Field of the invention
This invention relates to pharmaceutical compositions containing Florfenicol as the active ingredient, and particularly to injectable compositions having high concentration of Florfenicol.
Background of the invention
Florfenicol, a fluorinated derivative of thiamphenicol with a molecular weight of 358.22 and melting point ranging between 153-154°C is useful in veterinary medicine (Merck Index, 11th Edition, No. 4042) and U.S. Pat. No. 4,235,892 describes the compound and processes for making the said compound. Florfenicol, also known as [R-(R*,S*)]-2,2-dichloro-N-[l-(fluoromethyl)-2-hydroxy-2-[4-(methylsulfonyl)phenyl] ethyljacetamide, is a broad-spectrum antibacterial agent useful in the treatment of gram positive, gram negative and rickettsial infections as disclosed in U.S. Pat. No. 4,361,557, especially for the veterinary purposes.
Bacterial infections can be a major problem for cattle and other livestock. Florfenicol is useful for treating, among other things, respiratory problems due to bacterial infections in veterinary populations. Bovine Respiratory Disease (BRD) occurs in both dairy and beef cattle and is one of the leading causes of economic loss to the cattle industry throughout the world. These economic losses are due to excessive mortality, reduced weight gains as well as treatment and prevention costs. BRD is often referred to as the "bovine respiratory diseases complex" due to the multifactorial etiology. Accordingly, there is a need for conveniently administered, stable compositions that can control and prevent the infection and minimize the inflammation associated with bovine respiratory disease and other

infectious diseases, while minimizing the pain and stress to the animal associated with treatment and the potential for injection site tissue damage
NUFLOR, an injectable formulation of the broad-spectrum antibiotic Florfenicol from Schering-Plough Corporation, U.S.A, has emerged as one of the leading antibacterial on a global basis. It is indicated for the treatment and control of BRD associated with M. haemolytica, P. multocida and H, somnus as well as for the prevention of respiratory disease in cattle at high risk of developing BRD associated with these bacteria. NUFLOR is also indicated for the treatment of bovine interdigital phlegmon (footrot, acute interdigital necrobacillosis, infectious pododermatitis) associated with Fusobacterium necrophorum and Bacteroides melaninogenicus. NUFLOR may be administered subcutaneously as well as intramuscularly.
As per the disclosed information in the veterinarian's physician desk reference [PDR], NUFLOR composition contains other than Florfenicol, N-methyl-2-pyrrolidone as a solvent, polyethylene glycol and propylene glycol. U.S patent 5082863 by Schering Plough claims accordingly an injectable pharmaceutical composition for veterinary use comprising Florfenicol, N-methyl-2-pyrrolidone, polyethylene glycol and a viscosity reducing agent [propylene glycol is specifically claimed]. As a generic pharmaceutical company wishing to introduce a generic Florfenicol product in the U.S market and with NUFLOR as the only commercially available product that is under patent protection in the U.S, NUFLOR has presented us with a challenge to work on other unpatented/off patented solvents for the generic version of Florfenicol formulation. Given the limitations that exist in the realm of suitable solvents for the purpose of sterile injectable preparations with desirable toxicity profiles, we have undertaken a laborious and comprehensive study to identify a suitable solvent to meet the above challenges. After intensive investigations we have found a solvent, which is

comparable to N-methyl-2-pyrrolidone in terms of toxicity profile, handling ease and other properties that are needed for a injectable formulation like viscosity, syringeability etc.
U.S patent application, 20030068339 claims an antibiotic formulation, comprising a mixture of: Florfenicol; at least one preservative; and N-methyl-2-pyrrolidone, where the said Florfenicol and said preservative are dissolved in said N-methyl-2-pyrrolidone to form an antibiotic formulation for veterinary use which is syringeable even under cold weather conditions. On comparison of the claims of this patent application with the claims of the Schering Plough's U.S patent 5082863, it was found that the pyrrolidone solvent system was a common feature and the application has only a preservative along with Florfenicol and the solvent whereas the patent has in addition to the drug and the solvent a component of polyethylene glycol and a component of propylene glycol.
US patent application 20030216447, by Kohan, et al proposes a combination of anti-inflammatory drug flunixin and antibiotic Florfenicol for treatment of microbial infections. The composition comprises an aprotic polar solvent selected from-N, N-dimethyl acetamide, and N- methyl -2- pyrrolidone, glycerol formal, polyethylene glycol, propylene glycol alcohol and their combinations.
Objective of the invention
The present invention involves methodology for dissolving Florfenicol in a novel liquid vehicle(s) to provide a physiologically acceptable Florfenicol formulation for parenteral administration, such that the Florfenicol remains chemically stable and can be administered without unexpected toxicity from the liquid vehicle when the formulation is administered subcutaneously or intramuscularly to the veterinary population

According to the present invention, the foregoing and other objects are achieved by an injectable antibiotic formulation that includes a mixture of Florfenicol, N,N-dimethylacetamide [DMA] or a combination of DMA with a pyrrolidone solvent and other suitable excipients that may be used for injectable preparations. This formulation is made by mixing these components together until they have dissolved. The objects and advantages of the invention may be realized and attained by means of the combinations particularly pointed out in the appended claims.
Detailed description of the invention
Florfenicol has low solubility in water, about 1.3 mg/ml, and the preparation of a concentrated aqueous injectable solution is not practicable due to the large volume required to administer a therapeutic dose. Florfenicol also exhibits low solubility in many pharmaceutically acceptable organic solvents such as 1,2-propanediol, glycerin, and benzyl alcohol.
Encouragingly, Florfenicol has been found to be soluble in aprotic polar solvents
such as a pyrrolidone solvent, N, N-dimethylacetamide, N, N-
dimethylformamide, DMSO, acetone or glycerol formal. Preferred solvent is N, N-dimethylacetamide. Accordingly, such an aprotic polar solvent (or a combination of such solvents) is preferred for use in formulations of the present invention that contain Florfenicol or similar antibiotics. Preferably such a solvent is present at about 10% to about 30% by weight of the formulation.
A physiologically acceptable solvent is one that is tolerated by the individual in the concentrations and doses used. Physiologically acceptable Florfenicol solvent

is a solvent that dissolves Florfenicol and may be N,N-dimethylacetamide [DMA] or DMA in combination with other co-solvents as disclosed and claimed.
It is particularly desirable in the case of injectable compositions that they have suitable viscosities for the purposes of better syringebilities, which in turn can result in less pain and stress to the injected animal. Viscosity of the composition greatly depends on the amount of all the solid substances dissolved and their respective molecular masses or densities. In the background of the above guiding principle, it is extremely important for the formulators of injectable compositions of animals to keep the viscosities of their compositions as low as possible. NUFLOR product insert discloses that it has 250mg or 25% of an organic solvent, N-methyl-2- pyrrolidone [NMP] in its composition. NMP has a molecular mass of 99.1 and relative density [with water] of 1.03. It is interesting to note here that DMA has a molecular mass of 87.1 and relative density [with water] of 0.94. So from the above illustrations it would be apparent to anybody who is skilled in the art that, when the resulting viscosity effects of the remaining components are comparable in both the cases, the usage of a less denser solvent in comparable amounts of a different solvent in NUFLOR, our composition would most definitely be less viscous and therefore results in superior syringibility
When treating a large animal, it is sometimes required to administer a composition having a high concentration of Florfenicol. The large amount of Florfenicol thus administered should then preferably exhibit constant blood levels and be active for a prolonged period of time.
Given the above context, according to the present invention, a novel composition has been prepared which provides relatively high concentrations of Florfenicol in a unique organic solvent system of Florfenicol, N,N-dimethylacetamide [DMA] or a combination of DMA with a pyrrolidone and other suitable excipients that may

be used for injectable preparations like the viscosity-reducing excipients and etc. with minimal injection site irritation and tissue damage upon intramuscular administration. Therefore, a stable injectable compositions of Florfenicol is provided by means of a novel composition comprising:
(a) 10 to 50% by weight of Florfenicol;
(b) N,N-dimethylacetamide [DMA] either alone or in combination with a
pyrrolidone solvent and other suitable excipients
Other suitable excipients can be selected from the excipient groups—solubilizers, co-solubilizers, viscosity reducing agents, co-solvents, pH adjusters and etc.
Preferably, the other suitable excipients can be selected from the following group --polyethylene glycol [PEG], propylene glycol, cyclodextrin derivatives and glycerol formal or their combinations.
The polyethylene glycols that are used in the compositions of the present invention include those having an average molecular weight of from 200 to 400. The preferred polyethylene glycol has an average molecular weight of about 300 and is also referred to as PEG 300.
Due to the high solids content of Florfenicol in the compositions of the present invention, a viscosity reducing agent is required to provide a product with workable syringeability. Examples of viscosity reducing agents useful in the present invention include: ethanol, propylene glycol. The preferred viscosity reducing agent is propylene glycol.

Other pharmaceutically acceptable solvents may be present in the formulations of the present invention. The addition of one or more of such additional solvents or co-solvents or co-solubilizers may be desirable to reduce the viscosity of the formulation in order to provide a product with workable syringibility. Examples of solvents particularly useful for adjusting the viscosity of the formulations of the present invention include ethanol, benzyl alcohol, propylene glycol, polyethylene glycol (PEG) and cyclodextrin derivatives. Particularly preferred solvents include PEG having an average molecular weight between about 200 and about 400, propylene glycol and cyclodextrin derivatives. Preferably they comprise from about 0% to about 80%. More preferably they comprise from about 5% to about 80% of the formulation. Solution of polyethylene glycol or a mixture of N,N-dimethylacetamide and a carrier solution results in enhanced syringebility, solubility and stability of Florfenicol. The carrier may be polyethylene glycol or polyethylene glycol in combination with propylene glycol.
The compositions of the present invention are readily prepared by dissolving Florfenicol in the solvent, when only one solvent like DMA is used or in a solvent mixture when more than one solvent is present like the combination of DMA and glycerol formal. After the dissolution is completed in the suitable solvent propylene glycol is added followed by making up of the volume with polyethylene glycol and finally sonicating/mixing the components thoroughly to ensure complete dissolution.
The compositions of the present invention exhibit desirable properties which are useful for administration of relatively high concentrations of Florfenicol. The compositions have desirable viscosity characteristics, which allows for good syringeability over a wide temperature range and ease of processing, such as good flow rate through sterilizing filter membranes. The compositions are physically

and chemically stable over a prolonged period of time and also exhibit acceptable tissue toleration.
The Florfenicol formulation of the present invention may be administered to animals including, but not limited to, bovine, equine, swine, wild ungulates, bovine, cows, horses, sheep, goats, poultry, donkeys, mules, zebras, cats and dogs. It may be used to fight infections caused by bacterial organisms. Preferably, it is administered by injection in a dosage of about 20 mg-40 mg per kilogram of animal and may be repeated in about 48 hours. Florfenicol in the formulation of the present invention can be injected intramuscularly or subcutaneously
With regard to the invention disclosed here, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the claims
The present invention is illustrated by the following examples, which are provided for illustration purposes only and should not be construed to limit the scope of the invention.

Examples Example I

Dissolve Florfenicol in N,N-Dimethylacetamide. Add propylene glycol. Make up the volume with polyetylene glycol. Finally sonicate/mix the components thoroughly.
Sterilize the resulting solution by Filtration.
Observation made on the solution after storage for 3 months


Example 2

Mix N,N-Dimethylacetamide and N-methyl pyrrolidone. Dissolve Florfenicol and add propylene glycol. Make up the volume with polyethylene glycol. Sonicate/mix the components.
Sterilize the resulting solution by Filtration.

Claims
[1] An injectable pharmaceutical composition for veterinary use comprising:
(a) 10 to 50% by weight of Florfenicol;
(b) N,N-dimethylacetamide [DMA] either alone or in combination with a
pyrrolidone solvent and other suitable excipients.
[2] An injectable pharmaceutical composition for veterinary use as claimed in claim 1 comprising:
(a) 10 to 50% by weight of Florfenicol;
(b) N,N-dimethylacetamide [DMA],where the amount of DMA is not more than 25% by weight;
(c) 5 to 80% by weight of a co-solubilizer selected from the group of polyethylene glycol, propylene glycol, cyclodextrin derivatives, water and glycerol formal or their combinations.
[3] An injectable pharmaceutical composition for veterinary use as claimed in claim 1 comprising
(a) 10 to 50% by weight of Florfenicol;
(b) N,N-dimethylacetamide [DMA] in combination with a pyrrolidone solvent, N-methyl 2-pyrrolidone, where the amounts of DMA and N-methyl 2-pyrrolidone

are not more than 25% and 8% by weight respectively; total aprotic solvent concentration not more than 33% by weight.
(c) 5 to 80% by weight of a co-solubilizer selected from the group of polyethylene glycol, propylene glycol, cyclodextrin derivatives, water and glycerol formal or their combinations.