles as an effect of the added organic solvent. Figure 3 represents the concentrations of florfenicol in blood plasma after a single administration of a composition according to the invention, versus two administrations of a commercial product. Figure 4 represents the concentrations of florfenicol in blood plasma after single administration of other compositions according to the invention, versus two administrations of a commercial product. DETAILED DESCRIPTION OF THE INVENTION As described above, the sustained-release composition of the present invention comprises a biologically active agent. In some embodiments, this biological agent is preferably an antimicrobial agent, which exhibits poor solubility in aqueous media. Poor solubility can be understood as defined, for example, in the current United States Pharmacopeia, but can be better understood in the context of the formulation, as explained in more detail below. In a related embodiment, the antimicrobial agent used in the sustained-release composition of the invention is selected from the group consisting of florfenicol, lincomycin, tylosin, metronidazole, tilmicosin, spiramycin, erythromycin, tulathromycin, tiamulin, ampicillin, amoxicillin, clavulanic acid, penicillin, streptomycin, trimethoprim, sulfonamide, sulfamethoxazole, pleuromutilin, avilosin, tilvalosin, doxycycline, and oxytetracycline.In some current preferred formulations, the antimicrobial agent is florfenicol. According to the principles of the present invention, the loading (i.e., the amount of biologically active agent or antimicrobial agent introduced into the injectable dosage form) is high, allowing for prolonged and controlled release over several days. The high loading of the injectable composition of the invention is promoted, among other factors, by having a formulation comprising a biologically active agent that may be in an insoluble form, thereby forming a dispersion in the aqueous medium. According to the principles of the invention, the antibacterial agent dispersed in the formulation is, to some extent, in solid form. Preferably, more than 90% of the drug is in insoluble form, but the drug may be up to 99.999% insoluble. The insoluble form of the drug includes ML / t / ZUZ I / UO1110 generally basic compounds or salts that particularly have low solubility in water, even if a more soluble salt is known. Depending on the solid-state properties of the active agent, the loading may vary. When the drug readily interacts with the aqueous medium or with poloxamer or other surfactants, it may form a paste, i.e., a composition that is not easily absorbed by syringe (non-injectable) and / or is not injectable, at high loading values. In these cases, such drugs can be used at relatively low loading values, for example, between 12 and 20% by weight, but a high drug loading is generally preferable. Therefore, in some formulations, the loading is at least approximately 20% by weight of the injectable composition. In some additional formulations, the loading is between approximately 25% and approximately 30% by weight of the injectable composition.In some additional formulations, the loading is between approximately 30 and approximately 45% by weight of the injectable composition. In some additional formulations, the loading is between approximately 35 and approximately 50% by weight of the injectable composition. In some formulations, the loading is between approximately 30 and approximately 35% by weight of the injectable composition. In some specific formulations, when the biologically active agent is florfenicol, the florfenicol loading used for specific applications may be between 25 and 50% by weight, such as between 28 and 32% by weight, or between 36 and 42% by weight, or between 44% and 48% by weight. The biologically active agent forms a dispersion in the aqueous medium with the cosolvent. It is understood that the biologically active agent must be in solid form, for example, a powder. The powder may be in the form of aggregates, granules, or coated powder, but preferably the powder is a pure pharmaceutical powder with a defined particle size distribution. In some preferred embodiments, the powder has a particle size of less than approximately 90 microns, with a higher preference for less than approximately 50 microns. Sometimes it may also be advantageous to use smaller particles or even micronized powder. While not linked to any specific theory, it is believed that smaller particle size powders may increase the maximum plasma concentration achievable from an in vivo formulation compared to regular drug powder, even if the difference would be small or negligible in vitro.Micronized powder or powder of reduced particle size can be obtained directly from the powder of the biologically active substance, as commonly known in 7. MA / t / ZUZ I / UO1110 technique, for example, by high impact or high shear grinding, pressure sieving and other methods. In certain preferred embodiments, the biologically active material or antimicrobial agent is released from the in-situ formed gel of the composition of the present invention for at least 3 days. In some additional embodiments, the material is released for 2 to 3 days. In some further embodiments, the material is released for 4 to 5 days. In some embodiments, the material is released for more than 5 consecutive days from a single injectable composition of the invention. Therefore, the release can be described in terms of the duration of release rather than a specific rate. The duration of in vivo release can be detected in plasma as drug concentrations that maintain significant levels over time. In another embodiment, the duration of in vivo release can be detected in the target organ or tissue as drug concentrations that maintain significant levels over time.In particular, to the extent that the active agent is an antibiotic, the duration of release can be detected in blood plasma, and the concentrations obtained can be compared with the minimum inhibitory concentrations of antibiotics for specific pathogens. In vitro, due to the maintenance of immersion conditions, the duration of drug release can range from approximately 12 hours to approximately 3 days, for example, under the conditions described in the Examples section below. According to some of the principles of the present invention, the advantageous combination of an organic cosolvent, poloxamer in aqueous medium, and a cellulose derivative, at least partially soluble in organic solvents, results in a synergistic effect, enabling controlled and stable release of the biologically active agent for several days. The drug loading in formulations comprising such a cellulose derivative can be as low as approximately 5% or approximately 10% by weight. However, depending on the properties of the antibiotic in the solid state, the drug loading can be as high as 35%, 40%, 45%, 47.5%, or even 50% by weight.Furthermore, when the active agent is present at a concentration above 35% by weight, it has been unexpectedly discovered that relatively stable and repeatable drug release kinetics can be achieved from compositions comprising poloxamer, water, and an organic cosolvent as defined herein. While the presence of the cellulose derivative, which is at least partially soluble in organic solvents, proved beneficial even with a high drug loading, the release profiles without the excipient were surprisingly low. ML / t / ZUZ I / UO1110 constants sufficient to meet the requirements of the current United States Pharmacopeia for the variability of drug release of controlled-release dosage