WO2022123305A1 - Compositions comprising metronidazole for treatment of diabetic foot ulcers and venous ulcers - Google Patents

Abstract

A topical composition comprising about 10 wt % of metronidazole in a carrier for use to treat surface tissue ulcers, including venous stasis ulcers, arterial ulcers, diabetic neuropathic ulcers, and pressure ulcers, that are accessible for use of the topical composition.

Description

COMPOSITIONS COMPRISING METRONIDAZOLE FOR TREATMENT OF DIABETIC FOOT ULCERS AND VENOUS ULCERS

CROSS REFERENCE TO RELATED APPLICATIONS

[001] The present application claims priority to U.S. Provisional Patent Application Serial No. 63/122,013, filed on December 7, 2020, and U.S. Provisional Patent Application Serial No. 63/127,200 filed on December 18, 2020, the contents of which is incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

[002] Technical Field

[003] The present invention relates to a pharmaceutical composition, in particular a topical composition comprising metronidazole or a pharmacologically acceptable salt thereof, for the treatment of various ulcers, including venous stasis ulcers, arterial ulcers, diabetic neuropathic foot ulcers, and pressure ulcers, that are accessible for use of a topical composition.

[004] Related Art

[005] As the United States population ages, primary care physicians are likely to see increasing numbers of patients with leg ulcers. An estimated 2 million workdays are lost each year in the United States because of leg ulcers only and the medical costs of treating these nonhealing wounds can be enormous.

[006] The prevalence of pressure ulcers (pressure sores) of the lower body in the elderly has been estimated to be between 3-11%. The morbidity and mortality associated with pressure ulcers is significant. The death rate in those patients with pressure ulcers maybe fourfold greater than in those without pressure ulcers. In addition, septic, elderly patients with pressure ulcers have a hospital mortality rate in excess of 50%. Theoretically, pressure ulcers are preventable. However, even with the best care, pressure ulcers may still occur. When they occur, treatment of pressure ulcers can be expensive. This cost includes intensive nursing care as well as adjunctive therapies such as antipressure devices, protective dressings, and skin treatments. [007] Leg ulcers, which usually occur below the knee, can be caused by many factors, but most are due to venous disease, arterial insufficiency, or neuropathy, alone or in combination. Diabetes is an especially important underlying condition. Venous ulcers (or varicose ulcers) are wounds that are thought to occur due to improper functioning of valves in the veins usually of the legs. They are the major cause of chronic wounds, occurring in 70% to 90% of chronic wound cases. It is estimated that venous stasis ulcers affect 500-600,000 people in the United States every year and it is by far the most common type of leg ulcer seen. [Vasudevan B. 2014; Xie T. 2018], This type of ulcer accounts for the loss of 2 million working days and incurs treatment costs closing in on $3 billion dollars per year in the USA. Although compression therapy has been the gold standard of treatment of venous stasis ulcers, there are some individuals that cannot tolerate compression over the ulcer; as the pain is just too great.

[008] Of all lower amity amputations performed annually in the United States (usually because of skin ulcers), 45% to 70% are in patients with diabetes. More than 80% of diabetic patients with foot ulcers have neuropathy, and early detection of the condition, and of angiopathy, is essential in preventing and possibly reversing the accelerated development of complications in these patients.

[009] Diabetic Foot Ulcers (DFU)s are a complex medical condition that are notoriously difficult to heal. If left untreated, they can result in infection, extensive tissue damage, amputation and long-term disability [Edmonds, 2007], It is estimated that 19% to 34% of patients with diabetes have at least one DFU in their lifetime, and the International Diabetes Federation reports that 9.1 to 26.1 million people will develop DFUs annually [Armstrong, 2017], Furthermore, patients living with DFUs generally have a lower quality of life and poorer psychosocial adjustment [Goodridge, 2005] compared with the general population, and they have a higher burden of healthcare interactions [Skrepnek, 2017],

