Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C

Definitions

• This invention relates to a topical formulation which comprises Bacitracin and Polymyxin in combination with an antiseptic.
• the combination of the three actives is suitable for the treatment or prophylaxis of infection in minor cuts, wounds and scrapes.
• the topical application of the combination also facilities healing of minor cuts, wounds and scrapes.
• Bacitracin is a commercially available antibiotic and is a polypeptide complex produced by certain strains of Bacillus licheniformis and by B. subtilis var. Tracy.
• Commercial Bacitracin is a mixture of at least nine Bacitracins. On hydrolysis it yields the a ino acids L- cysteine, D-glutamic acid, L-histidine, L-isoleucine, L- leucine, L-lysine, D-ornithine, D-phenylalanine and DL- aspartic acid.
• Other reported forms of Bacitracin include Bacitracin methylenedisalicylic acid and its sodium salt and zinc Bacitracin.
• Polymyxin is a commercially available antibiotic complex produced by the growth of Bacillus polymyxa (Prazmowski) igula, or a mixture of two or more such salts. To date, Polymyxins A, B, C, D, E, F, K, M, P, S and T have been reported. Polymyxin B is a mixture of Polymyxins B. ⁇ and B 2 . Available derivatives of Polymyxin B include the sulphate salt, ie Polymyxin B sulphate, Polymyxin B-methanesulfonic acid and its sodium salt.
• the antiseptic suitable for use in the present combination include Cetrimide and Chlorhexidine both of which are commercially available. Cetrimide consists of tri ethyltetradecyl ammonium bromide and may contain smaller amounts of dodecyl- and hexadecyltrimethyl ammonium bromides. It contains not less than 96.0% and not more than 101.0% of alkyltrimethylammonium bromides, calculated as C 17 H 38 BrN (336.4) with reference to the dried substance.
• Chlorhexidine is N,N' -bis (4- chlorophenyl) -3, 12-diimino-2,4,11,13- etraazatetradecane- diimidamide. Available derivatives include the dihydrochloride salt and the diacetate and the digluconate.
• the present invention provides a pharmaceutical formulation comprising Bacitracin or a pharmaceutically acceptable derivative thereof, Polymyxin or a pharmaceutically acceptable derivative thereof and an antiseptic.
• the combination of the three actives is present in a pharmaceutically acceptable carrier.
• the antiseptic is selected from Cetrimide and Chlorhexidine.
• the Polymyxin is Polymyxin B sulphate.
• the combination of the three actives is presented is a gel, typically in a hydrogel for topical application.
• suitable forms of the formulation include ointment, cream, liquid, impregnated dressings or the like.
• the carrier is hydroxypropyl methylcellulose and water.
• the present invention provides a method of treatment or prophylaxis in a mammal of wound infection which comprises topical application to the wound a pharmaceutical formulation comprising Bacitracin, Polymyxin and an antiseptic.
• the present invention provides the use of Bacitracin and Polymyxin in combination with an antiseptic in the manufacture of a medicament for the treatment or prophylaxis of wound infection.
• compositions usually employed for topically administering drugs are applied in the form of an appropriate composition, in particular, compositions usually employed for topically administering drugs.
• compositions take a wide variety of forms such as for example, solid forms such as powders, liquid forms such as solutions or suspensions in aqueous or oily mediums; semi-liquid formulations, such as creams, gels, pastes, ointments, salves.
• the compositions ideally contain the active compounds in a wound-acceptable carrier. If desired, further ingredients may be incorporated into the composition. For example, anti- inflammatory agents, disinfectants, antibiotics, etc.
• wound covers such as plasters, bandages, dressings, gauze pads, and the like containing the combination according to the present invention may also be used. In particular, plasters, bandages, dressings, gauze pads and the like which have been impregnated or sprinkled with the liquid formulation containing the combination of the present invention can be used.
• Preferred composition of the present invention is a gel.
• the combination of the present invention is applicable to either humans or animals.
• An advantage of the present invention resides in the fact that beside having a beneficial effect on the prevention or reduction of infection, there is also a beneficial effect on the healing process. Wounds treated using the combination of the present invention will be less subject to or show an increased resistance to infections and the wound will heal more rapidly.
• compositions of the present invention can be prepared following methods generally employed in the art of pharmaceutical formulation.
• a typical formulation according to the present invention comprises Cetrimide (1,024 ⁇ g/ml) , Bacitracin
• Purified water 800 ml is heated to 80°C and hydroxypropyl methylcellulose (HPMC) USP (35g) is added slowly to the hot water with stirring until the dissolution of the powder is complete. The mixture is then allowed to cool to below 30°C.
• HPMC hydroxypropyl methylcellulose
• Polymyxin B sulphate USP (58.4 mg) is dissolved in purified water BP (30 ml) and to this solution is added, the solution comprising , HPMC and water.
• Cetrimide BP (1024 mg) is dissolved in purified water BP (50 ml) and to this is slowly added the solution of , HPMC and Polymyxin B sulphate. Finally, purified water BP is added to make the solution up to 1 litre.
• Geigy binomial confidence limits tables were used to determine the sample size of bacteria necessary to confirm the validity of an MIC value (Geigy Scientific Tables, 1982) . To have 95% confidence that an antimicrobial concentration would inhibit 97.5 ⁇ 2.5% of the bacteria of a given species, it was calculated that a sample of 72 organisms were required. Therefore it was aimed to collect 72 isolates of each of the eight targeted bacterial species for inclusion in MIC determinations for the four antimicrobials.
• M-H Mueller-Hinton (M-H) broth (Oxoid CM337) was prepared in deionised water, dispensed in 100ml volumes and sterilised at 121°C for 15 minutes. Each species of bacteria was subcultured into cooled broth and incubated at 35°C for 18 hours. Standardisation of Bacterial Inoculum
• the bacteria were adjusted to a known concentration of colony forming units/ml using spectrophotometric methods at 540nm.
• a 0.5 MacFarland standard is known to have an optical density which corresponds to 10 8 CFU/ml, and was prepared by adding 0.5ml of 0.048M BaCl 2 to 99.5ml of 0.18M H 2 S0 4 (NCCLS, 1985) .
• the overnight bacterial cultures were diluted with M-H broth until absorbance readings were equivalent to this and then further diluted 1/50 to standardize to 2xl0 6 CFU/ml.
• Antimicrobials are known to have an optical density which corresponds to 10 8 CFU/ml, and was prepared by adding 0.5ml of 0.048M BaCl 2 to 99.5ml of 0.18M H 2 S0 4 (NCCLS, 1985) .
• the overnight bacterial cultures were diluted with M-H broth until absorbance readings were equivalent to this and then further diluted 1/50 to standardize to 2xl
• Bacitracin, and Polymyxin B sulphate were prepared for each organism. Starting points were identified from MIC values previously determined using reference strains and from the literature.
• Each drug was prepared at the maximum required concentration in 100ml volumes of M-H broth, taking into account the standard units of activity associated with antibiotics. As assay units may differ widely from actual drug weight, the following formula was used to standardize solutions.
• MIC evaluations were carried out using standard microdilution methods for bacteria that grow aerobically (NCCLS, 1985) .
• the microtitre trays were Cel-Cult, 96 well, plastic, individually packaged, and gamma sterilised (Sterilin, code no. 239275) with lids.
• the growth medium used throughout was Mueller-Hinton broth.
• Antimicrobial drugs were evaluated in three drug combination with aims of
• the Geigy binomial confidence limits tables were used to determine the sample size of bacteria necessary to confirm the interactions of the three antimicrobial agents (Geigy Scientific Tables, 1982) . To have 95% confidence that a particular combination of drug concentrations would inhibit 85.5 ⁇ 14.5% of the bacteria of a given species, it was calculated that a sample of 11 organisms were required. These were collected from the hospitals and private pathology laboratories within the Sydney metropolitan area which were used for the MIC determinations. Growth Conditions Overnight cultures of bacteria were prepared as for the MIC evaluations. Antimicrobials
• the antimicrobials were the same as for the MIC determinations of the clinical isolates. Drugs were weighed and doubling dilutions prepared as for the MIC work. Concentrations ranged from the MIC to four dilutions below the MIC (MIC x 1/16) . Solutions were four times the required concentrations to account for the dilution occurring in the wells. The maximum recorded MICs were used to initiate concentration ranges for those antibacterial agents that individual organisms were not sensitive to.
• Microtitre trays were used as for the MIC determinations.
• An 8x8 matrix was established in the microtitre plates, with one antimicrobial increasing in concentration along the x-axis, and the other increasing along the y-axis.
• Each triple checkerboard was performed in duplicate.
• 40 ⁇ l of Bacitracin was dispensed into the wells, with a new concentration in each column (i.e. increasing along the x-axis) , commencing at column 2.
• 40 ⁇ l of Polymyxin B sulphate was dispensed into the wells, with a new concentration in each row (i.e. increasing along the y- axis) , commencing at row 2.
• Eight trays were prepared with the same two drug combination.
• Group G streptococci >4 0.5 >2 0.25 n.s. 64 n.s. this organism is not sensitive to this antibacterial drug
• a double-blind comparative clinical trial evaluated a topical preparation containing 1,024 ⁇ g/ml cetrimide, 16 units/ml bacitracin, and 512 units/ml polymyxin B sulphate in a 3.5% hydroxypropyl methylcellulose gel. Positive and negative controls were Betadine ® antiseptic cream and placebo gel, respectively.
• the multi-centre study was conducted in 5 primary schools using children aged 5-12 years with parental consent. As accidental minor injuries occurred, the participating children were treated with a randomly assigned topical preparation. Injuries were examined by a physician on the third day of treatment and a clinical outcome of 'no infection' or 'suspected' infection was established. If an infection was suspected, the injury was swabbed for microbiological evaluation.
• microbiological infections All those which were considered to be 'suspected infections' were recorded as clinical infections. Those clinical infections from which microbiological pathogens were isolated were classified as microbiological infections.
• Micro, infect. microbiological infection * _ one suspected infection was not swabbed
• test preparation containing cetrimide, bacitracin and polymyxin B sulphate prevented significantly more clinical infections of wounds than placebo.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Immunology (AREA)
• Medicinal Chemistry (AREA)
• Gastroenterology & Hepatology (AREA)
• Chemical & Material Sciences (AREA)
• Epidemiology (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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Cited By (2)

• 1994
  • 1994-11-11 AU AUPM9396A patent/AUPM939694A0/en not_active Abandoned
• 1995
  • 1995-03-23 WO PCT/AU1995/000159 patent/WO1996014859A1/en not_active Application Discontinuation
  • 1995-03-23 EP EP95912966A patent/EP0790832A4/de not_active Withdrawn
  • 1995-03-23 NZ NZ282738A patent/NZ282738A/en unknown

Non-Patent Citations (3)

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