forms. However, when the drug loading is less than 35% by weight, it is preferable that the composition comprise the cellulose derivative as described below. According to some embodiments, the poloxamer as described above is selected from the group consisting of poloxamer 407, poloxamer 188, poloxamer 237, and poloxamer 338, and combinations thereof. In some currently preferred embodiments, the poloxamer as described above is poloxamer 407. The presence of poloxamer allows the composition to gel at physiological temperature. Therefore, poloxamer must be present at an adequate concentration in the injectable composition to allow the formation of a stable gel, particularly in the presence of a large amount of undissolved active agent powder. Consequently, the poloxamer concentration, as described above, is greater than 8 percent by weight of the total formulation weight. Depending on the nature of the drug, for example, its particle size, solubility, affinity for poloxamer, and drug loading, the amount of poloxamer can be as low as 7 to 9 percent by weight and as high as 16 to 20 percent by weight. The synergistic effect of some embodiments of the present invention is achieved by combining said poloxamer with a unique combination of an organic cosolvent and a cellulose derivative that is at least partially soluble in organic solvents. The chemical compatibility between the cellulose derivative and the organic solvent, and the ratio between these two components, together with the poloxamer concentration, determine the release profile of the biologically active agent. While not linked to any specific mechanism or theory, it is postulated that although the organic solvent may increase the solubility of the biologically active agent, it also slows the release rate of said active agent from the gel composition under physiological conditions, due to its effect on the gel itself.It is further postulated that, at least for some drugs, the addition of the cellulose derivative as described above may be responsible for the increased release rate of the biologically active agent, and that the organic solvent contributes to reduced variability in the overall release profile over time. Although the molecular weight of the cellulose derivative to be used can be selected according to the required rheological properties and the intended release profile, according to some embodiments of the present invention, the concentration ratio between said cellulose derivative and said organic solvent can be 9 ivia / t / zuz i / uo 111 or generally from approximately 1:6 to approximately 1:20.When the drug is present in a particularly high load, for example, above 35% by weight and above 40% by weight, the concentration ratio between said cellulose derivative and said organic solvent may be from approximately 1:10 to approximately 1:100. A cellulose derivative that is at least partially soluble in organic solvents is generally one that dissolves to an appreciable extent in common pharmaceutical organic solvents, such as ethanol. Preferably, the suitable derivative forms a clear solution upon dissolution of, for example, 1 gram of the derivative in 100 ml of 96% ethanol at room temperature. One suitable cellulose derivative that is at least partially soluble in organic solvents is hydroxypropylcellulose. Hydroxypropylcellulose also possesses the additional useful property of being highly soluble in aqueous solutions at room temperature and becoming less soluble with increasing temperature.Without being linked to any theory or mechanism of action, it is postulated that after injection of the composition of the invention into the animal, the solubility of hydroxypropylcellulose decreases, which in turn contributes to the stability of the gel formed, resulting in better control over the release of the biologically active agent. In some related formulations, the concentration of the cellulose derivative, as described above, ranges from approximately 0.5% to approximately 1.5% by weight of the total weight of the injectable composition. In some additional formulations, the concentration of the cellulose derivative ranges from approximately 0.5% to approximately 1% by weight. When the drug is present in a very high loading, for example, above 40%, the concentration of the cellulose derivative may range from approximately 0.05% to approximately 0.7% by weight. In some embodiments, the organic solvent as described above is selected from the group consisting of N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), PEG 400, propylene glycol, and ethanol. In some currently preferred embodiments, the organic solvent is NMP. In some related embodiments, the concentration of the organic solvent, as described above, ranges from approximately 1.5% to approximately 20% by weight of the total weight of the injectable composition. In some additional embodiments, the concentration of the organic solvent ranges from approximately 3% to approximately 15% by weight of the total weight of the injectable composition. ML / t / ZUZ I / UO1110 weight. In some additional embodiments, the concentration of organic solvent is between approximately 8 to approximately 12% by weight. In other related embodiments, at least one poloxamer, an organic solvent, and the cellulose derivative are dissolved in an aqueous medium. The aqueous medium is generally water, which optionally comprises other dissolved additives, such as salts and / or buffers. The amount of aqueous medium in the preparation is generally the remainder of the 100% composition after subtracting the respective percentages of the biologically active agent, at least one poloxamer, the cellulose derivative, the cosolvent, and other excipients, if used. The salts may include sodium chloride, calcium chloride, or magnesium chloride, and the buffers may include mono-, di-, or tribasic salts of alkali metals and phosphates. While the synergistic effect that may be present for the cosolvent, the cellulose derivative that is at least partially soluble in organic solvents, and the poloxamer in an aqueous medium is clearly beneficial, when the drug is present at a very high loading, for example, above 35% or above 40% by weight, the effect of the cellulose derivative on stabilizing the system may become less necessary to obtain a pharmaceutically acceptable composition. This is demonstrated, for example, by the release profile showing a relative standard deviation in the concentration values ​​at each time point below 10%. This is illustrated in the examples below, such as the omission of hydroxypropylcellulose from a florfenicol formulation at a loading of 47%.5% by weight resulted in a mild burst effect with increased relative standard deviation (RSD) at early time points, but also in an acceptable release profile. According to the principles of the invention, the formulation obtained is a stable formulation that can be injected at room temperature (e.g., between 15 °C and 25 °C), or at cold temperatures (e.g., between 2 °C and 8 °C), which, when injected into the body of the animal (e.g., which has a temperature above 35 °C), transforms into a gel form, characterized by having a reproducible and well-controlled release profile of the biologically active agent incorporated therein. In another aspect, the present invention provides a method for preparing sustained-release injectable formulations comprising an antimicrobial agent, at least one poloxamer, an organic solvent, and a cellulose derivative that is at least partially soluble in organic solvents, in an aqueous medium, having the steps of: 1) mixing water and