Patent Description:
Both the (R)-ornidazole enantiomer (hereinafter refered to as, "(R)-ornidazole"), and the (S)-ornidazole enantiomer (hereinafter refered to as, "(S)-ornidazole") have both different and unique individual spectrums of activity as well as pharmacological & safety advantages over racemic ornidazole (rac)-ornidazole). (rac)-ornidazole is a new chemical entitiy (NCEs) in the United States and has not been marketed in this jurisdiction or cleared by the Food & Drug Administration (FDA).

The beneficial properties of (rac)-ornidazole include a favorable pharmacokinetic and pharmacodynamic profile and high degree of susceptibility to pathogenic strains of bacteria when the right (minimum inhititory or bacteriocidal) drug concentrations are employed at the site of infections. In addition, (rac)-ornidazole is effective at treating and eradicating bacterial biofilms of many pathogens that have sensitivity in their planktonic forms at lower MICs than the biofilm form. Many bacterial species are inducible facultative morphologs. An inducible facultative morpholog species can reversibly change configuration from planktonic to biofilm forms and morphological intermediates (such as round body / cystic / and spore forms) based on environmental conditions and through quorem sensing mediated by chemical signalling.

These inducible morphologies, e.g., biofilms and their intermediate forms, have MICs that can be orders of magnitude higher than the planktonic forms of the bacteria. The lethal dose of the antibiotics for bacteria in the biofilm form is called the "minimial bacterial eradication concentration" or "MBEC". The ability ability of the bacteria to shift into a biofilm form serves as an antimicrobial resistance (AMR) mechanism for usually adminstered dosages of antimicrobials.

(rac)-ornidazole is higly effective in treating biofilms bacterial configurations that these bacteria utilize to combat therapeutics and maintain recurrence reservoirs. The microorganisms in biofilms live in a self-produced matrix of hydrated extracellular polymeric substances (EPS) that form their immediate environment. EPS are mainly polysaccharides, proteins, nucleic acids and lipids; they provide the mechanical stability of biofilms, mediate their adhesion to surfaces and form a cohesive, three-dimensional polymer network that interconnects and transiently immobilizes biofilm cells. In addition, the biofilm matrix acts as an external digestive system by keeping extracellular enzymes close to the cells, enabling them to metabolize dissolved, colloidal and solid biopolymers.

Planktonic isolates are susceptible to common antibiotics. Strains in biofims and anaerobic configurations are markedly resistant to many antimicrobial agents. However, many of these biofilms and perisistor cells within the biofilm are sensitive to (rac)-ornidazole when exposed to a MBEC and when used in combination with monosaccharides and oligosaccharides that increase the metabolic activity of the cells within the biofilm increasing antimicrobial uptake and toxicity.

Thus, the use of (rac)-ornidazole may provide a number of advantages including, for example, formulations targeting the site of infections or dysbiosis / bacterial overgrowth in biofilms or forumulations utilizing smaller amounts of the active drug than alternative treatments, so that patients can ingest smaller tablets or capsules, or allowing the (rac)-ornidazole to be combined with other active agent(s) in a single unit dosage form; allowing more convenient dosing schedules and increasing patient compliance. For example, (rac)-ornidazole is rapidly absorbed after oral administration and have a longer terminal elimination half-life (approximately <NUM>-<NUM> hours) than commonly used drugs in the imidazole class. Accordingly these drugs may be administered less frequently and/or at a lower dose, thus improving patient compliance while providing a therapeutically effective treatment of an infection.

Additionally, (rac)-ornidazole is more active than metronidazole, another nitroimidazole used therapeutically, for many anaerobic and aerobic bacterial strains (including both Gram positive and Gram negative strains). Even against strains in which (rac)-ornidazole is as active, or even less active than metronidazole, they still offers other benefits.

(rac)-ornidazole is active against both susceptible and resistant strains of anaerobic or aerobic, Gram negative or Gram positive bacteria. Resistant strains of a specific bacteria are strains of that bacteria which are resistant to one or more drugs normally used to treat bacterial infections, e.g. strains of bacteria which are resistant to metronidazole.

