SK5682000A3 - 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

Pharmaceutical composition

Technical field

The invention relates to a pharmaceutical composition comprising thiamphenicol and diclofenac for use in veterinary medicine for the treatment of infections associated with inflammatory conditions.

BACKGROUND OF THE INVENTION

Different organs and systems infected with infections very often suffer from the effects of inflammation itself (swelling, pain, loss of functionality, increase in mucosal or mucosal / catarrh secretions, etc.) as well as general symptomatology characterized by fever, anorexia, sensory drowsiness, etc.

In the veterinary field, the damage caused by inflammation is sometimes more severe than those caused by the infection itself, both in terms of animal health and loss of production or quality changes in products (for example, milk quality in case of mastitis).

In veterinary practice, but also in humans, antibiotics and anti-inflammatory agents are often administered simultaneously, but in various formulations, to counteract the harmful effects of infection associated with inflammatory conditions. This method of treatment involves the non-negligible disadvantages of repeated administrations with the resulting possible errors at times and doses of various products, except for patient discomfort.

The combination of oxytetracycline (an antibiotic) with flunixineglumine (an anti-inflammatory agent) is known in the veterinary field. The disadvantage of the combination is that it is only effective against a narrow spectrum of infections caused by Gram + and Gram-bacteria, and its use is therefore limited.

Further, pharmaceutical compositions based on antibiotics and steroidal anti-inflammatory agents for topical use are known.

Surprisingly, it has been found that the combination of thiamphenicol with diclofenac

In a single preparation, it is more effective in treating infections associated with inflammatory conditions than the single administration of the two active main ingredients.

Thiamphenicol is an antibiotic belonging to the class of phenolates that have a broad spectrum of antibacterial activity. At the pharmacokinetic / pharmacodynamic level, thiamphenicol has low plasma protein binding, rapid and complete absorption, good tissue distribution; moreover, it is not metabolized and therefore circulates in free form in the body.

Diclofenac is a molecule that has higher anti-inflammatory, antipyretic and analgesic effects than other NSADs. At the pharmacokinetic level, diclofenac is rapidly and completely absorbed and widely distributed in tissues.

In addition to the benefit of clinical efficacy in the treatment of inflammation-related infections, the combination of two agents in a single formulation provides the following benefits in the veterinary field:

1. Reduction of dosing errors;

2. a wide range of antibiotic activity, which is particularly useful in veterinary medicine;

3. reduction of injection sites and injected volumes, as well as labor costs;

4. similar absorption and elimination of the two combined substances, which allows to control break times. For the farmer, this means the exact time to slaughter the animal or obtain milk and therefore better control of operations, especially on large-scale farms.

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition comprising thiamphenicol (TAF) and diclofenac (DCF) suitable for oral, parenteral and topical administration.

The pharmaceutical composition, which may be in solid, liquid, semi-solid or spray form, contains the active ingredients dispersed or dissolved and uses pharmaceutically acceptable vehicles and carriers selected to provide rapid or extensive release of the drug.

Dose interval ranges will depend on many factors, such as the weight of the animal and the severity of the infection being treated. Examples of preferred dosages for various pharmaceutical compositions are as follows.

Oral unit dosage formulations: DCF 20 mg to 1 g + TAF 100 mg to 5 g and preferably DCF 100 mg + TAF 500 mg.

Oral multidose pharmaceutical compositions: DCF 0.5 to 5% by weight + TAF 5 to 60% by weight and preferably DCF 5% by weight + TAF 20% by weight.

Injectable pharmaceutical compositions: DCF 2 to 10% by weight + TAF 10 to 50% by weight and preferably DCF 5% by weight + TAF 25% by weight.

Intramammary ointment / spray formulations: DCF 2 to 10% by weight + TAF 10 to 50% by weight and preferably DCF 5% by weight + TAF 25% by weight.

Topical pharmaceutical compositions: DCF 0.5 to 5% by weight + TAF 2 to 10% by weight and preferably DCF 1% by weight + TAF 5% by weight.

Intrauterine pharmaceutical compositions: DCF 2 to 10% by weight + TAF 10 to 50% by weight and preferably DCF 5% by weight + TAF 25% by weight.

