MXPA00003867A - Compositions containing thiamphenicol and diclofenac - Google Patents

Abstract

A combination of Thiamphenicol and Diclofenac for use in veterinary medicine in the treatment of infections associated with inflammatory conditions.

Description

COMPOSITIONS CONTAINING TIANPENICOL AND DICLOFENAC FIELD OF THE INVENTION The present invention relates to the combination of Tianfenicol and Diclofenac for use in veterinary medicine in the treatment of infections associated with inflammatory conditions.

PREVIOUS TECHNIQUE The different organs and systems affected by infections very often suffer from inflammation effects (swelling, pain, loss of function, increased mucous secretions, etc.) as well as general symptoms that are characterized by fever, anorexia, delayed sensitivity, etc. In the field of veterinary medicine, the damages caused by inflammation are sometimes more serious than those caused by the infection itself, both in terms of the health of the animal and loss of production or alteration of the quality of the products (for example, quality of milk in case of mastitis). In veterinary practice, but also in humans, an antibiotic and an anti-inflammatory are often administered simultaneously, but in different formulations, to counteract harmful effects of the infection, associated with inflammatory conditions. This type of treatment involves the important inconvenience of repeated administrations, which have as a consequence possible errors in times and doses of the different products, in addition to the inconvenience for the patient. In the field of veterinary medicine, a combination of oxytetracycline (antibiotic) with meglumine flunixin (anti-inflammatory) is known. The drawback of this combination is that it is only effective against a narrow spectrum of infections caused by Gram-positive and Gram-negative bacteria, therefore its use is restricted. In addition, antibiotic compositions and steroidal anti-inflammatories are known for local use. Surprisingly it has been found that the combination of Tianfenicol with Diclofenac in a simple formulation is more effective, in the treatment of infections associated with inflammatory conditions, than the simple administration of two active ingredients. Tianfenicol is an antibiotic belonging to the class of phenicolates that have a broad spectrum of antibacterial activity. At the pharmacokinetic / pharmacodynamic level, Tianfenicol has a low binding to plasma proteins, a rapid and complete absorption, a high distribution in the tissue, and it is not metabolized, so it circulates freely in the body. Diclofenac is a molecule that has a high anti-inflammatory, antipyretic and analgesic activity compared to other NSADs. At the pharmacokinetic level, Diclofenac is completely and rapidly absorbed, and it is widely distributed in the tissues. In addition to the advantage in the clinical effectiveness in the treatment of infections associated with inflammation, the combination of two compounds in a simple formulation provides the following advantages in the veterinary field: 1. reduction of erroneous doses; 2. broad spectrum of antibiotic activity, which is particularly useful in veterinary medicine; 3. reduction of injection sites and injected volumes as well as labor costs; 4. absorption and elimination similar to the two combined compounds, which allow to control discontinuous times. For the farmer, this means a precise time to sacrifice the animal or take advantage of it, and therefore better control of operations, mainly on farms with a large number of livestock animals.

DESCRIPTION OF THE INVENTION The present invention relates to compositions containing Tianfenicol (TAF) and Diclofenac (DCF) appropriate for oral, parenteral and topical administration.

The compositions, which may be in solid, liquid, semisolid or aspersion state, contain dispersed or solubilized active ingredients and make use of excipients and pharmaceutically accepted vehicles, selected to ensure rapid and extensive release. The dose ranges will vary depending on several factors, such as animal weight and severity of the infection to be treated. Examples of preferred doses for various compositions are reported below. Oral unit dose compositions: DCF, 20 mg - 1 g + TAF 100 mg - 5 g and preferably DCF, 100 mg + TAF 500 mg. Oral multiple dose compositions: DCF, 0.5-5% + TAF 5-60% and preferably DCF 5% + TAF 20% Injectable compositions: DCF, 2-10% + TAF 10-50% and preferably DCF 5% + TAF 25 %. Nommama compositions - ointments / sprays: DCF, 2 - 10% + TAF 10 - 50% and preferably DCF 5% + TAF 25%. Local compositions: DCF, 0.5 - 5% + TAF 2 - 10% and preferably DCF 1% + TAF 5%. Endoteurine compositions: DCF 2 - 10% + TAF 10-50% and preferably DCF 5% + TAF 25%. Ophthalmic compositions and headphones: DCF 0.05 - 1% + TAF 0.2 - 5% and preferably DCF 0.1% + TAF 5%.

