Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention provides medicaments and methods for the treatment of infections caused or contributed to by multi-drug resistant bacterial species.
• Drug resistant microorganisms are becoming increasingly problematic as infection rates continue to rise and effective methods of control become more and more limited.
• the transmission and control of drug-resistant organisms is becoming one of the most significant problems within healthcare.
• Staphylococcus that have developed or obtained varying levels of resistance to antibiotics such as methicillin (meticillin). These strains are commonly known as methicillin resistant Staphylococcus aureus (MRSA).
• MRSA methicillin resistant Staphylococcus aureus
• coagulase-negative Staphylococci such as Staphylococcus epidermidis
• MRSE methicillin resistant
• Resistance to multiple antibiotics and the ability of S. epidermidis to form biof ⁇ lms on inert surfaces exacerbate the challenges of treating infections caused by these organisms.
• the acquisition of methicillin resistance among Staphylococcal species not only precludes the use of all currently available ⁇ -lactam antibiotics, but also is commonly associated with resistance to multiple drug classes.
• MRSA and MRSE are genotypically and phenotypically distinct from other Staphylococci; tending to form discrete clonal lineages.
• the acquisition of large mobile genetic elements carrying virulence and resistance determinants by these strains results in staphylococci that are often resistant to a number of drugs. Resistance can be specific, i.e. particular to a certain drug or class of drugs or non- specific in that the resistance applies to a range of drugs, not necessarily related.
• Methicillin resistant Staphylococci may be defined as Staphylococci that harbour the mecA gene. Expression of this gene yields PBP2a which confers resistance to all currently available ⁇ -lactam antibiotics.
• the presence of the gene or protein product may be detected by polymerase chain reaction (PCR) or latex agglutination assay respectively.
• PCR polymerase chain reaction
• the mecA gene and its regulators are present on a large DNA elements (SCCmec) which often carry other resistance and virulence genes.
• SCCmec DNA elements
• vancomycin a glycopeptide antibiotic
• MRSA methicillin resistant bacteria
• An objective of the present invention is to provide a new and effective treatment for infections caused or contributed to by methicillin resistant Staphylococci.
• the present invention provides clotrimazole or a derivative thereof, for treatment of an infection caused or contributed to by a methicillin resistant Staphylococcus species.
• the present invention encompasses clotrimazole for treating infections caused or contributed to by methicillin resistant strains of Staphylococcus such as, for example, Staphylococcus aureus and/or Staphylococcus epidermidis.
• Such strains may commonly be known as methicillin resistant Staphylococcus aureus (MRSA) or methicillin resistant Staphylococcus epidermidis (MRSE). While MRSA and MRSE may be defined as being resistant to methicillin, they may also be resistant to other types of antibiotic particularly those belonging to the ⁇ -lactam family such as flucloxacillin and oxacillin. It should be noted that the Staphylococcal strains encompassed by this invention may also be resistant to other antibiotics not mentioned here .
• solvate is used herein to refer to a complex of solute, such as a compound or salt of the compound, and a solvent. If the solvent is water, the solvate may be termed a hydrate, for example a mono-hydrate, di-hydrate, tri-hydrate etc, depending on the number of water molecules present per molecule of substrate.
• the present invention provides a method of treating a subject suffering from an infection caused or contributed to by a methicillin resistant Staphylococcus species, said method comprising the step of administering an effective amount of a compound comprising clotrimazole, or a derivative thereof.
• the present invention encompasses a method of treating an infection caused or contributed to by a methicillin resistant Staphylococcus species, said method comprising the step of administering an effective amount of clotrimazole or clotrimazole nitrate.
• compounds comprising clotrimazole and/or a derivative thereof may be administered orally, topically to the site of an infection, or intravenously.
• compounds comprising clotrimazole and/or a derivative thereof may be formulated as polymeric nanoparticles such as alginate or polylactide-co-glycolide nanoparticles, or as sterile pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient.
• Such carriers or excipients are well known to one of skill in the art and may include, for example, water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins, such as serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, lactic acid, water salts or electrolytes, such as protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cyclodextrins, such as ⁇ -cyclodextrin, ⁇ -cyclodextrin, sulfobutylether 7 - ⁇ cyclodextrin and hydroxypropyl- ⁇ -
• Clotrimazole is well absorbed in humans following oral administration and is eliminated mainly as inactive metabolites. Oral administration of 1.5-3-g doses of clotrimazole gave a half-life of around 3 hours; single or twice daily oral administration may be suitable for the treatment of multiresistant staphylococcal infections with clotrimazole. Less than 1% of the administered dose was detected in urine as active drug after 6 hours.
• a clotrimazole topical solution containing, for example, 10 mg/ml (1%) clotrimazole would be suitable for the treatment of multi-resistant staphylococci.
• concentration of Clotrimazole varied from 100 ⁇ g/cm 3 in the stratum corneum to 0.5 to 1 ⁇ g/cm 3 in the stratum reticulare, and 0.1 ⁇ g/cm 3 in the subcutis.
• Compounds comprising clotrimazole or a derivative thereof may be administered in combination with another treatment.
• compounds comprising clotrimazole and/or a derivative thereof may be administered in combination with another antibiotic, for example vancomycin, to reduce the likelihood of emergence of antibiotic resistance, or antifungal or antiviral, agents or compounds.
• clotrimazole and/or a derivatives thereof may be administered in combination with a chemotherapeutic agent, an immunostimulatory compound or drug, an oligonucleotide, a cytokine, hormone or the like.
• transdermal delivery device it may be possible to administer a compound comprising clotrimazole and/or a derivative thereof or any combined regime as described above, transdermally via, for example, some form of transdermal delivery device.
