MXPA96006361A - Microbia combinations - Google Patents

Abstract

The present invention relates to: Use of a pharmaceutical composition comprising a fluorinated quinolone, an ester or a salt thereof and a silver sulfadiazine in the preparation of a medicament for the treatment of an infection

Description

MICROBIAL OBILE COMBINATIONS BACKGROUND OF THE INVENTION Field of the Invention: The present invention relates to otic formulations and antimicrobial agents and more specifically to otic formulations containing a combination of antimicrobials such as quinolones and silver sulfadiazine. Brief Description of the Prior Art: U.S. Pat. 4,404,197 describes the use of certain quinolones and silver sulfadiazine in the treatment of burns. More specifically, the patent discloses compositions that include silver sulfadiazine and 1-ethyl-6-fluoro-1, -dihydro-4-oxo-7- (1-piperazinyl) -3-quinolone carboxylic acid or its metal salts, for example , salts of silver, zinc, cobalt or cerium. Explicitly, the patent teaches the use of these compositions in the treatment of burns, and to combat topical, superficial or skin infections, including fungal and microbial infections and the like. However, the patent fails to teach or suggest the use of the compositions for otic applications. The U.S. Patent No. 3,761,590 describes the use of silver sulfadiazine alone in burn therapy. The silver sulfa diazine, preferably in a hydrophilic carrier dispersible in water, is applied to the burn. Bogaard et al. Dep. Med. Microbiol., Univ. Limburg, Netherlands describes the use of silver sulfadiazine cream in the chronic treatment of Pseudo-monas infection in the external auditory canal in dogs. As will be appreciated, there is a need for an effective composition for the treatment of otic infections. The present invention provides a therapeutically effective combination of active ingredients that are useful in the treatment of otic infections. SUMMARY OF THE INVENTION According to the foregoing, the present invention comprises a composition that is useful in the treatment of otic infections in animals, said composition comprising a therapeutically effective combination of an antimicrobial such as an antibacterial agent that is preferentially a quinolone or a salt thereof, and silver sulfadiazine. The invention further encompasses the use of a composition comprising a therapeutically effective combination of an antimicrobial such as an antibacterial agent which is preferably a quinolone or a salt thereof, and silver sulfadiazine in the treatment of otic infections. Also encompassed by the present invention is a method for the treatment of otic infections by administration of the composition to animals, particularly small animals such as dogs. The composition containing a combination of an antimicrobial such as an antibacterial agent which is preferably a quinolone and silver sulfadiazine can be administered as such or with a physiologically acceptable carrier such as an aqueous emulsion oil. The composition can be used to safely and effectively treat otic infections such as infections of the external auditory canal. In particular, the composition can be used to treat infections caused by the bacterium Pseudomonas, or fungi, Malessezia pachydermi -tis. The invention is described more fully hereinafter.