For many bacterial strains and parasitic protozoal organisms (R)-ornidazole and (S)-ornidazole are more active than (rac)-ornidazole. Likewise, for many bacterial strains and parasitic protozoal organisms, (R)-ornidazole and (S)-ornidazole are more active than (rac)-Ornidazole.

(rac)-ornidazole also confers certain specific efficacy and safety benefits. For example Ornidazole appears to be free of inductive and inhibitory activity against CYP enzymes know to cause drug-drug interaction problems, does not have a disulfirmam like interaction with alcohol that has been associated with other nitro-imidazoles, and is not a carcinogen.

Any subject-matter falling outside the scope of the claims is provided for information purposes only. The references to methods of treatment in this description are to be interpreted as references to the compounds, pharmaceutical compositions and medicaments of the present invention for use in a method for treatment of the human (or animal) body by therapy.

The present invention is directed to racemic mixture of (R)-ornidazole and (S)-ornidazole [rac-ornidazole], or pharmaceutically acceptable salts thereof, for use in the treatment of an anaerobic bacterial infection involving a biofilm in adult patients, wherein said bacterial infection is associated with a dysbiosis of a microbial microbiome in a disease selected from Glanders and Melioidosis infections, wherein the Glanders and Melioidosis infections are caused by biofilms of Burkholderia mallei or Burkholderia pseudomallei and at least some of the bacteria are present in an anaerobic configuration , wherein the daily dose for oral or parenteral administration is from <NUM>/day to <NUM>/day, wherein the racemic mixture or pharmaceutically acceptable salts thereof is administered orally in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection.

In an embodiment, the Ornidazole compounds are for use in combination with one or more antibiotics, the antibiotics being selected from β- lactam antibiotics, tetracycline antibiotics, penem antibiotics, quinolone antibiotics and macrolide antibiotics.

In any aspect or embodiment of the invention described in this specification, the (R)-ornidazole may be in the form of a pharmaceutically acceptable salt (e.g. the HCl salt) or ester. Alternatively, the (R)-ornidazole may be present as a free base, i.e. not in the form of a salt. The (R)-ornidazole, or pharmaceutically active salt or ester thereof, may be in the form of a hydrate.

Likewise, many of the embodiments of the invention are concerned with combinations of (rac)-ornidazole with one or more other active agents. Where appropriate, and irrespective of whether (rac)-ornidazole are in the form of a pharmaceutically acceptable salts, any one or more of the other active agents may be in the form of a pharmaceutically acceptable salt.

Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.

It is intended that the aspects and embodiments of this invention encompasses (R)-ornidazole and/or any other active agent in all solid forms, including amorphous forms, as well as crystalline forms, and polymorphs thereof.

By (S) enantiomer is intended to mean that enantiomer which produces a positive optical rotation. This has been shown, through independent synthesis, to be the (S)-enantiomer and is identified as such throughout this specification. In the unlikely event that this assignment has been done in error, this specification is directed to (+)-Ornidazole.

The term "(S)(+)-senidazole" thus includes (S)( +)-Ornidazole by itself or when it is available in an enantiomeric excess over the (R)(-)-Ornidazole enantiomer.

Macrolide antibiotics are antibiotics which comprise a large (e.g. <NUM>-, <NUM>- or <NUM>-membered) macrocyclic lactone ring. Exemplary macrolide antibiotics include: dirithromycin, roxithromycin, telithromycin, erythromycin, clarithromycin, & azithromycin and in particular erythromycin, clarithromycin, & azithromycin.