the organic solvent (known as the cosolvent) and preferably cooling the resulting mixture, 2) adding 11 ML / t / ZUZI / UO1110 consecutively or concomitantly the at least one poloxamer and said cellulose derivative in the [cold] mixture of step 1, followed by mixing until dissolved; and 3) adding the antimicrobial agent to the resulting mixture. In some embodiments, the organic solvent, as described above, is selected from the group consisting of N-methylpyrrolidone (NMP), DMSO, PEG 400, propylene glycol, and ethanol. In some currently preferred embodiments, the organic solvent is NMP. In some embodiments, the poloxamer as described above is selected from the group consisting of poloxamer 407, poloxamer 188, poloxamer 237, poloxamer 338, and combinations thereof. In some currently preferred embodiments, the poloxamer as described above is poloxamer 407. In some forms, the cellulose derivative is hydroxypropylcellulose. In some formulations, the antimicrobial agent used in step 3 is selected from the group consisting of florfenicol, lincomycin, tylosin, metronidazole, tilmicosin, spiramycin, erythromycin, tulathromycin, tiamulin, ampicillin, amoxicillin, clavulanic acid, penicillin, streptomycin, trimethopromin, sulfonamide, sulfamethoxazole, pleuromutilin, avilosin, tilvalosin, doxycycline, and oxytetracycline. In some current preferred formulations, the antimicrobial agent is florfenicol. The term biologically active agent as it appears in the present description and in the claims is interchangeable with the term antibacterial agent, drug or antibiotic. As stated in the present description and claims, the term cosolvent refers to the organic solvent that is mixed with the aqueous carrier or water in the formulation of the invention. In some embodiments, the organic solvent as described above is selected from the group consisting of N-methylpyrrolidone (NMP), DMSO, PEG 400, propylene glycol, and ethanol. In a further aspect, a method for treating veterinary infections, or the use of the compositions in treating veterinary infections, is provided by administering to a patient in need at least one injection of a sustained-release injectable composition as generally described herein, comprising, in an aqueous medium, an antimicrobial agent, at least one poloxamer, an organic solvent, and optionally a cellulose derivative that is at least partially soluble in organic solvents. Preferably, the method comprises a single administration of the 12 The formulation ML / UO1110 is used, but more than one injection may be administered depending on the need and duration of treatment. When treating a veterinary patient, it is advantageous to minimize handling, thereby reducing the animal's distress and the effort required to locate, capture, and handle the sick animal. Therefore, single-administration is preferred. Alternatively, the method comprises multiple administrations of the formulation, provided the number of administrations is less than that currently required for the specific biologically active agent. Administration may involve a single injection or multiple injections at multiple sites if a large injection volume is required. Due to the advantages of the formulations of the present invention, multiple injection sites may not be necessary, as the poorly soluble drug is present in sufficient quantity in relatively small injection volumes. Administration is generally by intramuscular injection. However, administration can also be subcutaneous, intraperitoneal, intradermal, or via specific sites such as intravulval administration for cows and sheep, intracaudal or ear administration for cattle, intramammary administration, and similar routes. Veterinary infections that can be treated according to the invention include infections caused by pathogens of pigs, cattle infections, poultry infections, pet animal infections, or zoo and wildlife animal infections. In some embodiments, the organic solvent as described above is selected from the group consisting of N-methylpyrrolidone (NMP), DMSO, PEG 400, propylene glycol, and ethanol. In some currently preferred embodiments, the organic solvent is NMP. In some embodiments, the poloxamer as described above is selected from the group consisting of poloxamer 407, poloxamer 188, poloxamer 237, poloxamer 338, and combinations thereof. In some currently preferred embodiments, the poloxamer as described above is poloxamer 407. In some embodiments, the cellulose derivative is hydroxypropylcellulose.In some formulations, the antimicrobial agent is selected from the group consisting of florfenicol, lincomycin, tylosin, metronidazole, tilmicosin, spiramycin, erythromycin, tulathromycin, tiamulin, ampicillin, amoxicillin, clavulanic acid, penicillin, streptomycin, trimethoprim, sulfonamide, sulfamethoxazole, pleuromotulin, avilosin, tilvalosin, doxycycline, and oxytetracycline. In some currently preferred formulations, the antimicrobial agent is florfenicol. MA / t / ZUZI / UO1110 EXAMPLES Materials and methods Florfenicol and N-methylpyrrolidone (NMP) were purchased from Sigma-Aldrich, Israel. Poloxamers 407, 188, 338, and 237 were obtained from the local BASF representative. Amoxicillin, tylosin, Klucel® polymers (hydroxypropylcellulose), PEG-400, and propylene glycol were donated by pharmaceutical companies. Water was purified in a column and distilled before use. Sodium chloride was purchased from Merck, Israel. Unless otherwise indicated, florfenicol injectable formulations were prepared as follows: Weighed quantities of water and cosolvent were mixed at room temperature, and salts or buffers, if present in the formulation, were added and mixed in to achieve dissolution. Weighed quantities of poloxamer and cellulose derivative were cooled to 4 °C in a cold chamber; the water and cosolvent mixtures were also cooled separately. The polymers were added to the water and cosolvent mixture under the same conditions and mixed vigorously using a magnetic stirrer until a clear solution was obtained. Florfenicol powder (flakes) was then added to the resulting solution and mixed for 24 hours in a cold chamber to ensure good distribution in the preparation.Alternatively, particularly for high-load formulations, a heavy quantity of florfenicol was placed in a mortar and levigated geometrically, i.e., mixed in a mortar with comparable aliquots of the solution, until the entire heavy aliquot of the prepared solution was exhausted. Measurement of the gelling point Gelation was measured by inverting a glass tube containing 0.5–1 mL of the formulation at increasing temperatures. The temperature at which the formulation stopped flowing downwards after inversion was considered the primary gelation point. Alternatively, for preliminary testing, the temperature was raised to 40 °C and the time it took for the formulation to gel was recorded. The gel point was also measured rheometrically using an Anton Paar Rheometer Physica MCR 101, with parallel-plate spindles separated by a 200 µm gap, and a temperature sweep at a reciprocal shear rate of 100 seconds. The second derivative of the viscosity curve provided the sharpest viscosity change, which was considered the true gel point. MA / t / ZUZI / UO1110 Florfenicol determination Florfenicol was determined by HPLC using an HP1090 instrument with a UV detector that measured absorbance at 224 nm. A C-18 250x4.6 5 pm column was used, with elution at 1.2 ml / min, using a 25:75 ACN:DDW mobile phase. Florfenicol eluted under these conditions in 4–4.5 minutes. Dissolution tests To test the dissolution kinetics of florfenicol from the formulations, 5 ml