The solid compositions (mainly for oral use) comprise powders, tablets, granulated materials, capsules, (soft gelatin capsules and hard gelatin capsules) pills, tablets, boluses and pessaries (for uterine use). The antibiotic and the anti-inflammatory can be mixed with solid diluents, such as sugars, for example lactose, mannitol, sucrose, sorbitol, and / or calcium phosphates; binders, such as starch, gelatin, gums, polyvinylpyrrolidone, cellulose compounds, disintegrants, such as amides and carboxymethylamide, interlaced polyvinylpyrrolidone, agar, alginic acid and salts thereof, such as sodium alginate. In addition, such compositions may also contain glidants, lubricants and tableting aids such as talc, stearic acid, magnesium stearate, silicic acid, polyethylene glycols, hydrogenated castor oil, pigments, such as titanium dioxide and dyes, release controlling agents. such as cellulose polymers and others. In any case, all the materials used in pharmaceutical technology can be used, as long as they are compatible with the active ingredients. Alternatively, the active ingredients can be included in conventional gelatin capsules in the form of granules, and preferably in the form of suspensions in vegetable or mineral oils, or in low molecular weight polyethylene glycols. The capsules consist of gelatin and a plasticizer, usually glycerol and sorbitol.

The syrups, oral suspensions and oral pastes contain the active ingredients dispersed in a suitable vehicle consisting of water, fatty solvents, alcohols or polyalcohols and inorganic suspending agents, for example colloidal silicates with high content of aluminum and magnesium, such as bentonite, veegum, kaolin, and colloidal silica, such as Aerosil, Carbosil; organic stabilizers; inflammatory agents such as alginates, gum arabic, tragacanth, carrageenans, guar gum, agar and thickening lipophilic agents in the case of, for example, oily pastes, synthetic or semi-synthetic agents such as ethylene oxide homopolymers, for example polyoxyl, preferably cellulose ethers , for example methylcellulose or ethylcellulose, hydroxyethylcellulose, hydroxypropylethylcellulose, carboxymethylcellulose, microcrystalline cellulose, soluble polyvinyl compounds, such as polyvinyl acetate, polyvinyl alcohol and polyvinylpyrrodoline, sweetening agents such as glucose, fructose, xylose, colorants, flavors, antioxidants such as sulfites, propylgalates, butyl hydroxyanisole, dithiopropamic acid, and pH regulating agents. Parenteral compositions comprise liquid dosage forms formulating the antibiotic and the anti-inflammatory in a sterile vehicle. The active ingredients must also be suspended or solubilized in the vehicle, depending on the nature and concentration of the same. In the preparation of solutions, the active ingredients are dissolved in mixtures of water and organic solvents, for example N, N-dimethylacetamide, N-methylpyrrolidone, 2-pyrrolidone, propylene glycol, low molecular weight alcohols, low molecular weight polyethylene glycols, and filtered and sterilized before being distributed in suitable containers. Specific auxiliaries such as preservatives, local anesthetics, pH regulating agents can be dissolved in the vehicle. The compound can be freeze-dried to increase its stability, and marketed together with a container with solvent to reconstitute it before use. Parenteral suspensions are prepared in substantially the same manner, except that the sterilized active ingredients are suspended and not solubilized in the vehicle. A wetting agent, or a surface active agent, can be used to facilitate the homogeneous distribution of the active components. Parenteral suspensions are often oily with a lipophilic vehicle, such as fatty acids, for example sesame oil, synthetic esters of fatty acids, such as ethyl oleate, or triglycerides or diglycerides such as fractionated coconut oil or propylene glycol dicaprildicaprate. In the case of aqueous suspensions, thickeners may be included such as sodium carboxymethyl cellulose, polyvinyl pyrrolidone, dextrans, sorbitol and stabilizing agents. The preparations for local use in the field of veterinary medicine are administered through intramammary, endouterine, ophthalmic or auricular routes and mainly are ointments, creams, gels, ointments, and liquid products in aspersion or foams, dyes or drops.

The ointments contain properly micronized active principles, dispersed in an emulsified base (cream) or in a single phase, generally an anhydrous excipient. The oil in oil emulsions have a water content > 50%, the water in the oil emulsions contain more than 70%, but preferably 20-50%, water or aqueous phase. Suitable hydrophilic emulsifiers are present, for example nonionic surfactants, such as esters of fatty acids with polyalcohols or ethylene oxide, such as sorbitan polyethoxylate (tween) esters, polyoxyethylene alkyl ethers (cetheareth-20), and ionic derivatives such as derivatives of alkylsulfonate or aryisulfonate derivatives, such as sodium lauryl sulfate, sodium cetyl sulfate, and lipophilic emulsifiers such as sorbitan esters, for example sorbitan monooleate and sorbitan iso-stearate. The oily components of these formulations comprise hydrocarbons, for example white soft paraffin and / or liquid paraffin or hard paraffin, natural or synthetic fats, for example coconut oil triglyceride, hydrogenated oils, such as hydrogenated castor oil, partial glycerol esters with fatty acid, such as glyceryl mono- and distearate fatty acids, for example palmitic and stearic acids, solid waxes such as beeswax, wool grease, fatty alcohols or esters such as cetyl or stearyl alcohols, or wax alcohol derivatives woolen. Excipients for the aqueous phase can be used in creams to prevent dryness, for example polyalcohols such as glycerol, sorbitol, propylene glycol, and / or polyethylene glycol and also antimicrobial preservatives.

In the case of gels, which may be anhydrous or aqueous, generally various gelling agents are used, such as those already mentioned for oral suspensions, comprising inorganic, natural compounds, synthetic or semi-synthetic macromolecules. The endomamari ointments are prepared in simple doses, usually in syringes, to facilitate intracanalicular administration and preserve the sterility of the product. The foams and sprays are dispensed from pressurized containers containing suitable propellants, for example halogenated hydrocarbons, such as dichlorodifluoromethane and dichlorotetrafluoroethane and hydrocarbons such as butane, propane and isobutane. Such products are obtained by preparing the concentrate containing the active principles in the form of a solution, an emulsion or anhydrous base is added with surfactants in the case of anhydrous foams. Any organic solvents compatible with the active ingredient and with the characteristics of the container, and in particular, low boiling alcohols, for example ethyl alcohol, low boiling point acids, for example methylal, solvents, can be suitable as vehicles. highly soluble, such as acetone, N-methylpyrrolidone. The emulsion foams may be similar to the fomulations of locally used creams, or anhydrous bases in cases of non-aqueous foams containing mainly oils, higher alcohols such as cetylstearyl alcohol, myristyl alcohol, glycols such as propylene glycol, propylene glycol monostearate, and generally ethoxylated surfactants, such as polyglycosylated glycerides of vegetable oils. The invention relates to the combination of Diclofenac and Tianfenicol for the treatment of infections and related inflammatory conditions, preferably in the form of pharmaceutical formulations. The following examples further illustrate the invention without limiting it: EXAMPLE 1 Syrup containing 1% Diclofenac and 2.5% Tianfenicol Composition A dispersion of the active ingredients in polyethylene glycol, span 20 and sorbitol is prepared separately. In 30% of the volume of water, citric acid, potassium sorbate, polyvinylpyrrolidone is dissolved in sequence and veegum and carboxymethylcellulose are dispersed by means of a turbine diffuser. The dispersion of the active ingredients is added and diluted to the final volume with water. The resulting suspension has a pH of 4.20 and a viscosity of 150 cPs.

EXAMPLE 2 Antimastitis ointment containing 5% Diclofenac and 20% Tianfenicol Composition The fatty components are heated in a convenient melting of fat masses at a temperature of 15 ° C higher than the melting temperature of the mixture. The mixture is filtered in a sterile environment with a convenient filtering system equipped with a 0.2μ cartridge previously heated to 90 ° C and the mixture is transferred to an appropriate turbodifuge by means of a pump, the temperature is lowered to 30 ° C and the active ingredients sterilized previously are then introduced by vacuum suction. The turbine is kept shaking for 15 to 20 minutes, without exceeding a temperature of 50 ° C. The resulting ointment is distributed in a sterile environment in 5 ml syringes. The ointment is whitish and its viscosity is 300,000 cPs.

EXAMPLE 3 Ophthalmic or ear drops contain 0.1% sodium Diclofenac and 0.5% Tianfenicol Composition for a powder bottle Composition for a solution bottle In a volume of water corresponding to 2 ml per bottle, boric acid, borax, polyvinylpyrrolidone and diclofenac sodium are dissolved, heating slightly. The resulting solution is filtered in sterile environment and micronized Tianfenicol is added dispersing with a turbine. The suspension is distributed in sterilized bottles and dried by freezing. The diluent solution is prepared separately, solubilizing sodium ethylmercury thiosalicylate in the amount of water indicated. The formulated vials of 10 ml are sterilized in an autoclave at 121 ° C for 15 min.

EXAMPLE 4 The local spray contains 1% Diclofenac sodium and 5% Tianfenicol.

Composition for 100 g 120 g of the concentrate are distributed in pressure pumps containing 60 g of propellant of 25:75, propane / butane. The solution of the concentrate is prepared by dissolving the Tianfenicol and Diclofenac sodium at room temperature in N-methylpyrrolidone. The solution is heated to a temperature of 70-75 ° C and Patent Blue is dissolved, maintaining the stirring for 15 min. The temperature is lowered to 25-30 ° C. The plastoid B is solubilized separately in the alcohol and the methylal mixture and this solution is added to the one containing the active ingredients. The concentrate is distributed in pumps, which are pressurized with the propellant.

EXAMPLE 5 Injectable solution containing 5% Diclofenac sodium and 25% Tianfenicol Composition The injectable solution is obtained by solubilizing in succession Tianfenicol and Diclofenac in N, N-dimethylacetamide and subsequently diluting the final volume with propylene glycol. The resulting solution is filtered in a sterile environment through a 0.2μ filter and distributed aseptically in the previously sterilized bottles.

EXAMPLE 6 Tablets containing 100 mg of Diclofenac sodium and 500 mg of Tianfenicol Composition All solid components are sieved first with a 0.5 mm mesh screen. A mixture of the active ingredients and lactose is prepared separately, which is moistened and granulated with an aqueous solution of polyvinyl pyrrolidone, then dried in a forced air oven for 8 h at 60 ° C. The resulting granulated material is sieved through a 0.8 mm mesh screen and then mixed with the other components for 10 min. The final mixture is formed in 2g tablets.

Claims (5)

NOVELTY OF THE INVENTION CLAIMS

1. - Pharmaceutical compositions for veterinary use containing a combination of Tianfenicol and Diclofenac.

2. Compositions according to claim 1, for oral, parenteral or topical administration.

3. Compositions according to claim 2, for oral administration, in the form of powders, tablets, granules, capsules, pills, troches, syrups, oral suspensions and oral pastes.

4. Compositions according to claim 2, for parenteral administration in the form of large pills, injectable solutions and suspensions.

5. Compositions according to claim 1, for topical, intramammary, uterine, otic and auricular administration, in the form of ointments, creams, gels, ointments, foams or liquid sprays, dyes, drops, pessaries, gels.