β-Lactam antibiotics are antibiotics in which the structure features a β-lactam moiety. They include cefalosporins (e.g.corecefazolin, cefacetrile, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefapirin, cefatrizine, cefazedone, cefazaflur, cefradine, cefroxadine, ceftezole, cefaclor, cefamandole, cefminox, cefonicid, ceforanide, cefotiam, cefbuperazone, cefuroxime, cefuzonam, cefoxitin, cefotetan, cefmetazole, flomoxef, loracarbef, cefixime, ceftazidime, ceftriaxone, cefcapene, cefdaloxime, cefetamet, cefmenoxime, cefodizime, cefoperazone, cefotaxime, cefpimizole, cefpiramide, cefpodoxime, cefsulodin, cefteram, ceftibuten, ceftiolene, ceftizoxime, latamoxef, cefepime, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, cefdinir, cefprozil, cefalexin), penems (e.g. faropenem, biapenem, doripenem, ertapenem, imipenem, meropenem, panipenem) and penicillin derivatives (e.g. amoxillin and penicillin). Exemplary β-lactam antibiotics include amoxillin, amoxiclav, cefazolin, cefuroxime, ceftriaxone, cefipime, ceftazidine, & cefoxitin. Further exemplary β-lactam antibiotics include penicillin & cephalosporin.

Quinolone antibiotics (which include the fluoroquinolone antibiotics) are antibiotics with a quinolone (or aza-quinolone) backbone. They include enoxacin, fleroxacin, lomefloxacin, nadifloxacin, norfloxacin, rufloxacin, balofloxacin, grepafloxacin, pazufloxacin, sparfloxacin, temafloxacin, tosufloxacin, besifloxacin, clinafloxacin, garenoxacin, gemifloxacin, gatifloxacin, sitafloxacin, trovafloxacin, prulifloxacin, ciprofloxacin, levofloxacin and ofloxacin. Exemplary quinolone antibiotics include ciprofloxacin, levofloxacin, enoxacin, fleroxacin, & ofloxacin.

Where antibiotics (and particularly quinolone antibiotics) are used in combination with (R)-ornidazole, the antibiotic will typically be administered orally.

Proton pump inhibitors slow the production of gastric acid. Examples include omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole, ilaprazole. A particular proton pump inhibitor suitable for use in the combinations of the invention is omeprazole (e.g. s-omeprazole).

Antiinflammatory agents may be steroidal (e.g. corticoids) or non-steroidal (e.g. aspirin, ibuprofen, mesalazine). An particular anti-inflammatory agent suitable for use in the combinations of the invention is mesalazine. Antifungal agents suitable for use in the combinations of the invention include: fluconazole, miconazole nitrate, clotrimazole, econazole, saperconazole, terconazole, fenticonazole, sertaconazole, posaconazole, itraconazole, ketoconazole, butaconazole, tioconazole, cyclopirox, caspofungin, micafungin, and anidulafungin.

Throughout this specification, the terms aerobic and anaerobic bacteria are used to describe the bacterial species against which (rac)-ornidazole are active against. Bacterial species may be obligate aerobic species or they may be non-obligate aerobic species. Likewise, bacterial species can be obligate anaerobic species or non-obligate species. Sometimes, an obligate aerobic species is able to survive in anaerobic conditions by the actions of accompanying anaerobic bacteria. (R)-ornidazole is useful against biofilm infections caused by any or all of the above bacteria.

Throughout this specification the term 'in combination' means (rac)-ornidazole and the one or more other actives are both administered to the patient over the same period of treatment. They may be administered together, i.e. at the same time. In this case they may be administered in a single formulation, (e.g. as a single tablet or capsule or sachet) or in separate formulations administered simultaneously or nearly simultaneously. Alternatively, they may be administered at separate times of day. Where (rac)-ornidazole and other active(s) are administered separately it is to be under stood that the timing of separate dosing is selected such that the beneficial effect of the first administered agent is not lost prior to administration of the second or further agent. Whatever the precise timing of the administration, (rac)-ornidazole and the one or more other actives may be administered via different means, e.g. the (R)-ornidazole may be administered in an oral formulation and the other active may be administered as a topical formulation or vice versa.

The combinations of the invention provide benefits which are at least additive compared to the use of either agent alone. In many embodiments, the combinations are something more than additive e.g. synergistic compared to the use of either agent alone.

References to kits in this specification where (rac)-ornidazole, or pharmaceutically acceptable salts or esters thereof, is used in kit form with one or more different active agents optionally further comprise instructions for the administration of (rac)-ornidazole, or pharmaceutically acceptable salts or esters thereof, and the other active agent(s) in the kit.