DETAILED DESCRIPTION OF THE INVENTION As shown above, the present invention relates to a composition that is useful in the treatment of otic infections. The composition comprises a therapeutically effective co-nation of an antimicrobial such as an antibacterial agent which is preferably a quinolone or a salt thereof and silver sulfadiazine. Typically, quinolone is a fluorinated quinolone. The effective combination is described hereinafter with specificity as regards the quinolones. The invention, however, encompasses combinations of silver sulfadiazine and other antimicrobials that can be combined with silver sulfadiazine to provide effective treatment of otic infections in the form of the combination of silver sulfadiazine and quinolones. Non-limiting examples of fluorinated quinolone can be selected from the group consisting of Enrofloxacin, 6-fluoro-l, 4-dihydrodihydro-l- (methylamino) -7- (4-methyl-l-pi-perazinyl) -4-oxo- 3-quinolonecarboxylic acid (Amifloxacin); Be-nofloxacin; 6-Fluoro-1- (4-fluorophenyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolonecarboxylic acid (Di-floxacin); Flerofloxacin, 6, 8-difluoro-1- (2-fluoreyl)) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-qui-nolonacarboxylic acid (Fleroxacin) , l-ethyl-6,8-difluoro-1,4-dihydro-7- (3-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid (Lomefloxacin); Marbofloxacin; 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (piperazinyl) -3-quinolo-nacarboxylic acid (Norfloxacin); 9-Fluoro-2, 3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyrido [1,2,3-de] -1,4-benzoxazin- acid 6-carboxylic acid (Ofloxacin); Perfloxacin; Ru-floxacin; Sarafloxacin; and Temafloxacin. The fluorinated quinolone preferred herein is Enrofloxacin. The U.S. Patent4. 556,658 which is incorporated herein by reference provides an illustrative but non-limiting description of quino-canvas with particularity Enrofloxacin and a method for preparing the same. The quinolone or the salt thereof and the silver sulfadiazine are employed in an amount sufficient to provide a composition that will be pharmaceutically effective. The quinolone or the salt thereof may be employed in an amount of 0.005 to 1.5 weight percent of the composition and preferably 0.1 to 1 weight percent of the composition. The silver sulfadiazine may be employed in an amount of 0.05 to 2 percent of the composition, and preferably in an amount of 0.5 to 1.5 percent of the composition. In the preparation of the composition, the quinolone and the silver sulfadiazine may be combined in any conventional manner. For example, sulfadiazine from ground silver and quinolone can be mixed with one another. The composition can be used directly or preferably in formulation with a pharmaceutically acceptable physiological carrier. A non-limiting example of a pharmaceutically acceptable physiological carrier can be an aqueous emulsion oil. Typically, the oil is a non-irritating emollient oil. An illustrative but not limiting example thereof may be selected from the group consisting of a mineral oil, vegetable oil and a reformed vegetable oil of known composition. More specific but non-limiting examples of the oil can be selected from the group consisting of peanut oil, sesame seed oil, cottonseed oil, etc; medium chain triglycerides (C6 to C? 2) (for example, Miglyol Neutral Oil 810, 812, 818, 829, 840, etc.) available from Huils America Inc. Typical emulsifiers employed herein can be selected from the group consisting of Span 60 which is sorbitana monostearate and T een 60, which is Polysorbate 60 (both of which are available from ICI Americas). Preferably, the emulsifiers are nonionic. The emulsifiers can be employed in an amount of 1.5 to 6.5 weight percent of the composition and preferably 3.0 to 5.0 weight percent of the composition. The hydrophobic phase of the emulsion may be in an amount of 15.0 to 25.0 weight percent of the composition and preferably 18.0 to 22.0 weight percent of the composition. It is a distinctive feature of the invention that the composition of the invention can be formulated as an emulsion base comprising oil-in-water emulsions described herein. Until now, silver sulfadiazine had been formulated as a cream base or a solid synthetic dressing for use in burn therapy. The related silver nitrate solutions were considered undesirable. In addition to the above components, a formulation of the composition of the invention may contain other components such as preservatives (benzyl alcohol, para-benzenes, or benzoates), stabilizers (cetyl stearic alcohol, glycerol esters), odor masking agents and coloring agents. The following is an illustrative but not limitative description of a method for providing the compositions of the invention. In an appropriately equipped vessel, an emulsifier and a fatty acid alcohol were heated in an oil to form a suspension, and the active ingredients were added to the suspension. In a different