Ophthalmic and aural pharmaceutical compositions: DCF 0.05 to 1% by weight + TAF 0.2 to 5% by weight and preferably DCF 0.1% by weight + TAF 5% by weight.

Solid pharmaceutical compositions (especially for oral use) include powders, tablets, granules, capsules (both soft gelatin and hard gelatin capsules), pills, lozenges, boluses and pessaries (for intrauterine use).

The antibiotic and the anti-inflammatory agent may 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, cellulosic substances; disintegrants such as amides and carboxymethylamide, cross-linked polyvinylpyrrolidone, agar, alginic acid and salts thereof,

Such as sodium alginate. In addition, such compositions may also contain glidants, lubricants, and tabletting aids such as talc, stearic acid, magnesium stearate, silicic acid, polyethylene glycols, hydrogenated castor oil; pigments such as titanium dioxide and coloring agents; release controlling agents such as cellulose polymers and other substances.

Thus, all pharmaceutical technology materials can be used as long as they are compatible with the active constituents.

Alternatively, the active ingredients may be incorporated 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, generally glycerol and sorbitol.

Syrups, oral suspensions and oral pastes contain the active ingredients dispersed in a suitable carrier consisting of water, oily solvents, alcohols or polyalcohols and inorganic suspending agents such as colloidal silicates having a high aluminum and magnesium content such as bentonite, veegum, kaolin and colloidal silica such as Aerosil, Carbosil; organic stabilizers; swelling agents such as alginates, acacia, tragacanth, carrageenans, guar gum, agar and lipophilic thickening agents, for example, in the case of oil pastes, synthetic or semi-synthetic agents such as ethylene oxide homopolymers, for example Polyoxil, preferably cellulose ethers, for example methyl or ethylcellulose , hydroxyethylcellulose, hydroxypropylethylcellulose, carboxymethylcellulose, microcrystalline cellulose; soluble polyvinyl materials such as polyvinyl acetate, polyvinyl alcohol and polyvinylpyrrolidone; sweeteners such as glucose, fructose, xylose; coloring agents; flavors; antioxidants such as sulfites, propyl gallates, butylhydroxyanisole, dithiopropionic acid; buffering agents.

Parenteral pharmaceutical compositions include liquid pharmaceutical forms prepared by treating an antibiotic and an anti-inflammatory agent in a sterile carrier.

The active ingredients may be either suspended or dissolved in the carrier, depending on their nature and their concentration. In the preparation of solutions are active

The 5-major components dissolve 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 for sterilization before they are divided into suitable containers. Specific adjuvants such as preservatives, local anesthetics, buffering agents may be dissolved in the carrier. The compositions may be freeze-dried to increase stability and marketed with a solvent container for reconstitution prior to use.

Parenteral suspensions are prepared in substantially the same manner except that the previously sterilized active ingredients are suspended and not dissolved in the carrier. A humectant or surfactant may be used to facilitate the homogeneous distribution of the active ingredients. Parenteral suspensions are typically oil suspensions with a lipophilic carrier, such as fatty oils, for example, sesame oil, synthetic fatty acid esters, such as ethyl oleate, or triglycerides or diglycerides, such as fractionated coconut oil and propylene glycol dicypryldicaprate. In the case of aqueous suspensions, thickeners such as sodium carboxymethylcellulose, polyvinylpyrrolidone, dextrans, sorbitol and stabilizing agents may be incorporated.

Formulations intended for topical use in the veterinary field are administered by the intramammary, intrauterine, ocular and ear routes, and are mainly ointments, creams, gels, healing ointments and liquid spray products or foams, elixirs and drops. Ointments contain the active principal ingredients suitably micronized, dispersed in an emulsified base (cream) or in a single phase, generally in an anhydrous vehicle. Oil-in-water emulsions have a water content of> 50% by weight, water-in-oil emulsions containing up to 70% by weight, but preferably 20 to 50% by weight, of water or an aqueous phase. Suitable hydrophilic emulsifiers, for example nonionic surfactants, such as fatty acid esters of polyalcohols or ethylene oxide, such as sorbitan polyethoxylate esters (tween), polyoxyethylene alkyl ethers (cetheareth-20), and ionic surfactant derivatives such as alkylsulfonate are present. arylsulfonate derivatives such as sodium lauryl sulfate, sodium cetyl sulfate, and