The definition of the term 'treatment' in this specification encompasses prophylaxis and prevention (i.e. reducing or eliminating the risk of contracting the disease). As well as meaning curing a person of the disease, 'treatment' also includes preventing the onset of symptoms, controlling (e.g. by slowing or eliminating) progression of disease, preventing the spread of the disease to other parts of the body and/or to other persons, reducing the spread of the disease and other facets of medical practice which will be readily understood by the person skilled in the art to fall within the meaning of the term 'treatment'.

For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, if the (R)-ornidazole is administered orally, then the daily dosage of the compound of the invention may be in the range from <NUM> micrograms per kilogram body weight (µg/kg) to <NUM> milligrams per kilogram body weight (mg/kg). In a specific embodiment, the formulations for administration to a subject contain about <NUM> of (R)-ornidazole, about <NUM> of (R)-ornidazole, about <NUM> of (R)-ornidazole, about <NUM> of (R)-ornidazole, about <NUM> of (R)-ornidazole. <NUM> of (R)-ornidazole, <NUM> of (R)-ornidazole, and about <NUM> of (R)-ornidazole. This is also true of the (S) enantiomer of Ornidazole [(S)-ornidazole] and the Ornidazole racemic mixture.

The beneficial properties of (rac)-ornidazole include a favorable pharmacokinetic and pharmacodynamic profile. (R)-ornidazole and (S)-ornidazole are components of rac-ornidazole and have similar, but slightly improved PK profiles. Indeed, In particular embodiments, after administration of rac-Ornidazole in a formulation, the Tmax of rac-Ornidazole ranges about <NUM> hours to about <NUM> hours inclusive of all ranges therebetween.

In another embodiment, after administration of rac-ornidazole in a formulation, the Cmax of rac-ornidazole ranges (after single administration) from about <NUM>/L to about <NUM>/L, inclusive of all ranges therebetween.

In another specific embodiment, rac-ornidazole concentrations, including the (R)-ornidazole and (S)-ornidazole components, have been measured in the colonic (<NUM>/g) and abdominal (<NUM> to <NUM>/g) walls and epiploic fat (<NUM> to <NUM>/g) throughout colorectal surgery in those receiving a <NUM> intravenous dose for surgical prophylaxis. In another study, concentrations were measured in epiploic fat (<NUM> to <NUM>/g) throughout liver transplantation after a <NUM> intravenous dose was given together with ceftriaxone <NUM> for surgical prophylaxis. Penetration rates for this study compared with plasma concentrations ranged between <NUM> and <NUM>%.

In another embodiment, after a single administration of rac-ornidazole in a formulation, the present invention provides an AUC<NUM>-∞ for rac-ornidazole of about <NUM> to about <NUM>-hr/L, and about <NUM> to about <NUM>-hr/L, inclusive of all ranges there between. The AUC for the (R)-ornidazole and (S)-ornidazole components are similar.

In another embodiment, after a single administration of rac-ornidazole in a formulation, the elimination half-life (T<NUM>/<NUM>) of rac-ornidazole is about <NUM> hours to about <NUM> hours. The (T<NUM>/<NUM>) of the (R)-ornidazole and (S)-ornidazole components are similar.

(rac)-ornidazole, or pharmaceutically acceptable salts or esters thereof, may be used on their own but will generally be administered in the form of a pharmaceutical composition in which (rac)-ornidazole, or pharmaceutically acceptable salts thereof, are in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "<NPL>.

Depending on the mode of administration of (rac)-ornidazole, the pharmaceutical composition which is used to administer (rac)-ornidazole will preferably comprise from <NUM> to <NUM> %w (per cent by weight) (rac)-ornidazole, more preferably from <NUM> to <NUM> %w (rac)-ornidazole, still more preferably from <NUM> to <NUM> %w (rac)-ornidazole, and even more preferably from <NUM> to <NUM> %w (rac)-ornidazole, of active ingredient, all percentages by weight being based on total composition.