container, an emulsifier was added to hot water to form an aqueous solution. A condom and suspension were added to the solution, with vigorous mixing. The resulting mixture comprising the composition of this invention is effective for the treatment of otic infections. In the treatment of otic infection, the composition is preferably administered by topically applying it in a pharmaceutically effective amount. The composition can be applied at a dose of five to twenty drops per ear and preferably at a dose of eight to twelve drops per ear when it is necessary to cover the ear canal. The composition can be applied twice a day. These and other aspects of the invention are further illustrated by the following non-limiting examples in which all parts and percentages are by weight unless otherwise specified. EXAMPLES The following examples illustrate the ear compositions of the present invention and the methods of preparation and use thereof. In the present embodiment of the invention, silver sulfadiazine and quinolone are combined as follows. Polysorbate 60 (Tween 60) was added to water in an SS-coated cu-beta at a temperature of 50 to 60 ° C. The resulting aqueous solution was heated from 61 to 75 ° C. At a temperature of 66 ° C, a condom (benzyl alcohol) was added to the aqueous solution while mixing for three to ten minutes. At a temperature of 75 ° C, Enrofloxacin and silver sulfadiazine were added to Mygliol Oil in a separate vessel for a period of three to five minutes. They were added to the oil mixture sorbitan monostearate (Span 60) and cetyl stearyl alcohol. The resulting oily mixture was heated to 62 to 75 ° C. The oily mixture was then added with vigorous mixing to the aqueous solution at a temperature of 66 ° C for a period of three to five minutes. The resulting composition was cooled from 35 to 45 ° C and homogenized by mixing with a high shear emulsifier or processing it through a homogenizer. The composition was further cooled from 25 to 30 ° C. The final composition was packed in appropriate containers. Examples 1-3 describe the use of the above method and the following ingredients in parts by weight listed below to prepare formulations containing the compositions of the invention. Example 1: Ingredients Parts by weight Enrofloxacin 0.005-1.5 Sulfadiazine silver (SSD) 0.05-2.0 Polysorbate 60 0.5-3.5 Sorbitan monostearate 0.5-3.0 Cetyl stearyl alcohol 0, 5-3.0 Benzyl alcohol 1.0-3.0 Miglyol oil 8-18 Water 89.4-68 Example 2: Ingredients Parts by weight Enrofloxacin 0.5-1.0 Silver sulfadiazine (SSD) 0.5-1.5 Polysorbate 60 1.0-3.0 Sorbitan monostearate 1.0-2.0 Cetyl stearyl alcohol 1.0-2.0 Benzyl Alcohol 1.5-2.5 Miglyol Oil 12-16 Water 85-74 Example 3: Ingredients Part is by weight Enrofloxacin 0.5 Sulfadiazine silver (SSD) I r 0 Polysorbate 60 2.5 Sorbitan monostearate 1.5 Cetyl stearyl alcohol 1/5 Benzyl alcohol 2.0 Miglyol oil 14.5 Water 76, 5 Example 4 An in vitro microbiology study of the combination of Enrofloxacin (quinolone) and sulfadiazine on multiple canine otic pathogens was carried out. The study was carried out under the guidelines of the National Coalition for Clinical Laboratory Standards (NCCLS) using ATCC control organisms for each agar plate tested. Initially, minimal inhibitory concentrations (MICs) were established for each active ingredient. Both, enrofloxacin and silver sulfadiazine (SSD) were active on common dermal (otic) pathogens, based on MICs. Each one has a different mode of action, although both are bacterial. The different modes of action reduce the potential for the development of resistance. Additionally, Enrofloxacin was not effective on Melessezia or Candida at the concentrations tested. Silver sulfadiazine was effective on both. Evidence of activity on Malassezia by silver sulfadiazine has not been previously reported. Using MIC data, agar plates were prepared containing serial dilutions of each antimicrobial in combination, using a standardized checkerboard system. To identify the possible interactions between Enrofloxacin and silver sulfadiazine, dilutions were prepared, which were for the most part, from three dilutions above to three dilutions below the MIC for each of the antimicrobials. The growth patterns (inhibition) of the individual isolates were compared after exposure to antimicrobials. Those of a single gender with the same answer were grouped together. All the isolates were then subjected to a mathematical calculation designed to indicate whether the antimicrobials were antagonists, synergists or elsewhere among them. The normalized calculation called Fractional Inhibitory Concentration Index (FIC) is presented below: X + - ^ - = FICX + FICY = FIC MICX MICY Index where X is equal to a concentration of drug X which is the lowest inhibitory concentration in its checkerboard row, and Y is equal to a concentration in its checkerboard row. The FIC index equal to or less than 0.5 indicates synergism or.

The FIC index equal to or greater than 2.0 indicates antagonism. The FIC index equal to or greater than 0.5 but less than 2.0 indexes without effect. For comparison purposes, Enrofloxacin was also combined with clotrimazole. Clotrimazole has antifungal activity but essentially has no activity on bacteria. The same series of pathogens was used to evaluate both antimicrobial combinations. The FIC data are presented below from the study indicating the response observed from the two combinations.

(Table 1) TABLE 1 Antimicrobial interaction range Fractional inhibitory concentration index Enro * Entity + Enro + Clotr SSD Pseudomonas aeruginosa (15) ** 0.507 to 0.751.167 to 2.67 Staphylococcus intermedius (12) 1.5 1.5 Escherichia coli (7) 0.36 to 1.5 0.8 to 1.8 Klebsiella pneumoniae (5) 0 , 62 to 1.5 1.8 to 2.3 Beta-hemol Streptococcal (9) 0.625 to 1.5 0.75 to 2.25 Malassezia sp (12) 1.5 0.56 to 1.5 Candida sp (4) 1.5 to 1.75 1.5 * The abbreviations of the drugs are: Enro = Enrofloxacin SSD = Sulfadiazine silver Clotr = Clotrimazole The numbers in parentheses indicate the numbers of isolates tested. As for the isolates mentioned above, the combination of Enrofloxacin and silver sulfadiazine had no values in the antagonist category. The FIC indices for many of the bacterial isolates were less than 1.0 showing a clear tendency towards an additive effect. A few calculations suggested synergism. There was less of a trend for an additive effect with Malassezia and Candida.

The additive effect of Enrofloxacin and silver sulfadiazine could not have been predicted because the combination of antimicrobials with different modes of activity could easily have already demonstrated antagonism. The antagonism was clearly demonstrated, for example, with the combination of Enrofloxacin and Clotrimazole. In three of the five bacterial genera cited above, a score higher than 2 was calculated. Clotrimazole has no antibacterial activity, even the data indicated that the drug apparently interfered with the antibacterial effect of Enrofloxacin. Although the invention has been described in detail in the foregoing for purposes of illustration, it is understood that said detail is for that purpose only and that variations may be made therein by those skilled in the art without departing from the spirit and scope of the invention. except in what may be limited by the claims.

Claims (17)

1. CLAIMS 1. A composition that is useful in the treatment of otic infections, comprising a silver antimicrobial and sulfadiazine in a therapeutically effective combination for treating otic infections in animals.
2. 2. The composition of Claim 1, wherein the antimicrobial is a quinolone or a salt thereof.
3. 3. The composition of Claim 2, wherein the quino-tarpaulin is a fluorinated quinolone, a fluorinated quinolone ester or a fluorinated quinolone salt.
4. 4. The composition of Claim 3, wherein the fluorinated quino-sheet is selected from the group consisting of Amifloxa-cin, Benofloxacin, Difloxacin, Enrofloxacin, Flerofloxacin, Fleroxacin, Lomefloxacin, Marbofloxacin, Norfloxacin, Oflo-xacin, Perfloxacin, Rufloxacin, Sarafloxacin and Temafloxa-cin.
5. 5. The composition of Claim 4, wherein the fluorinated quino-sheet is Enrofloxacin.
6. The composition of Claim 1, wherein the anti-microbial is present in an amount of 0.005 to 1.5 weight percent of the composition.
7. The composition of Claim 6, wherein the antimicrobial is present in an amount of 0.1 to 1 weight percent of the composition.
8. The composition of Claim 1, wherein the sulfadiazine is present in an amount of 0.05 to 2 weight percent of the composition.
9. 9. The composition of Claim 8, wherein the sulfadiazine is present in an amount of 0.5 to 1.5 percent of the composition.
10. 10. The composition of Claim 1 which further comprises a pharmaceutically acceptable carrier.
11. 11. The composition of Claim 10, wherein the carrier comprises an emulsion.
12. 12. The composition of Claim 11, wherein the emulsion is oil in water.
13. The composition of Claim 11, wherein the emulsion contains an emulsifier which is present in an amount of 1.5 to 6.5 weight percent of the composition.
14. 14. The composition of Claim 11, wherein the emulsion contains a non-aqueous phase in an amount of 15 to 25 weight percent of the composition.
15. 15. A method of treating an otic infection in an animal comprising administering the composition of Claim 1 to an animal having an otic infection.
16. 16. The method of Claim 15, wherein the composition is administered in a pharmaceutically effective amount.
17. 17. The method of Claim 15, wherein the composition is administered twice a day.