-6 lipophilic emulsifiers such as sorbitan esters, for example sorbitan monooleate and sorbitan isostearate. The oily components of these formulations comprise hydrocarbons such as white soft paraffin and / or liquid paraffin and / or hard paraffin, natural or synthetic fats such as coconut oil triglyceride, hydrogenated oils such as hydrogenated castor oil, glycerol partial esters of fatty acids such as glyceryl mono- and distearate, fatty acids such as palmitic acid and stearic acid, solid waxes such as beeswax, sheep wool fat, fatty alcohols or esters such as cetyl or stearyl alcohols, or alcohol derivatives of sheep's wax. In creams, aqueous phase vehicles, for example polyalcohols such as glycerol, sorbitol, propylene glycol, and / or polyethylene glycol, as well as antimicrobial preservatives, can be used to prevent drying of the aqueous phase.

In the case of gels, which may be anhydrous or aqueous, various gelling agents are generally used, such as those already cited for oral suspensions, including inorganic substances, natural, synthetic or semisynthetic organic macromolecules. Endomammary ointments are prepared in unit dosage form, usually in syringe tubes, to facilitate intra-canal administration and to protect the sterility of the product.

Foams and spray solutions are extruded from pressurized containers containing a suitable propellant such as halogenated hydrocarbons such as dichlorodifluoromethane and dichlorotetrafluoroethane and hydrocarbons such as butane, propane and isobutane. Such products are obtained by preparing a concentrate containing the active ingredients in the form of a solution, emulsion or anhydrous base added with surfactants in the case of anhydrous foams.

Suitable carriers for topical sprays can be all organic solvents compatible with the active ingredient and container characteristics, and in particular are low-boiling alcohols such as ethyl alcohol, low boiling acetals such as methyl, high performance solvents such as acetone, N-methylpyrrolidone. Emulsion foams may be similar to cream preparations for topical use, or anhydrous bases in the case of non-aqueous foams containing mainly oils, higher alcohols such as cetyl stearyl alcohol, myristyl alcohol, glycols,

Such as propylene glycol, propylene glycol monostearate and generally ethoxylated surfactants such as polyglycosylated vegetable oil glycerides.

The invention relates to a combination of diclofenac and thiamphenicol for the treatment of infections and related inflammatory conditions, preferably in the form of suitable pharmaceutical preparations.

The following examples further illustrate the invention without limiting it.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Syrup containing 1% diclofenac and 2.5% thiamphenicol

Composition of diclofenac thiamphenicol

Polyvinylpyrrolidone polyethylene glycol 200 solution 70% by weight sorbitol veegum span 20 potassium sorbate

Average viscosity carboxymethylcellulose sodium citric acid saccharin sodium water

1.00 g 2.50 g 2.00 g 20.00 g 25.00 g 0.50 g 1.00 g 0.10 g

0.60 g 0.20 g 0.30 g to 100.00 ml

Dispersions of the active constituents in polyethylene glycol, span 20 and sorbitol were prepared separately. It dissolves gradually in 30% by volume of water

-8 citric acid, potassium sorbate, polyvinylpyrrolidone and dispersed veegum and carboxymethylcellulose using a turbine diffuser. A dispersion of the active ingredient is added and diluted to a 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% thiamphenicol

Ingredients micronized diclofenac 5.00 g micronized thiamphenicol 20.00 g white soft paraffin 10.00 g mono- and diglycerides of fatty acids 10.00 g polyoxyethylated cetylstearyl alcohol 1.00 g light liquid paraffin up to 100 ml

The fatty components are heated in a suitable fatty melter to a temperature 15 ° C higher than the melting point of the mixture.

The mixture is filtered for sterilization with a suitable filtration system equipped with a 0.2 μ cartridge pre-heated to 90 ° C and transferred by pump to a suitable turbo-diffuser, cooled to 30 ° C, then pre-sterilized active ingredients are sucked under vacuum. . Stirring is maintained for 15 to 20 minutes while the temperature does not reach 50 ° C. The resulting ointment is dispensed into sterile 5 ml syringes.

The ointment is whitish and has a viscosity of 300,000 cPs.

Example 3

Eye and ear drops containing 0.1% diclofenac sodium and 0.5% thiamphenicol

-90.01 g

0.05 g

0,07 g

Composition for 1 powder vial diclofenac sodium micronized sterile thiamphenicol boric acid borax polyvinylpyrrolidone

Composition for 1 solvent vial ethylmercuritiosalicylate sodium distilled water

0.0075 mg 0.100 g

0.001 mg to 10 ml

Boric acid, borax, polyvinylpyrrolidone and sodium diclofenac are dissolved in a volume of water corresponding to 2 ml for each vial and gently warmed. The resulting solution is filtered for sterilization and micronized thiamphenicol is added and the mixture is dispersed by turbine. The suspension is dispensed into sterile vials and dried. Separately, a diluent solution is prepared by dissolving sodium ethylmercurithosalicylate in a given amount of water.

The 10 ml vials thus prepared are autoclaved at 121 ° C for 15 minutes.

Example 4

Topical spray containing 1% diclofenac sodium and 5% thiamphenicol

Ingredients for 100 g diclofenac sodium 1 g thiamphenicol 5 g methyl 30 g absolute ethyl alcohol up to 100 g

-1025 g

1.4 g

0.1 g

120 g of the concentrate is dispensed into pressurized cylinders containing 60 g of propane / butane propellant / 25:75 propellant. A solution of the concentrate is prepared by dissolving at room temperature thiamphenicol and sodium diclofenac in N-methylpyrrolidone.

The solution is heated to 70-75 ° C and the Blue patent is dissolved, stirring is maintained for 15 minutes. Cool to 25-30 ° C.

Separately, the plastoid B is dissolved in a mixture of alcohol and methyl and this solution is added to a solution containing the active constituents.

The concentrate is divided into cylinders which are pressurized with propellant.

Example 5

Injectable solution containing 5% diclofenac sodium and 25% thiamphenicol

Patent-methylpyrrolidone plastoid B patent Blue

Ingredients diclofenac sodium thiamphenicol (N, N) -dimethylacetamide propylene glycol

5g 25 g 40 g to 100 ml

The injectable solution is obtained by successively dissolving thiamphenicol and diclofenac in N, N-dimethylacetamide and then diluting to a final volume with petroleum glycol oil. The resulting solution was filtered for sterilization through a 0.2 µ filter and distributed under aseptic conditions into pre-sterilized vials.

Example 6

Tablets containing diclofenac sodium 100 mg and thiamphenicol 500 mg

-11 Ingredients diclofenac sodium thiamphenicol lactose for direct tableting anhydrous colloidal silica polyvinylpyrrolidone microcrystalline cellulose corn starch purified water

100 mg 500 mg 350 mg 30 mg 50 mg 350 mg 620 mg required

All solids are first sieved with a 0.5 mm sieve. Separately, a mixture of the active ingredients and lactose is prepared which is wet and granulated with a polyvinylpyrrolidone aqueous solution, then dried in a forced air oven for 8 hours at 60 ° C. The resulting granulate is passed through a 0.8 mm sieve and then mixed with the other ingredients for 10 minutes. The finished mixture is tableted to 2 g tablets.

Claims (5)

PATENT CLAIMS Pharmaceutical composition for veterinary use, characterized in that it comprises a combination of thiamphenicol and diclofenac. 2. A pharmaceutical composition according to claim 1 which is in a form for parenteral or topical administration. Pharmaceutical composition according to claim 2, characterized in that it is in the form of oral administration in the form of powders, granules, capsules, pills, lozenges, suspensions and oral pastes. 4. A pharmaceutical composition according to claim 2 in the form of parenteral administration in the form of injectable solutions and suspensions. Pharmaceutical composition according to claim 2, characterized in that it is in the form of topical, intramammary, intrauterine, ocular and ear administration, in the form of ointments, creams, gels, balsams, liquid spray products or in the form of foam. tinctures, drops, pessaries, gels.