syringe cylinders were cut into 2 ml segments to serve as tube-shaped holders. One end was sealed with a sheet of Parafilm®, and approximately 2 ml aliquots of the formulation at room temperature were accurately weighed into these prepared holders through a 19G needle using a suitable syringe to assess the injectability of the formulation. The top end was sealed with another sheet of Parafilm®, and the holder was placed in a preheated oven at 40 °C for at least 15 minutes to ensure gelation. The Parafilm® sheets were then carefully removed, the tube holder was placed in an immersion basket, and immediately transferred to the Caleva 6ST dissolution meter (USP 2 equipment), set to 20 rpm at 40 °C. The temperature was chosen to match and mimic the body temperature of the target animal (pig).The dissolution medium was USP phosphate buffer, pH 6.8, and a volume of 900 mL was used per test tube holder. Samples were drawn from the dissolution medium at predetermined time points, and the volume was corrected with fresh dissolution medium. At the end of the test, the test tube holders were washed in the dissolution containers and vigorously mixed to obtain the amount of material recovered to serve as a 100% reference. The percentile of maximum florfenicol concentration at each time point was reported with the standard deviation. Additionally, the dissolution of some of the florfenicol compositions was carried out using the USP 5 equipment (paddle over disc), as indicated below. Example 1 - comparative example A. To evaluate the efficiency of the formulations described in Chinese patent application CN103202802, Example 7 (30% florfenicol) from that publication was reproduced and tested under the described conditions. Since the publication contains little guidance regarding the grade of hypromellose used, two grades with apparent viscosity below 20 cP at the low concentrations tested (HPMC K4M and HPMC K15M) were tested separately. Briefly, the poloxamers were accurately weighed, cooled, and dissolved in a large portion of water. MA / t / ZUZ I / UO1110 was chilled to 4 °C, followed by the addition of hydroxypropyl methylcellulose (HPMC). The remaining excipients were obtained from stock solutions, and the remaining water content was added and thoroughly mixed. Formulation samples were prepared in total quantities of 25 grams; samples prepared using HPMC K4M are designated sample preparation 1.1, and samples prepared using HPMC K15M are designated sample preparation 1.2. To test the advantageous effect of the organic solvent according to the present invention, the same formulations were prepared as described above, this time using ca. 20 wt. of N-methylpyrrolidone as a cosolvent, of the total solvent weight (20% of the water is replaced by an organic solvent), thereby obtaining sample preparation 1.3 and sample preparation 1.4, corresponding to HPMC K4M and HPMC K15M, respectively. It was discovered that under the experimental conditions, i.e., at room temperature, the samples prepared according to 1.1 and the samples prepared according to 1.2 could not be drawn into a syringe even without a needle. This demonstrates that the formulation prepared according to the description in CN103202802 (Example 7) appeared to be unsuitable for injection under the reported conditions. To obtain the release profile and results for these unsuitable formulations, the samples were dispensed using a spatula. It should also be noted that the addition of NMP as a co-solvent increased the viscosity beyond practical limits (forming a hard gel even at 4 °C); however, the samples prepared according to 1.3 and 1.4 were tested for drug release, even though they too could not be injected. B. To produce injectable compositions, 20% loading formulations were prepared, following the trend of Example 7 and Example 6 of prior art publication CN103202802. Briefly, the florfenicol loading was reduced due to the addition of water. Sample preparation 1.5 included HPMC K15M and pure water, and sample preparation 1.6 included HPMC K15M and 20 wt% NMP as a cosolvent. Consequently, the resulting formulations from preparations 1.5 and 1.6, containing 20 wt% florfenicol, were readily injected through the tested needle and gelled under the sample preparation conditions for the dissolution test. To test the florfenicol release profile of the formulations described above despite the lack of injectable properties of the compositions prepared according to 1.1MA / / UO1110 1.4, these compositions were applied to the tubes using a spatula in a standard circular semisolid filling technique. The results are shown in Table 1 below. It can be seen in Table 1 that the addition of NMP to the HPMC-comprising composition generally accelerates the florfenicol release rate from the preparations and, occasionally, decreases variability, for example, when comparing preparations 1.1 with 1.3, 1.2 with 1.4, and 1.5 with 1.6. It can also be seen that the injectable formulation according to the prior art publication can only have a 20% florfenicol loading, which is also evidenced in another publication by the same inventors, ZX Geng, H. M. Li, J. Tian, ​​TF Liu, ZG Yu, J Vet Pharmacol Ther, Vol 38, No. 6, Dec 2015, 596-600). A higher loading could not be achieved as injectable compositions by using the formulation according to the prior art. ΜΛ / Ε / ΖυΖΊ / υΟΊ Ί Ί O Table 1 Preparation 1.1 Preparation 1.2 Preparation 1.3 Preparation 1.4 Preparation 1.5 Preparation 1.6 Time (h) mean sd mean sd mean sd mean sd mean sd mean sd 0.25 2.52 0.51 2.6 1 0.44 2.61 0.44 2.98 0.38 2.47 2.15 3.94 0.61 0.5 4.25 1.16 5.8 0 0.79 5.80 0.79 7.39 0.47 5.52 4.35 9.34 0.49 1 6.54 1.49 11.02 2.12 11.0 2 2.12 15.5 0 1.06 10.4 1 7.06 15.2 5 1.15 1.5 8.34 1.45 15.44 2.92 15.4 4 2.92 22.3 0 1.78 15.7 6 7.09 20.2 8 1.48 2 9.43 1.60 18.70 3.28 18.7 0 3.28 27.9 0 2.65 19.5 9 6.84 24.1 3 1.81 3 12.5 6 3.02 23.94 3.23 23.9 4 3.23 36.2 8 3.94 27.2 0 6.40 30.8 0 2.96 4 16.4 0 3.22 28.94 2.33 28.9 4 2.33 43.8 2 3.11 32.6 1 5.57 37.2 3 4.07 5 20.6 5.31 35.4.10 35.1 4.10 49.7 2.01 36.7 4.77 42.6 4.02 3 19 9 9 5 0 6 23.7 3 5.72 38. 59 1.59 38.5 9 1.59 55.4 2 2.43 41.7 8 6.86 48.1 7 3.10 7 27.1 2 6.67 42. 20 1.93 42.2 0 1.93 57.6 9 1.87 43.6 9 4.76 53.7 0 2.96 8 30.2 2 7.38 45. 46 1.71 45.4 6 1.71 63.6 2 5.77 46.2 7 4.46 59.2 1 5.93 24 48.6 8 9.42 72. 25 7.96 72.2 5 7.96 87.1 1 7.07 75.2 3 8.86 85.6 6 7.62 Maximum Viscosity 44.9 Pa*s 38.4 Pa*s 18.3 Pa*s 22.9 Pa*s Minimum viscosity 0.59 Pa*s 0.49 Pa*s Hard gel at 4 °C 0.18 Pa*s 0.27 Pa*s Gelling t °C 12.9 °C 12.8 °C 18.4 °C 17.1 °C Gelling range 12.3-14.4 12.3-14.8 17.5-19.9 16.2-1 MA / t / JUDGE / UO1110 Example 2 To evaluate the advantages of the florfenicol sustained-release formulation according to the principles of the present invention compared to another known gel-based sustained-release formulation described in International Patent Application WO2012131678, gels comprising 30% florfenicol by weight were produced. The effect of the cosolvent NMP, the cellulose-based material hydroxypropylcellulose, and their synergistic combination was isolated and studied. All formulations demonstrated gelation between 25°C and 35°C (individual data are given below), and the release profiles were evaluated according to the above method. The formulations are summarized in the following tables, along with their respective release profile data. Preparation 2.1 is according to an embodiment of the present invention and comprises both the hydroxypropylcellulose-based material; preparation 2.2 shows the effect of omitting the cosolvent; preparation 2.3 shows the effect of omitting