• Such devices are advantageous, particularly for the administration of antibiotic compounds, as they may allow a prolonged period of treatment relative to for example, an oral or intravenous medicament.
• transdermal delivery devices may include, for example, a patch, dressing, bandage or plaster adapted to release a compound or substance through the skin of a patient.
• a person of skill in the art would be familiar with the materials and techniques which may be used to transdermally deliver a compound or substance and exemplary transdermal delivery devices are provided by GB2185187, US3249109, US3598122, US4144317, US4262003 and US4307717.
• clotrimazole and/or a derivative thereof may be combined with some form of matrix or substrate, such as a non-aqueous polymeric carrier, to render it suitable for use in a transdermal delivery system.
• matrix or substrate such as a non-aqueous polymeric carrier
• the clotrimazole (and/or derivative)/matrix or substrate mixture may be further strengthened by the use of a woven or knit, non-woven, relatively open mesh fabric, to produce a patch, bandage, plaster or the like which may be temporarily attached to a particular region of a patient's body. In this way, while in contact with a patient's skin, the transdermal delivery device releases the compound or substance directly to the site of infection or through the skin as required.
• the medicaments and/or methods described herein may have particular application in institutions housing, sheltering, caring or otherwise holding people or patients vulnerable to or "at risk" of developing or contracting a methicillin resistant Staphylococcus species, especially for example MRSA or MRSE.
• the medicaments and methods may be particularly useful in hospitals, nursing homes, nurseries and/or schools. More generally, an elderly, young or immunocompromised person or patient may particularly benefit from the medicaments and methods described herein.
• the methods and medicaments of the present invention may be particularly useful to those undergoing a prolonged stay in hospital, for example in an intensive care facility. Additionally, or alternatively, the medicaments and methods described herein may be useful in community centres, sports facilities, shops, restaurants, cafes or other places where transmission of bacteria, particularly methicillin resistant Staphylococcus species, is likely.
• the methods and medicaments described herein may be used prophylactically as a means to prevent the development of an infection caused or contributed to by a methicillin resistant Staphylococcus species.
• Medicaments and/or methods for prophylactic use may be administered or applied to any person at risk of developing an infection caused or contributed to by a methicillin resistant Staphylococcus species. For example, people working in care homes, nursing homes, sports centres, community centres, shops, restaurants, cafes, nurseries and/or schools may require prophylactic treatments.
• the compounds provided herein may also be used as sterilising or cleaning aids for use, for example, on surfaces to reduce and/or eliminate contamination by methicillin resistant Staphylococcus species such as MRSA or MRSE.
• clotrimazole or derivatives thereof such as, for example clotrimazole, may be prepared for application to any surface suspected of being contaminated by methicillin resistant Staphylococcus species.
• compounds of the present invention may be added to or diluted in an appropriate excipient or solution prior to use as a sterilising or cleaning agent. Exemplary excipients are described above.
• Such sterilising or cleaning solutions may be used to decontaminate, for example, furniture, floors, equipment including for example specialised hospital equipment and/or surgical equipment.
• the present invention concerns the use of clotrimazole, or a derivative thereof, in the manufacture of an antibacterial agent against methicillin resistant Staphylococcus species.
• the compounds described herein may be used to eliminate and/or reduce contamination by methicillin resistant Staphylococcus species on parts of the body, particularly for example, the hands.
• Clotrimazole and/or a-derivative thereof may be diluted as an aqueous or non-aqueous solution (dissolved in aqueous, non aqueous or organic solvent) and which may be applied to a body part, for example the hands.
• aqueous or non-aqueous solution dissolved in aqueous, non aqueous or organic solvent
• Such a solution may find particular application in, for example hospitals, care homes and or nurseries where the prevalence and transmission rates of methicillin resistant Staphylococcus species are often high.
• clotrimazole was dissolved in methanol.
• Other solvents that may be used include caster oil, pyridine, DMSO and 0.9% saline.
• IV administration agents may be solubilised in polyethoxylated caster oil, or cyclodextrins such as sulfobutylether 7 - ⁇ cyclodextrin or hydroxypropyl- ⁇ -cyclodextrin and lactic acid.
• Minimum inhibitory concentrations (MICs) of a range of clinical and control bacterial organisms were measured according to BSAC (British Society for Antimicrobial Chemotherapy) guidelines, described briefly as follows; PREPARATION OF AGAR PLATES AND BROTHS.
• V volume required (niL)
• test organisms were grown overnight in 5mL 1ST broth. Using a dilution in 0.9% saline of 1:500 for Gram-negative organisms and 1:100 for Gram-positive organisms,
• the MIC is the minimum amount of an antibiotic at which there is no visible growth of bacteria. Tiny single colonies or faint hazes were not counted as growth.
• Clotrimazole demonstrated good activity against S. epidermis and a range of clinical MRSA strains (Table 1), but had no significant activity against Gram-negative organisms. Other related imidazoles did not inhibit the growth of any strain tested (Table 2).
• MICs Minimum inhibitory concentrations

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• 2007
  • 2007-11-15 EP EP07824594A patent/EP2094264A1/en not_active Withdrawn
  • 2007-11-15 KR KR1020097012452A patent/KR20090100358A/ko not_active Application Discontinuation
  • 2007-11-15 AU AU2007320931A patent/AU2007320931A1/en not_active Abandoned
  • 2007-11-15 JP JP2009536792A patent/JP2010510200A/ja active Pending
  • 2007-11-15 WO PCT/GB2007/004373 patent/WO2008059261A1/en active Application Filing
  • 2007-11-15 CA CA002669594A patent/CA2669594A1/en not_active Abandoned

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