[0010] Treatment of DFUs accounts for approximately one-third the total cost of diabetic care, but despite these high healthcare costs, approximately 20% of patients with DFUs have at least one unhealed ulcer after one year [Everett, 2018], Since the mid- 1850s, sharp debridement of DFUs has been common practice, with an antiseptic cream being applied to the debrided skin and a thick pad of dressing applied over the ulcer to reduce pressure and prevent recurrence of the wound. Off-loading pressure using a variety of devices and education about foot care and footwear is also used to aid healing [Naves, 2016],

[0011] Patients with DFUs who develop an infection in the ulcer need urgent antibiotic treatment. The most common pathogens isolated from previously untreated, acute, superficial infected DFUs are aerobic gram-positive bacteria, particularly Staphylococcus aureus and beta-haemolytic Streptococci (group A, B, and others) [Naves, 2016], In deep limb-threatening infected DFUs or chronic wounds the infection is usually caused by a mixture of aerobic grampositive, aerobic gram-negative (e.g., Escherichia coli, Proteus species, Klebsiella species), and anaerobic organisms (e.g., Bacteroides species, Clostridium species) [Abdulrazak, 2005], Based on this information, the antibiotic treatment should at least have anti -staphylococcal coverage, but the choice of antibiotics will also depend on the severity of the infection, the duration of the DFU, and any allergies etc. of the patient [Bader, 2008], The aim of antimicrobial therapy is primarily to cure the infection, not to heal the wound. Long-term treatment may be needed but this has to weighed up with the increased the risk of drug-related toxic effects and development of antibiotic resistance with long-term use [Cavanagh, 2005],

[0012] Metronidazole (or "Flagyl") is a synthetic antibacterial and antiprotozoan antibiotic having the formula 2-methyl-5-nitroimidazole-l-ethanol. The medication is used for its antiinflammatory properties in the treatment of several skin or tissue damage due surgery or skin diseases. However, in its oral and intravenous forms, metronidazole is frequently associated with a number of serious side effects. These negative side effects include GI manifestations, such as nausea, vomiting, a metallic taste in the mouth, or inflammation of the oral cavity. Serious neurological side effects can occur which usually manifest as numbness or tingling of the extremities. These neurological side effects can be debilitating, are often irreversible, and necessitate stopping the Metronidazole. Serious hematological, cardiovascular, or renal complications are also common and can be life-threatening. In addition, the overgrowth of opportunistic organisms such as Candida can result from oral or intravenous metronidazole treatment. In addition, oral metronidazole can interact in an adverse manner with other medications, such as oral anticoagulants (e.g., coumadin), which can cause potentially fatal bleeding.

[0013] Some other therapies for chronic leg ulcers, such as surgical debridement and splitthickness skin grafting, have been used for many years and still have a role in management. Several new methods including multiplayer compression-bandage systems, topical recombinant human platelet-derived growth factor, and human skin equivalent for use in grafting are available which may aid in wound healing however, many of these therapies are expensive and cost prohibitive for many patients.

[0014] Thus, it would be advantageous to provide a topical composition that overcomes the shortcomings of the prior art and is effective in treating tissue ulcers and particularly foot and venous leg ulcers while minimizing the risks associated with high systemic exposure following oral administration.

SUMMARY OF THE INVENTION

[0015] It is, therefore, an object of the present invention to topically apply a 10% concentration of metronidazole to treat tissue ulcers, including venous stasis ulcers, arterial ulcers, diabetic neuropathic foot ulcers, and pressure ulcers.

[0016] Metronidazole, 2-methyl-5-nitroimidazole-l-ethanol, is a nitroimidazole derivative with activity against anaerobic protozoa, aerobic and microaerophilic bacteria, having the following structure.

CgHgHgOg M- W. 171.16

[0017] In one aspect, the present invention provides a method for treating tissue damage due to venous ulcers and diabetic foot ulcers, the method comprising topically administering to a damaged area of a subject in need thereof, a therapeutically effective amount of a composition comprising from about 5 wt. % to 25 wt. % of metronidazole or pharmaceutically acceptable salt thereof; and preferably in an amount of about 10 wt. % concentration and a pharmaceutically acceptable excipient or carrier. [0018] In yet another aspect, the present invention provides a topical composition comprising metronidazole or a pharmacologically acceptable salt thereof at a concentration of about 10 % weight in a pharmacologically acceptable aqueous or non-aqueous carrier or vehicle. The concentrations are based on the total weight of the composition. In some embodiments, the metronidazole is the sole active agent.

[0019] The carrier is preferably an organic vehicle and, typically, comprises at least one hydrocarbon compound. Preferably, the vehicle comprises a mixture of at least two semi-solid saturated hydrocarbon compounds. An example of a suitable vehicle is white petrolatum (USP), also known as white soft paraffin (BP). Other suitable vehicles include zinc oxide, Vaseline™, Aquaphor (a combination of mineral oil, petrolatum ceresin and lanolin), lanolin or a petroleum-based carrier.

[0020] The topical composition is preferably in a form suitable for direct application to the damaged tissues via a topical application. Suitable forms include an enema, suppository, ointment, lotion, gel, foam, soap, aerosol, transdermal patch, paste, shampoo, a mousse, wax, a stick, a mask, a moisturizer and/or a cream.

[0021] The composition may consist essentially of metronidazole and the carrier. However, a therapeutic amount of at least one other therapeutic agent may be added to the composition to add to its effectiveness. Additional therapeutic agents that may be added include calcium channel blockers, e.g. nifedipine and diltiazem; steroids, e.g. hydrocortisone or a pharmacologically acceptable derivative thereof; analgesic agents, preferably from the amide or ester class such as pramoxine or benzocaine; antimicrobial agents (antibacterial or antiviral), e.g. ciprocfloxacin, amoxicillin-clavulonic acid, erythromycin, tetracycline, clindamycin or doxycycline; substances that either promote skin integrity or inhibits skin breakdown, e.g. vitamin E, aloe, zinc oxide or other barrier cream; anti-inflammatory agents, e.g. a nonsteroidal anti-inflammatory agent selected from aminosalicylic acid, ibuprofen, sulindac, piroxicam or diflunisal.

[0022] The topical composition is preferably in a form suitable for direct application to the damaged area of the tissue. As previously stated, suitable forms include solutions, a lotion, a tonic, a shampoo, a gel, a mousse, a wax, a stick, a mask, a soap, a moisturizer, a cream, foam an ointment, or a paste to be used for treatment of tissue damage in warm-blooded animals, such as mammals and especially humans. In particular, the present invention is concerned with inflammation-associated tissue damage and is particularly directed to prophylactic and therapeutic methods for treating localized tissue damage described herein.

[0023] In yet another aspect, the present invention provides a topical composition comprising metronidazole or a pharmacologically acceptable salt thereof at a concentration of about 5 wt. % to about 25 wt.%, more preferably about 7 to 12 %, and most preferably at about 10%, in a pharmacologically acceptable carrier or carrier vehicle for use in the topical treatment of the damaged surface skin and tissues, such as leg and foot ulcers. Notably, the metronidazole composition of the present invention relieves pain, reduces inflammation and edema, promotes wound healing and reverses tissue induration and granulation.

[0024] No standard dose is given since sufficient metronidazole ointment needs to be applied to cover the infected area and so the dose will vary depending on the size of the affected venous tissue. The dose of a metronidazole onement or composition for each application is preferably between from about 125 mg to about 1250 mg, more preferably between from about 500 mg to about 800 mg. The most preferred dose is based on an application of 1.5 cm³ to 3.0 cm³ of a 10 % wt. of metronidazole ointment. The composition is preferably applied between from 1 to 4 times daily and more preferably 1 to 2 times daily.

[0025] The composition of the present invention can be used topically by applying over an area to be treated. A typical method of use is to apply or rub the composition over the entire area, until the composition disappears. Several methods are available for the dispensing of the composition on the tissue damage including by physical means including applicator pads, swabs, or other devices intended to apply the composition in a thin film such as roller bottles, felt tip or sponge tip applicators.

[0026] In a final aspect, the present invention relates to kits for the treatment of damaged tissue, wherein the kit includes packaging comprising at least an effective amount of metronidazole or salt thereof in a pharmaceutically acceptable carrier or vehicle. In one aspect, the present invention provides for a kit comprising a sufficient amount of single use applicators, wherein each applicator comprises a composition comprising from about 10% concentration of metronidazole. Preferably, the kit includes a sufficient number of the single use applicators to treat the symptoms over a period from 1 to 30 days. The kits can also include adaptors such as pads, brushes, syringes for delivery of the metronidazole.

[0027] These and other advantages and features of the present invention will be described more fully in a detailed description of the preferred embodiments which follows.

BRIEF DESCRIPTION OF THE FIGURES

[0028] Figure 1A shows the leg ulcer wound before treatment and Figure IB shows the effectiveness of treatment of a venous leg ulcer using 10% metronidazole for about 9 days.

[0029] Figure 2A shows the leg ulcer wound before treatment and Figure 2B shows the effectiveness of treatment of a venous leg ulcer using 10% metronidazole for about 4 weeks.

[0030] Figure 3 A shows a diabetic foot ulcer wound before treatment and Figure 3B shows the effectiveness of treatment of a venous leg ulcer using 10% metronidazole for about 5 weeks.

[0031] Figure 4A shows a diabetic foot ulcer wound before treatment and Figure 4B shows the effectiveness of treatment of a venous leg ulcer using 10% metronidazole for about 3 weeks.

[0032] Figure 5 A shows a diabetic foot ulcer wound before treatment and Figure 5B shows the effectiveness of treatment of a venous leg ulcer using 10% metronidazole for about 6 weeks.

DETAILED DESCRIPTION OF THE INVENTION

[0033] Throughout the instant specification and claims, the following definitions and general statements are applicable.

[0034] As used herein, whether in a transitional phrase or in the body of a claim, the terms "comprise(s)" and "comprising" are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases "having at least" or "including at least." When used in the context of a process, the term "comprising" means that the process includes at least the recited steps but may include additional steps. When used in the context of a composition, the term "comprising" means that the composition includes at least the recited features or components but may also include additional features or components.

[0035] The terms "consists essentially of or "consisting essentially of have a partially closed meaning, that is, they do not permit inclusion of steps or features or components which would substantially change the essential characteristics of a process or composition; for example, steps or features or components which would significantly interfere with the desired properties of the compositions described herein, i.e., the process or composition is limited to the specified steps or materials and those which do not materially affect the basic and novel characteristics of the invention.

[0036] The terms "consists of and "consists" are closed terminology and allow only for the inclusion of the recited steps or features or components.

[0037] As used herein, the singular forms "a," "an" and "the" specifically also encompass the plural forms of the terms to which they refer, unless the content clearly dictates otherwise.

[0038] The term "about" is used herein to mean approximately, in the region of, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" or "approximately" is used herein to modify a numerical value above and below the stated value by a variance of 10%.

[0039] As used herein, "treating" means reducing, hindering or inhibiting the development of, controlling, alleviating and/or reversing the symptoms in the individual to which a combination or composition of the invention has been administered, as compared to the symptoms of an individual not being treated according to the invention. A practitioner will appreciate that the combinations, compositions, dosage forms and methods described herein are to be used in concomitance with continuous clinical evaluations by a skilled practitioner to determine subsequent therapy.

[0040] Without wishing to be bound by any particular theory, it is believed that the use of metronidazole by direct application to the affected tissue is primarily a local effect. Minimal systemic absorption is observed and therefore systemic side effects are effectively reduced or eliminated. As such, the dose of metronidazole can be altered for specific tissue and applied directly to the diseased or otherwise effected area thereby increasing the efficacy of the medication.

[0041] The composition according to the present invention may also comprise additional pharmaceutically acceptable compounds and/or compositions. It is thus to be understood that all the additional compounds and/or compositions mentioned below have to be physiologically acceptable.

[0042] The metronidazole may be formulated into various pharmaceutically compositions, e.g., a solution, a lotion, a tonic, a shampoo, a gel, a mousse, a wax, a stick, a mask, a soap, a moisturizer, a cream, an ointment, or a paste.

[0043] The composition according to the present invention may be topically applied as such within a suitable carrier, solvent, dissolvent, emulgent, extract, solutions e.g., aqueous, nonaqueous, alcoholic, oily, suspension; microemulsion, vesicles, etc. Where employed, the carrier or vehicle is inert in the sense of not bringing about a deactivation or oxidation of the metronidazole, and in the sense of not bringing about any adverse effect on the tissue or skin areas to which it is applied.

[0044] According to one embodiment of the present invention, the pharmaceutical composition comprise metronidazole dissolved or dispersed in a suitable flowable or spreadable carrier. The composition can be thickened with one or more thickeners, can contain a buffer, and can also comprise an effective amount of a lubricant such as a natural or synthetic fat or oil, e.g., a tris-fatty acid glycerate or lecithin. Non-toxic non-ionic surfactants can also be included as wetting agents and dispersants. Preferably, the composition does not include an alcohol because of the painful effect caused by alcohol on damaged skin. Further, the pH of the composition is preferably 5.5 to 8.5, and more preferably a pH of about 7.

[0045] The composition according to the present invention may be topically applied as such within a suitable carrier, solvent, dissolvent, extract, solutions e.g., oily, suspension; microemulsion, vesicles, etc. Where employed, the carrier or vehicle is inert in the sense of not bringing about a deactivation or oxidation of the metronidazole, and in the sense of not bringing about any adverse effect on the skin areas to which it is applied. [0046] In one aspect of the invention, the metronidazole is applied in admixture with a dermatologically acceptable carrier (e.g., as a lotion, cream, ointment, soap or the like) so as to facilitate topical application and, in some cases, provide additional therapeutic effects as might be brought about, e.g., by moisturizing of the affected and/or damaged skin. The metronidazole carrier for dermatological compositions preferably comprises a carrier which will form a film or layer on the skin to which it is applied so as to localize the application and provide some resistance to washing off by immersion in water or by perspiration.

[0047] Many preparations are known in the art and include lotions containing oils and emollients such as hydrocarbon oils and waxes, silicone oils, vegetable, animal or marine fats or oils, glyceride derivatives, fatty acids or fatty acid esters, lanolin and derivatives, wax esters, sterols, phospholipids and the like, and generally also emulsifiers (nonionic, cationic or anionic), although some of the emollients inherently possess emulsifying properties. These same general ingredients can be formulated into a cream, lotion, or into gels, by utilization of different proportions of the ingredients and/or by inclusion of thickening agents such as gums or other forms of hydrophilic colloids.

[0048] Various types of other ingredients may be present in the metronidazole compositions of the present invention. For example, sunscreens may be included such as those materials commonly employed to block ultraviolet light. Illustrative compounds are the derivatives of PABA, cinnamate and salicylate. The exact amount of sunscreen employed in the compositions can vary depending upon the degree of protection desired from the sun's UV radiation.

[0049] The compositions for use in the methods of the present invention may include components suitable as carriers, such as starches, emollients, sugars, microcrystalline cellulose, diluents, polyols, granulating agents, lubricants, surfactants, binders, fatty acids, disintegrating agents, and the like, with the topical preparations being preferred.

[0050] Emollients are often incorporated into the therapeutic compositions of the present invention. Levels of such emollients may range from about 0.5% to about 60%, preferably between about 5% and 30% by weight of the total composition. Emollients may be classified under such general chemical categories as esters, fatty acids and hydrocarbons. Esters may be mono- or di-esters. Acceptable examples of fatty di-esters include dibutyl adipate, diethyl sebacate, diisopropyl dimerate, and dioctyl succinate. Acceptable branched chain fatty esters include 2-ethyl-hexyl myristate, isopropyl stearate and isostearyl palmitate. Acceptable tribasic acid esters include triisopropyl trilinoleate and trilauryl citrate. Acceptable straight chain fatty esters include lauryl palmitate, myristyl lactate, oleyl eurcate and stearyl oleate.

[0051] Suitable fatty acids include those compounds having from 10 to 20 carbon atoms. Especially preferred are compounds such as cetyl, arachidyl, behenyl, cetearyl, myristyl, palmitic and stearyl acids.

[0052] Exemplary hydrocarbons which may serve as emollients are those having hydrocarbon chains anywhere from 12 to 30 carbon atoms. Specific examples include mineral oil, petroleum jelly, paraffin oil, squalene and isoparaffins.

[0053] Among the polyols which may serve as emollients are linear and branched chain alkyl polyhydroxyl compounds. For example, propylene glycol, resorcinol, menthol, sorbitol and glycerin are preferred. Also, useful may be polymeric polyols such as polypropylene glycol and polyethylene glycol.

[0054] Another category of functional ingredients within the therapeutic compositions of the present invention are thickeners. A thickener will usually be present in amounts anywhere from 0.1% to 20% by weight, preferably from about 0.5% to 10% by weight of the composition. Exemplary thickeners are cross-linked polyacrylate materials. Gums may be employed such as xanthan, carrageenan, gelatin, karaya, pectin and locust beans gum. Under certain circumstances the thickening function may be accomplished by a material also serving as a silicone or emollient. For instance, silicone gums having a viscosity in excess of 10 mPas and esters such as glycerol stearate have dual functionality.

[0055] Still further, the therapeutic compositions of the present invention may include preservatives, moisturizers, surfactants, antimicrobials, etc. Preservatives may include tetrasodium ethylene-diamine tetraacetic acid (EDTA), methylparaben, benzophenone-4, methylchloroisothiazolinone, sodium benzoatemethylisothiazolinone, trehalose and similar sugars, and mixtures thereof. Preservatives, when used, are typically present in an amount from about 0.01% to 10% weight, preferably about 0.05% to 4% weight, and more preferably, from about 0.1% to 2% weight. [0056] Preferred moisturizers may include wheat protein (e.g., laurdimonium hydroxypropyl hydrolyzed wheat protein), hair keratin amino acids, sodium peroxylinecarbolic acid, panthenol, tocopherol (Vitamin E), dimethicone, arachidylglucoside and the like, and mixtures thereof. Moisturizers, when used, are typically present in an amount from about 0.01% to 10% weight, preferably about 0.05% to 1.5% weight, more preferably, from about 0.1% to 1% weight of the composition.

[0057] Preferred surfactants, including both the foaming and non-foaming type, include sodium laureth sulfate, sodium laureth-13 carboxylate, disodium laureth sulfosuccinate, disodium cocoamphodi acetate, glycol stearate, PEG-150 distearate and the like, and mixtures thereof. More preferably, at least one amphoteric surfactant is included in the composition, selected from the group consisting of lauroamphocarboxypropionate, lauroamphopropi onate, lauroamphoglycinate, lauroamphocarboxyglycinate, lauroamphopropylsulfonate,

1 auroamphocarb oxy propi oni c acid, my ri stoamphocarb oxy-propionate, myristoamphopropi onate, myristoamphoglycinate, myristoamphocarboxyglycinate, myristoamphopropyl sulfonate, myri stoamphocarb oxy propionic acid, cocoamphocarb oxy propi onate, cocoamphopropionate, cocoamphoglycinate, cocoamphocarboxyglycinate, cocoamphopropyl sulfonate, cocoamphocarboxypropionic acid and mixtures thereof. The surfactant component may be present in an amount from about 0.1% to about 20% weight of the composition.

[0058] Any pharmaceutically acceptable antimicrobial agent available to those of ordinary skill in the art may be used in combination with the metronidazole, including: echinacea, golden seal, benzalkonium chloride, triclosan, benzethonium chloride, iodine, grape seed extract, pomegranate extract, green tea extract or polyphenols, and the like, or combinations thereof. The antimicrobial agent is typically present in an amount from about 0.01% to 2% weight, preferably from about 0.1% to 1.2% weight, and more preferably from about 0.3% to 1% weight of the composition. The antimicrobial agent inhibits the formation, and may further reduce, the presence of microbes that cause redness, inflammation, and irritation of the skin.

[0059] The compounds of the present invention include pharmaceutically acceptable salts that can be prepared by those of skill in the art. As used herein, by "pharmaceutically acceptable salt" it is meant those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art, such as hydrochloride, hydrobromide, mesylate, acetate, trifluoroacetate, propionate, fumarate, tartrate, citrate, phosphate, succinate, bisulfate, etc.

[0060] The topical skin treatment composition of the invention can be formulated as a lotion having a viscosity of from 4,000 to 10,000 mPas, a fluid cream having a viscosity of from 10,000 to 20,000 mPas or a cream or a gel having a viscosity of from 20,000 to 100,000 mPas or above.

[0061] The metronidazole composition can be packaged in a suitable container to suit its viscosity and intended use by the consumer. For example, a lotion or fluid cream can be packaged in a bottle, a syringe, a propellant-driven aerosol device or a container fitted with a pump suitable for finger operation. When the composition is a cream, it can simply be stored in a non-deformable bottle or squeeze container, such as a tube or a lidded jar.

[0062] Because of its ease of administration, a cream, lotion, gel or ointment represents the most advantageous topical dosage unit form, and such forms may be prepared as rinse-off or leave-on products, as well as two stage treatment products for use with other skin cleansing or managing compositions. Each of these forms is well understood by those of ordinary skill in the art, such that dosages may be easily prepared to incorporate the pharmaceutical composition of the invention.

[0063] In general, the compositions of the present invention are intended to be applied topically and directly to the damaged tissue, as described above. When the wound is deep and/or severe, it is preferred that the composition is in the form of an ointment, salve or cream which is spread directly onto the wound and then covered with a standard sterile dressing pad or other appropriate dressing material. Alternatively, the ointment, cream or salve of the present composition is applied directly onto the dressing pad or other appropriate dressing material. The pad or dressing material is then placed over the wound or bum with the medicine-side down. This latter approach works better when applying dressing to severe bums and shallow wounds. [0064] Thus, the pharmaceutical composition of the present invention is applied to a wound so as to cover the injured surface completely. Dressing-change schedules are of course dictated by the condition of the wound. Dressings are advantageously changed three to four times a day. Repeated daily dressing changes are continued until the wound or burn is healed. Healing time varies, depending upon the type and depth of the wound or the severity of the tissue damage.

[0065] Example 1

[0066] Leg and foot ulcers are chronic diseases, and it is generally caused by ischemia and diabetes mellitus. In this study, the aim was to evaluate the effectiveness of 10% metronidazole ointment on patients having venous leg and/or foot ulcers.

[0067] Patients and Methods

[0068] Numerous patients were included in this study and inclusion criteria was either venous leg ulcers or diabetic foot ulcers. 10% metronidazole ointment (Ortem-Slapharma-UK) was applied to the wounds of the patients. Median age of the patients was 60 (55-69) years. The diameter of the ulcer range between 2-15 cm. The minimum duration of treatment was about 10 days with an advantageous effect by treatment of from 2 to 10 weeks.

[0069] Results

[0070] Local treatment of leg ulcers or diabetic foot ulcers by ointment of metronidazole increased the healing process shows a marked difference in wounds shown in Figures 1 to 6 all showing the specific wound before and after treatment. This advantageous effect is caused by both anti-inflammatory and anti-infective effect of metronidazole in about a 10% concentration. Notably as shown in after treatment figures, the diameter of the respective ulcers is greatly decreased in a time period of 2 weeks to 10 weeks depending on the seriousness of the wound.

[0071] The present invention has been described in terms of preferred embodiments, but the skilled artisan will appreciate that various alterations, substitutions, omissions, and changes may be made without departing from the scope of the present invention. The amounts of said compounds being used may be varied in accordance with the specific requirements.

[0073] References wherein the contents of same is incorporated by reference herein.

[0074] Abdulrazak A, Bitar ZI, Al-Shamali AA, Mobasher LA. Bacteriological study of diabetic foot infections. J Diabetes Complications. 2005; 19(3): 138-41.

[0075] Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med. 2017;376(24):2367-2375.

[0076] Bader MS. Diabetic foot infection. Am Fam Physician. 2008;78(l):71-9.

[0077] Cavanagh PR, Lipsky BA, Bradbury AW, Botek G. Treatment for diabetic foot ulcers. Lancet 2005;366: 1725.

[0078] Edmonds M. Diabetic foot ulcers. In: Skin Breakdown: The silent epidemic. Hull: Smith and Nephew Foundation; 2007.

[0079] Everett E, Mathioudakis N. Update on management of diabetic foot ulcers. Ann N Y Acad Sci. 2018;1411(1): 153-165.

[0080] Goodridge D, Trepman E, Embil JM. Health-related quality of life in diabetic patients with foot ulcers: literature review. J Wound Ostomy Continence Nurs. 2005;32(6):368-77.

[0081] Naves CCLM. The diabetic foot: a historical overview and gaps in current treatment. Adv Wound Care (New Rochelle). 2016;5(5): 191-197.

[0082] Skrepnek GH, Mills JL, Lavery LA, Armstrong DG. Health care service and outcomes among an estimated 6.7 million ambulatory care diabetic foot cases in the U.S. Diabetes Care. 2017; 40(7):936-942.

[0083] Vasudevan, B,; Venous leg ulcers: Pathophysiology and Classification, Indian Dermatol Online J. 2014 Jul-Sep; 5(3): 366-370.

[0084] Xie, T., Junna Ye, Kittipan Rerkasem, Rajgopal Mani,; The venous ulcer continues to be a clinical challenge: an update. Burns Trauma. 2018; 6: 18.

Claims

Claims That which is claimed is:

1. A method of treating and/or healing a tissue ulcer, the method comprising: applying to the tissue damaged area a topical composition, wherein the topical composition comprises metronidazole in a therapeutically effective concentration of from about 8 wt % to 12 wt % in a pharmacologically acceptable carrier.

2. The method of claim 1, wherein the pharmacologically acceptable carrier is selected from starches, emollients, sugars, microcrystalline cellulose, diluents, polyols, granulating agents, lubricants, surfactants, binders, fatty acids, and/or disintegrating agents.

3. The method of claim 1, the metronidazole in a therapeutically effective concentration is about 10 wt%.

4. The method of claim 1, wherein metronidazole is applied at a dosage for each application from about 125 mg to about 1250 mg.

5. The method of claim 1, wherein said topical composition is applied between from 1 - 2 times daily.

6. The method of claim 1, wherein the metronidazole is the sole active agent.

7. The method of claim 1, further comprising an additional therapeutic agent.

8. The method of claim 7, wherein the additional therapeutic agent is selected from a group consisting of calcium channel blockers, e.g. nifedipine and diltiazem; steroids, e.g. hydrocortisone or a pharmacologically acceptable derivative thereof; analgesic agents, preferably from the amide or ester class such as pramoxine or benzocaine; antimicrobial agents (antibacterial or antiviral), e.g. ciprocfloxacin, amoxicillin-clavulonic acid, erythromycin, tetracycline, clindamycin or doxycycline; substances that either promote skin integrity or inhibits skin breakdown, e.g. vitamin E, aloe, zinc oxide or other barrier cream; anti- inflammatory agents, e.g. a non-steroidal anti-inflammatory agent selected from aminosalicylic acid, ibuprofen, sulindac, piroxicam or diflunisal.

9. The method of claim 1, wherein the tissue ulcer is a venous stasis ulcer, arterial ulcer, diabetic neuropathic foot ulcer, or pressure ulcer.

10. A method of healing a tissue ulcer, the method comprising: applying to the tissue damage area a topical composition, wherein the topical composition comprises metronidazole in a therapeutically effective concentration of about 10 wt. % in a pharmacologically acceptable carrier, wherein the topical composition is applied once a day in an amount of about 500 to 800 mg of the topical composition.

11. The method of claim 10, wherein the tissue ulcer is a venous stasis ulcer, arterial ulcer, diabetic neuropathic foot ulcers, of pressure ulcer.

12. Use of a medicament for the treatment of a foot or leg ulcer, wherein the medicament is a topical composition consisting of metronidazole in a 10 % wt concentration.