hydroxypropylcellulose (Klucel® EF) and the NMP cosolvent; and preparation 2.4 is a comparative preparation according to WO2012131678, which has no cosolvent or cellulose additive. Preparations 2.5 (of an embodiment of the invention) demonstrate a lower loading (20 wt% florfenicol) and 2.6 contain 20% florfenicol and do not contain NMP compared to preparation 2.6. Comparing the results of preparations 2.1 and 2.3, it is readily apparent that the addition of NMP to the formulation according to WO 2012131678 leads to a significant decrease in drug release, with a significant reduction in variability among the results. Furthermore, the addition of hydroxypropylcellulose to the formulation according to WO 2012131678 results in a significant reduction in the release rate and relatively high variability in the release profile. According to the results, only the addition of both components (NMP and HPC) is responsible for the synergistic effect that leads to lower variability (the standard deviation of the mean relative to the mean is lower) and increases drug release compared to the purely aqueous preparations 2.2 and 2.3.Furthermore, it can be seen that the formulations having a 20% loading according to the invention produce a comparable but somewhat more attenuated florfenicol release with even less variability than the hypothetical 20% formulation of CN'802 with hypromellose instead of hydroxypropylcellulose (preparation 1.5). The results are summarized in Table 2 below, and also in Figure 1. In Figure 1, the release profiles are shown with error bars indicating the RSD at each time point. The rhombuses (♦) represent preparation 2.1, solid squares () preparation 2.2, solid triangles (A) preparation 2.3, and X-signs (x) preparation 2.4, with % FFC indicating the percentile of cumulative florfenicol release, and yt(h) indicating the time elapsed since the start of the experiment, in hours. MA / E / ZuZu / UO1110 Preparation Preparation Preparation Preparation Preparation Preparation Preparation 2.1 2.2 2.3 2.4 2.5 2.6Weight (g) % w / w Weight (g) % w / w Weight (g) % w / w Weight (g) % w / w Weight (g) % w / w Weight (g) % w / w Florfenicol 7.50 30.0 0 7.50 30.0 0 7.50 30.0 0 7.50 30.0 0 5.00 20.0 0 5.00 20.0 0 Poloxamer 407 3.00 12.0 0 3.00 12.0 0 3.13 12.5 0 3.13 12.0 0 3.43 13.7 2 3.43 13.7 2 Klucel® EF 0.19 0.75 0.19 0.75 ___ ___ ___ — 0.22 0.88 0.22 0.88 DDW 11.8 1 47.2 5 14.3 1 57.2 5 11.8 1 47.5 0 14.3 8 57.5 0 13.5 0 54.0 0 16.3 6 65.4 4 NMP 2.50 10.0 0 ___ ___ 2.50 10.0 0 — ___ 2.86 11.4 4 ___ — Time (h) mean sd mean sd mean sd mean sd mean sd mean sd 0.25 1.37 0.50 1.33 0.56 1.05 0.52 9.29 1.05 1.75 0.87 4.40 1.55 0.5 2.80 0.98 2.75 1.24 1.72 0.65 14.9 7 1.44 3.46 0.31 5.66 2.81 1 5.70 2.02 5.21 2.30 2.89 1.11 21.8 5 4.01 7.34 0.62 9.69 4.11 1.5 8.76 2.76 7.64 3.57 3.96 1.43 26.2 0 4.98 11.0 6 0.74 12.1 8 4.95 2 11.6 7 3.86 9.42 4.03 5.48 1.23 28.2 8 5.34 15.9 0 1.11 13.8 5 5.75 3 16.5 3 4.56 12.3 9 4.45 8.71 2.23 32.9 1 5.76 20.7 0 1.08 16.2 9 7.76 4 20.3 9 4.78 15.0 1 4.77 11.4 2 3.22 36.2 9 6.21 26.2 5 1.17 18.8 4 8.52 5 24.0 0 4.61 17.3 4 4.72 13.5 3 3.75 39.6 1 6.67 30.5 4 1.56 21.0 9 9.93 6 27.5 9 4.94 19.6 4 4.45 15.3 0 3.88 42.8 3 7.66 33.5 9 1.10 23.2 4 8.98. ΜΛ / Ε / ^υ^Ί / US! Ί Ί O 7 30.3 4 4.63 21.8 0 4.20 16.9 3 3.97 45.9 3 8.81 36.5 7 0.64 27.3 2 8.40 8 33.6 7 4.68 23.6 1 4.24 18.4 9 4.00 48.5 7 9.02 39.7 4 0.71 30.2 2 8.09 24 64.1 8 4.63 57.3 8 6.57 40.4 7 4.47 78.0 6 11.6 8 66.6 9 5.16 59.4 5 12.5 8 Rheology Viscosity maximum 9.69 Pa*s 12.3 Pa*s 11.4 Pa*s 13Pa*s 8.11 Pa*s 8.3 Pa*s Minimum viscosity 0.38 Pa*s 0.262 Pa*s 0.181 Pa*s 0.346 Pa*s 0.125 Pa*s 0.0819 Pa*s Gelling t°C 27.1°C 24°C 27.6°C 23.9°C 27.9°C 25.3°C Gelling interval 27.0-31.6 23.6-27.1 27-31.2 23.5-27.1 27.5-31.2 24.4-27.5 Table 2 ΜΛ / Ε / ΖυΖΊ / UO! Ί Ί O Example 3 To evaluate the effect of the cosolvent of choice, NMP, on the formulation, gels of 5 were produced according to preparation 2.1 and the NMP content was varied from 5 to 20 percent by weight, to provide preparation 3.1 (5% by weight) and 3.2 (20% by weight). The release data are shown in Table 3 below, and the profiles are shown in Figure 2, with the error bars indicating the RSD at each time point. The diamonds (♦) represent preparation 3.1 (designated as “5 wt%”), the solid squares ( ) preparation 2.1 10 (designated as “10 wt%”), and the solid triangles ( A) preparation 3.2 (designated as “20 wt%”), where “% FFC ” indicates the percentile of cumulative florfenicol release, and “t(h)” indicates the time elapsed since the start of the experiment, in hours. It can be seen that at 5% by weight of NMP the variability increases while the release profile remains almost unchanged, while at 20% the release accelerates slightly. Table 3 Preparation 3.1 Preparation 3.2 Time (h) mean SD mean SD 0.25 2.79 1.06 5.92 0.48 0.5 5.05 1.73 9.14 1.31 1 8.88 3.45 13.81 2.57 1.5 11.49 4.53 17.69 4.17 2 13.67 5.70 21.63 4.57 3 17.21 7.16 28.77 6.72 4 20.37 8.25 33.16 7.55 5 22.74 9.32 37.94 7.03 6 24.86 10.01 43.80 6.41 7 28.79 12.15 46.57 5.34 8 31.25 12.73 51.41 5.88 24 43.06 15.81 76.69 3.56 Rheology Maximum viscosity 6.16 Pa*s 10.9 Pa*s Minimum viscosity 0.23 Pa*s 0.39 Pa*s Gelation t°C 26.4 °C 21.6 °C Gelation range 26.2 -29.3 21.1-24.7 ML / t / ZUZ I / UO1110 Example 4 To evaluate the effect of additional cosolvents in the formulation, gels were produced according to preparation 2.1 and NMP was replaced with DMSO (preparation 4.1), propylene glycol (preparation 4.2), PEG 400 (preparation 4.3) or ethanol (preparation 4.4). The release profiles are summarized in Table 4 below. It can be easily seen that both DMSO and PEG 400 give a release profile comparable to NMP, but they significantly decrease the gelling point of the solution. ML / t / ZUZ I / UO1110 Preparation 4.1 Preparation 4.2 Preparation 4.3 Preparation 4.4 Time (h) mean SD mean SD mean SD mean SD 0.25 2.27 0.36 1.38 0.37 2.44 0.69 1.53 0.80 0.5 4.44 0.70 2.36 0.90 4.86 1.35 2.57 1.39 1 8.61 1.18 3.65 1.36 9.52 2.57 3.94 1.96 1.5 11.14 1.00 4.44 1.59 12.93 3.94 4.92 2.27 2 13.09 0.92 5.34 1.63 15.28 4.50 5.86 2.45 3 15.98 1.59 6.89 1.72 19.62 6.25 7.66 2.82 4 18.70 2.62 8.14 1.91 23.53 7.55 9.17 3.37 5 21.61 4.36 9.61 2.08 27.58 8.78 10.84 3.61 6 24.26 5.55 10.82 2.05 30.58 9.32 12.20 3.72 7 27.28 6.75 12.45 2.21 33.89 9.78 13.97 4.29 8 30.14 7.61 13.70 2.42 36.84 10.1 2 15.49 5.06 24 68.9 7.22 32.8 4.48 69.36 4.96 36.31 11.6 6 Rheology Maximum viscosity 10.5 Pa*s 10.5 Pa*s 8.16 Pa*s 4.25 Pa*s Minimum viscosity 0.29 Pa*s 0.37 Pa*s 0.35 Pa*s 0.21Pa*s Gelation t°C 15.1 °C 22.0 °C 20.2 °C 33.8 °C Gelation range 14.7-17.0 21.6-24.7 19.4-22.9 General Table 4 Example 5 To demonstrate the in vivo effect of the invention, a pharmacokinetic study was conducted to demonstrate prolonged and effective plasma levels from a single administration of florfenicol in pigs. The study was approved by the Ethics Committee for Animal Research Studies of the Hebrew University of Jerusalem. A total of six animals were used, consisting of two 3-4 month old female pigs. A 20G central venous catheter was inserted into the jugular vein of each pig to facilitate blood collection. All animals received a single dose of 40 mg / kg of the preparation 2.1 in the first study group, and 20 mg / kg as Nuflor® (Merck Animal Health—30% florfenicol solution in MPN) administered twice 48 h apart, or a different test treatment in the second group, after a two-week washout period. Blood samples were drawn before each treatment administration (time 0) and 1, 2, 4, 6, 8, 10, 24, 30, 52, 72, 96, 144, and 196 hours after the first administration. Samples were collected in heparinized tubes, and the plasma was immediately separated and stored at -20 °C until analysis. On the day of analysis, samples were enriched with an internal standard (chloramphenicol) and extracted with acetonitrile. Standards were prepared on the same day. The determination of the parent drug, florfenicol, and the main metabolite, florfenicol-amine, was performed using UHPLC-MS / MS (TSQ Quantum Access Max mass spectrometer in positive ion mode using electron sputtering ionization (ESI) and multiple reaction monitoring (MRM) mode with duplicate acquisition. Results were obtained for florfenicol (parent compound) and florfenicol-amine (main metabolite). Data analysis was performed using Microsoft Excel software. Area under the curve (AUC) values ​​were obtained using the trapezoidal rule. Terminal slopes were identified using a semi-logarithmic transformation, and the slope was calculated by fitting the curves to the exponential decay data. All further calculations were performed using the fitted functions. Deconvolution was not performed due to the complexity of the model, particularly for the double-injection groups. For these Nuflor® arms, the terminal slope data were also used to extrapolate the 48-hour points. Data were calculated from an average curve; the range of individual values ​​is presented where applicable. The results of the plasma concentration-versus-time graph for the original florfenicol compound are shown in Figure 3 for relevant comparisons. The dashed line 24 MA / t / ZUZI / UO1110 in each graph indicates the maximum probable MIC90 for typical target pathogens of porcine respiratory diseases. Error bars indicate the standard error of the mean. Arrows indicate administration times. Diamonds (♦) represent Nuflor, designated as Treatment: Nuflor 20 mg / kgx2, n=2) and solid squares () preparation 2.1 (designated as Treatment P2.1, 40 mg / kg xl, n=5), with Conc. (pg / ml) indicating the concentration of florfenicol in blood plasma, and Time (hours) indicating the time elapsed since the start of the experiment, in hours. The pharmacokinetic parameters obtained for these data are summarized in Table 5 below. MA / t / ZUZI / UO1110 Parameter P2.1 40 mg / kg Nuflor 20 mg / kg x2 Terminal ti / 2 (h) 43.5 (36.7-53.2) 53.1 h (20.3-78.2) AUCinf (ug xhx mL1) 224.9 176.0 AUC above MIC (AUIC) (ug xhx mL1) 178.7 84.4 Percentile of time above MIC (%) 79.4 47.9 Cmax (ug / mL) 2.24 (1.62-2.79) 2.77 (2.28-3.25) Tmax (h) 10.8 (6-24) 8 (6-10) Table 5 The terminal half-life of Nuflor® was calculated from the second injection; data from the first injection show a significantly shorter half-life, indicating rapid elimination in the early stages. The maximum concentration reported for the Nuflor group is the maximum concentration of the first injection. It can be readily seen that the preparation according to the invention produces a higher relevant exposure to florfenicol, as demonstrated by the AUIC and the time percentile above the MIC, after a single injection, relative to the commercial product. Example 6 To evaluate the system's ability to handle an ultra-high drug load, the following florfenicol formulations were also prepared along the lines described herein. Preparation 6.1 contained approximately 33 wt% florfenicol, 6.2 approximately 36 wt%, and 6.3 approximately 39 wt%. The compositions could be injected with a syringe through a 16G needle, and exhibited inverse thermal behavior; for example, they gelled upon heating and liquefied again upon cooling. Release profiles and rheological data are summarized in Table 6 below. MA / t / ZUZI / UO1110 Preparation 6.1 Preparation 6.2 Preparation 6.3 Weight (g) % w / w Weight (g) % w / w Weight (g) % w / w Florfenicol 8.0 32.6 8.5 36.2 9.25 39.3 Poloxamer 407 3.0 12.2 3.0 12.8 2.5 10.6 Klucel® EF 0.2 0.8 0.2 0.8 0.2 0.8 DDW 11.4 46.2 10.1 43.3 10.0 42.6 NMP 2 8.2 1.6 6.9 1.6 6.9 Time (h) mean SD mean SD mean SD 0.25 1.41 0.31 1.59 0.40 2.26 0.47 0.5 2.41 0.35 2.85 0.63 4.28 0.93 1 4.38 0.87 5.41 1.09 7.69 1.17 1.5 5.94 1.32 7.42 1.57 11.33 1.54 2 7.19 1.72 9.36 2.07 14.64 1.32 3 9.33 2.36 13.14 3.10 20.54 1.27 4 11.09 2.71 16.40 4.21 25.56 1.42 5 12.57 3.22 19.10 5.10 29.44 1.77 6 14.27 3.55 21.04 5.31 33.14 1.31 7 15.64 3.55 23.39 6.01 36.91 1.64 8 17.12 4.00 25.23 6.10 40.65 0.84 24 36.45 7.16 59.74 7.54 77.95 5.15 Rheology Maximum viscosity 13.1 Pa*s 34.2 Pa*s 18.9 Pa*s Minimum viscosity 0.28 Pa*s 2.3 Pa*s 1.01 Pa*s Gelation temperature °C 24.4 °C 18.2 °C 26.2 °C Gelation range 23.9-28.4 18.0-20.3 25.8-28.1 MA / t / ZUZI / UO1110 Table 6 It can be easily seen that the formulations created gels sensitive to temperature increase, releasing the drug in a controlled manner with low variability, as demonstrated by the low relative standard deviation of 5 at each point. Additional compositions were prepared with a loading of 45 wt% and higher. The florfenicol was sieved through a 50-micron mesh to obtain a smaller particle size fraction. The formulations and results are summarized in Table 7 below. Preparation 6.4 Preparation 6.5 Preparation 6.6 Preparation 6.7 Preparation 6.8 Weight (g) % w / w Weight (g) % w / w Weight (g) % w / w Weight (g) % w / w Weight (g) % w / w Florfenicol 45.0 45.0 — — — — — — 47.5 47.5 Sieved Florfenicol — — 45.0 45.0 45.0 45.0 47.5 47.5 — — Poloxamer 407 12.0 12.0 12.0 12.0 10.0 10.0 9.0 9.0 9.0 9.0 Klucel® EF 0.5 0.5 0.5 0.5 0.5 0.5 0.4 0.4 0.4 0.4 DDW 37.5 37.5 37.5 37.5 39.5 39.5 38.1 38.1 38.1 38.1 NMP 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 Time (h) mean sd mean sd mean sd mean sd mean sd 0.5 21.76 3.91 17.64 4.24 10.51 2.38 6.96 1.72 10.03 2.29 1 26.14 5.38 22.02 5.75 13.35 2.50 9.40 1.66 12.35 2.29 2 30.91 5.40 27.45 6.10 18.28 2.67 13.72 1.52 16.42 2.23 4 39.71 5.53 35.80 6.28 27.11 2.88 21.74 1.27 24.02 2.07 6 47.61 5.43 43.25 6.05 35.31 3.04 29.12 1.23 31.11 2.11 24 86.47 5.00 77.75 3.87 76.36 3.09 70.49 1.89 68.40 3.21 48 99.9 1.38 90.8 1.07 95.68 2.37 91.77 2.11 84.41 1.38 Rheology Minimum viscosity NP NP 0.95 Pa*s 0.75 Pa*s 0.57 Pa*s Maximum viscosity NP NP 16.8 Pa*s 12.9 Pa*s NP Gelation t °C 16.7 °C 17.1 °C 21.5 °C 24.2 NP Table 7 The dissolution test was carried out using the paddle-on-disc method. The amount of approximately 1 g was tested in 900 ml of USP phosphate buffer, pH 6.8, with 1% CTAB added. The rheometry was performed at 500 reciprocal seconds with a 500 pm interval. The results show that smaller particles do not negatively affect release profiles at high loading rates, which slightly accelerates drug release, so an injectable florfenicol formulation with a very high loading rate can be obtained. Example 7 Additional compositions were prepared with a loading of 47.5 wt%. Sieved florfenicol was used, as in Example 6. The formulations and results are summarized in Table 8 below. Preparation 7.1 Preparation 7.2 Preparation 7.3 Preparation 7.4 Weight (g) % w / w Weight (g) % w / w Weight (g) % w / w Weight (g) % w / w Florfenicol* 57 47.5 57 47.5 57 47.5 57 47.5 Poloxamer 407 10.2 8.5 10.2 8.5 10.2 8.5 10.8 9 Klucel® EF 0.12 0.1 — — 0.12 0.1 0.12 0.1 DDW 46.68 38.9 46.8 39 40.68 33.9 46.08 38.4 NMP 6 5 6 5 12 10 6 5 Time (h) mean sd mean sd mean sd mean sd 0.5 8.97 3.77 24.31 8.04 7.16 2.42 24.56 2.94 1 11.15 3.98 26.80 7.80 9.72 2.50 27.15 3.53 2 15.40 4.49 30.98 7.35 14.14 2.38 31.38 4.14 4 23.36 5.31 38.21 6.81 22.32 2.18 38.19 4.16 6 30.48 6.02 44.52 6.60 29.72 1.91 44.27 4.26 24 69.82 7.55 77.28 4.67 71.41 0.99 77.95 4.42 48 90.04 4.27 94.71 3.18 92.76 2.09 96.84 1.65 Rheology Minimum viscosity 0.34 Pa*s 0.34 Pa*s 0.71 Pa*s 0.38 Pa*s Maximum viscosity 10.05 Pa*s 9.95 Pa*s 7.9 Pa*s 12.7 Pa*s Gelling t °C 27.23 °C 29.86 °C 28.09 °C 27.23 °C Table 8; * sieved florfenicol MA / / UO1 It can be easily seen from the results that compositions comprising 47.5 percent by weight of florfenicol can be made injectable, for example, with good viscosity in the room and a suitable gelling point. Additionally, it can be seen that even with a low amount of hydroxypropylcellulose (see, for example, preparation 7.1 versus 6.7) the release profile remains stable, with a relatively low RSD (although in fact the variability is slightly higher with 7.1). Quite unexpectedly, the variability without hydroxypropylcellulose (preparation 7.2) was still within the pharmaceutically acceptable range, although even just 0.1% of the cellulose additive significantly reduced the variability without negatively affecting the release profile. Furthermore, the addition of more cosolvent (preparation 7.3 vs. 7.1) further improved the variability, and even more so compared to preparation 7.2 without the cellulose additive. Example 8 To further demonstrate the effect of the invention in vivo, another pharmacokinetic study was conducted to demonstrate prolonged and effective plasma levels from a single administration of florfenicol in pigs. A total of 20 pigs received concurrently either 40 mg / kg of the single treatment of preparations 6.6–6.8, or 30 mg / kg of Nuflor® (Merck Animal Health—30% florfenicol solution in MPN), administered according to the manufacturer's recommendations. Additionally, a preparation (referred to herein as 8.1) comprising 40 wt% florfenicol, 12 wt% poloxamer 407, 0.5 wt% Klucel EF, 5 wt% MPN, and 42.5 wt% water, with a gelling point of 21.7 °C, was administered at 40 mg / kg. The release profile of preparation 8.1 under the same conditions as in Example 7 is shown in Table 9 below. ML / t / ZUZ I / UO1110 Time (h) 0 0.5 1 2 4 6 24 48 average 0 18.85 23.01 26.70 32.97 38.48 64.37 72.78 RSD 0 5.98 6.74 6.51 6.20 5.78 3.05 1.82 Table 9 Blood samples were taken at time points 0, 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 50, 72, 84, 96, 120, 144 and 168 hours. The graph of plasma florfenicol concentrations as a function of time is shown in Figure 4. In Figure 4, the plasma florfenicol concentrations at each sampling point are shown. The diamonds (♦) represent Nuflor, solid squares () preparation 8.1, solid triangles (A) preparation 6.6 and X signs (x) preparation 6.7, and the asterisks (*) preparation 6.8, where C (ng / mL) indicates the concentration of florfenicol in blood plasma, and yt (h) indicates the time elapsed since the start of the experiment, in hours. It is readily apparent from the results that the commercially available product is rapidly eliminated from the blood of pigs, whereas all preparations according to the invention maintain blood plasma levels above 1000 ng / mL for an average of 72 to 84 hours. It is worth noting that the dose-corrected AUC of the 30 treatments is comparable across groups, indicating that bioavailability was not reduced with the controlled-release formulations. The peak plasma concentration was clearly higher with the immediate-release commercial product; however, preparation 6.7 exhibited a significantly higher peak concentration than preparation 6.8, which differed only in drug particle size. The times above the minimum inhibitory concentration of Streptococcus suis, a virulent porcine pathogen (currently considered to be 2 mcg / mL), of the tested items, are shown in Table 10 below. MA / t / ZUZ I / UO1110 Above MIC Nuflor P8.1 P6.6 P6.7 P6.8 Time (h) 7.44 18.5 27.8 34.2 14.8 Table 10 It is evident from the results that the preparations tested according to the invention give superior results with significant clinical potential for combating S. suis. Example 9 To demonstrate the ability of the compositions according to the invention to release other antibiotics, formulations comprising 30 wt% amoxicillin were prepared. Preparation 9.1 contained both the cosolvent and the cellulose derivative at least partially soluble in organic solvents (hydroxypropylcellulose), preparation 9.2 contained only hydroxypropylcellulose, and preparation 9.3 contained none of the additional excipients. The formulations were prepared along the lines as described for florfenicol. The compositions could be injected with a syringe through a 16G needle, were injectable thereafter, and exhibited inverse thermal behavior; for example, they gelled upon heating and liquefied again upon cooling. The release profile data are summarized in Table 11 below. Preparation 9.1 Preparation 9.2 Preparation 9.3 Weight (g) % w / w Weight (g) % w / w Weight (g) % w / w Amoxicillin 6.0 30 6.0 30 6.0 30 Poloxamer 407 2.4 12 2.4 12 2.4 12 Klucel® EF 0.15 0.75 0.15 0.75 — — DDW 9.45 47.25 11.45 57.25 11.6 58 NMP 2.0 10 — — — — Time (h) mean sd mean sd mean sd 0.5 2.99 0.94 2.52 0.45 3.14 0.50 1 6.34 1.40 5.10 0.58 5.61 0.47 1.5 9.26 1.65 7.69 0.55 7.83 0.47 2 11.76 1.81 10.04 0.75 9.68 0.66 3 16.68 2.76 14.12 1.17 12.63 1.18 4 20.90 3.43 19.03 1.63 16.06 1.88 5 25.39 3.16 22.94 2.27 21.59 6.45 6 30.12 5.44 26.56 3.10 21.40 3.31 7 34.14 6.85 29.14 2.93 23.40 2.60 8 36.52 4.86 33.34 5.34 25.65 5.81 24 68.70 7.66 84.69 22.44 77.00 21.35 ML / t / ZUZI / UO1110 Table 11 It can be easily seen that the formulations created gels, releasing the drug in a controlled manner with low variability, as evidenced by the low RSD at each point, but without NMP 5 or Klucel, the drug release at a later stage becomes more erratic, which could indicate the formation of a less stable gel in the absence of both excipients. Example 10 To further demonstrate the ability of the compositions according to the invention to release other antibiotics, formulations comprising 15% by weight of tylosin were prepared. Preparation 10.1 contained both the cosolvent and the cellulose derivative at least partially soluble in organic solvents (hydroxypropylcellulose), preparation 10.2 contained only hydroxypropylcellulose, and preparation 10.3 contained none of the additional excipients. The formulations were prepared along the lines as described for florfenicol. The compositions could be injected with a syringe through a 16G needle, were injectable thereafter, and exhibited inverse thermal behavior; for example, they gelled upon heating and liquefied again upon cooling. The release profile data are summarized in Table 12 below. ML / E / ^υ^Ί / UO! Ί Ί O Preparation 9.1 Preparation 9.2 Preparation 9.3 Weight (g) % w / w Weight (g) % w / w Weight (g) % w / w Tylosin 3.0 15 3.0 15 3.0 15 Poloxamer 407 2.92 14.6 2.4 12 2.4 12 Klucel® EF 0.18 0.9 0.15 0.76 — — DDW 11.47 57.3 14.45 72.24 14.6 73 MPN 2.43 12.2 — — — — Time (h) mean SD mean SD mean SD 0.5 11.40 1.80 5.48 0.09 4.83 1.65 1 20.95 1.16 9.33 0.99 8.24 2.96 1.5 35.71 1.47 12.51 1.56 11.26 4.24 2 37.27 1.54 15.63 1.75 14.35 5.54 3 46.75 1.72 21.51 2.09 20.05 7.60 4 52.50 1.28 25.64 2.04 25.18 9.34 5 57.97 1.95 31.04 1.60 30.63 11.46 6 61.14 1.07 36.23 2.67 36.67 13.35 7 70.25 3.08 40.72 4.02 41.42 14.09 8 72.71 3.49 45.10 6.39 46.19 15.39 24 94.05 3.02 97.94 1.60 96.85 2.08 Table 12 It is readily apparent that the formulations formed gels and released the drug in a controlled manner. Preparation 10.1 contained slightly more poloxamer to compensate for the increased drug solubility caused by NMP. The release profile of 10.1 demonstrates low variability, as evidenced by the low RSD at each time point, particularly in the intermediate time intervals. Preparation 10.2 exhibits slightly greater variability, but without NMP and Klucel, drug release becomes more variable.

Claims

1. A pharmaceutical composition comprising a biologically active agent, poloxamer, an aqueous carrier and an organic cosolvent, wherein said composition is an injectable composition at room temperature, provided that where said concentration of active agent is less than 35% by weight the composition further comprises a cellulose-based material that is at least partially soluble in organic solvents.

2. The pharmaceutical composition according to claim 1, wherein a concentration of said biologically active agent is between 10% by weight and 35% by weight.

3. The pharmaceutical composition according to claim 1, wherein a concentration of said biologically active agent is greater than 35% by weight, and wherein said composition is devoid of a cellulose-based material that is at least partially soluble in organic solvents.

4. The pharmaceutical composition according to claim 1, wherein a concentration of said biologically active agent is greater than 35% by weight, and wherein said composition further comprises a cellulose-based material that is at least partially soluble in organic solvents.

5. The pharmaceutical composition according to any one of claims 3 or 4, wherein the concentration of said biologically active agent is between 35% by weight and 50% by weight.

6. The pharmaceutical composition of any one of the preceding claims, wherein said biologically active agent is selected from florfenicol, lincomycin, tylosin, metronidazole, tilmicosin, spiramycin, erythromycin, tulathromycin, tiamulin, ampicillin, amoxicillin, clavulanic acid, penicillin, streptomycin, trimethoprim, sulfonamide, sulfamethoxazole, pleuromotulin, avilosin, tilvasoline, doxycycline, and oxytetracycline.

7. The pharmaceutical composition of any one of the preceding claims, wherein said biologically active agent is florfenicol. ML / t / ZUZI / UO1110 8. The pharmaceutical composition of claim 6, wherein said biologically active agent is present in said composition in a loading of between approximately 25% by weight and approximately 50% by weight.

9. The pharmaceutical composition of any one of the preceding claims, wherein said organic cosolvent is present in an amount of from approximately 5 to approximately 15% by weight.

10. The pharmaceutical composition of any one of the preceding claims, wherein said cellulose-based material that is at least partially soluble in organic solvents is hydroxypropylcellulose.

11. The pharmaceutical composition of any one of the preceding claims, wherein said organic solvent is selected from the group consisting of N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), PEG 400, propylene glycol, and ethanol.

12. The pharmaceutical composition of any one of the preceding claims, wherein said organic solvent is N-methylpyrrolidone.

13. The pharmaceutical composition of any one of the preceding claims, wherein said organic solvent is N-methylpyrrolidone, and wherein said cellulose-based material that is at least partially soluble in organic solvents is hydroxypropylcellulose, and further wherein said biologically active agent is florfenicol in a concentration of between 25% by weight and 50% by weight.

14. The pharmaceutical composition of any one of the preceding claims, wherein said organic solvent is N-methylpyrrolidone, and wherein said biologically active agent is florfenicol, and furthermore, wherein a concentration of said florfenicol is between 35% by weight and 50% by weight.

15. A pharmaceutical composition as defined in any one of the preceding claims for use in the treatment of a veterinary infection in a non-human animal by administering to said animal a pharmacologically effective dose of an antibiotic in said composition.

16. The pharmaceutical composition of claim 15, wherein said composition is administered once to said non-human animal during the course of treatment.

17. The pharmaceutical composition of any one of claims 15-16, wherein said administration comprises intramuscular injection or subcutaneous injection.

18. The pharmaceutical composition of any one of claims 15-17, wherein said infection is caused by a porcine pathogen.