In many of the embodiments of the invention, (rac)-ornidazole are used in combination with other active agents (e.g. antibiotics, antifungal, anti-inflammatory agent, proton pump inhibitors etc.). Depending on the mode of administration of the other active agent, the pharmaceutical composition used to administer the other active agent (which may or may not be the same pharmaceutical composition which is used to administer (rac)-ornidazole will preferably comprise from <NUM> to <NUM> %w (per cent by weight) of the other active agent, more preferably from <NUM> to <NUM> %w of the other active agent, still more preferably from <NUM> to <NUM> %w of the other active agent, and even more preferably from <NUM> to <NUM> %w of the other active agent, of active ingredient, all percentages by weight being based on total composition.

The pharmaceutical compositions may be administered systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion).

For oral administration (rac)-ornidazole and/or one or more other active agents may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.

For the preparation of soft gelatine capsules, (rac)-ornidazole and/or one or more other active agents may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules. Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.

For intravenous (parenteral) administration (rac)-ornidazole and/or one or more other active agents may be administered as a sterile aqueous or oily solution. Parenteral formulations are particularly suitable for patients suffering from a severe infections. The person skilled in the art would be well aware of what differentiates a serious infection from a non-serious infection. By way of example, severe infections include those which render the patient unable to take (rac)-ornidazole orally, e.g. infections which render the patient unconscious, emetic, weak, delirious etc. The HCl salt of (rac)-ornidazole are particularly suitable for parenteral administration, e.g. for the treatment of severe infections.

The size of the dose for therapeutic or prophylactic purposes of (rac)-ornidazole and/or one or more other active agents will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.

Dosage levels, dose frequency, and treatment durations of (rac)-ornidazole are expected to differ depending on the formulation and clinical indication, age, and co-morbid medical conditions of the patient. In adult patients, as a single agent monotherapy, the daily dose of orally or parentally administered forms of (rac)-ornidazole vary from <NUM>/day- <NUM>/day. Downward dose adjustments from these levels are likely to be needed in infants (<NUM>-<NUM> years of age), children (<NUM>-<NUM> years of age), and elderly patients (greater than <NUM> years of age), as well as individuals with renal or liver disease, and upward dose adjustments may be necessary in obese individuals. As a single agent monotherapy, the standard duration of (rac)-ornidazole treatment is expected to vary between one and seven days for most clinical indications. It may be necessary to extend the duration of treatment beyond seven days in instances of recurrent infections or infections associated with tissues or implanted materials to which there is poor blood supply including bones/joints, respiratory tract, endocardium, and dental tissues.

When (rac)-ornidazole is combined with other medications in fixed dose combinations treatments , the daily dose of orally or parentallyadministered forms of (rac)-ornidazole are expected to vary from <NUM>/day- <NUM>/day.

A specific example of (rac)-ornidazole oral sachet formulations contains (rac)-ornidazole and the following excipients: sugar spheres, Povidone, Polyethylene glycol <NUM>, Aerosil <NUM>, Talc and Eudragit NE30D. The formulation weighs <NUM> and contains <NUM> of (R)-ornidazole, i.e. the formulation contains about <NUM>% (R)-ornidazole by weight.

(rac)-ornidazole, or pharmaceutically acceptable salts or esters thereof, for use in the treatment of Glanders and Melioidosis infections wherein the Glanders and Melioidosis infections are caused by biofilms of Burkholderia mallei or Burholderia pseudomallei and at least some of the bacteria are present in an aneroebic configuration.

Claim 1:
The racemic mixture of (R)-ornidazole and (S)-ornidazole [rac-ornidazole], or pharmaceutically acceptable salts thereof, for use in the treatment of an anaerobic bacterial infection involving a biofilm in adult patients, wherein said bacterial infection is associated with a dysbiosis of a microbial microbiome in a disease selected from Glanders and Melioidosis infections, wherein the Glanders and Melioidosis infections are caused by biofilms of Burkholderia mallei or Burkholderia pseudomallei and at least some of the bacteria are present in an anaerobic configuration , wherein the daily dose for oral or parenteral administration is from <NUM>/day to <NUM>/day, wherein the racemic mixture or pharmaceutically acceptable salts thereof is administered orally in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection.