Formulations and methods for the topical treatment of Mycobacterium ulcerans in Buruli ulcer

Abstract

Disclosed herein are pharmaceutical compositions and methods for the treatment and prevention of bacterial infections of the skin, such as local ulcers caused by Mycobacterium ulcerans in Buruli ulcer and / or other types of local infections and inflammation. In particular, the compositions include clofazimine, its derivatives, its polymorphs and / or its analogs in solutions, suspensions, creams, oils, emulsions and ointments for topical application. Methods for making the compositions are also disclosed.

Description

[Technical field]

[0001] Disclosed herein are compositions, methods for making the compositions, and methods for the treatment and prevention of bacterial infections of the skin, such as localized ulcers, caused by Mycobacterium ulcerans. In particular, the compositions include clofazimine in solutions, suspensions, and ointments for topical application to localized infections, inflammation, and other skin conditions. [Background technology]

[0002] Buruli ulcer is a severe skin disease caused by infection of the skin with Mycobacterium ulcerans, and is most commonly found throughout West and Central Africa. Buruli ulcer is a rare global disease, with approximately 61,119 cases diagnosed worldwide between 2002 and 2017 (Non-Patent Document 1). The disease is the third most common mycobacterial disease after tuberculosis and leprosy, and is usually diagnosed at a late stage when it has caused considerable damage and disability. Surgery is the primary treatment.

[0003] Currently, the World Health Organization (WHO) recommended treatment is an 8-week combination of oral antibiotics such as rifampicin and intramuscular streptomycin. This regimen is microbiologically effective, but requires hospitalization due to the number and route of administration (Non-Patent Document 2). New oral-only treatment regimens are under consideration, but the WHO guidelines have not changed so far (reviewed in Non-Patent Document 1).

[0004] Clofazimine is classified as Biopharmaceutical Classification System (BCS) Class 2, is practically insoluble in water, and exhibits high membrane permeability. Severe side effects are dose-dependent and mainly affect the gastrointestinal tract. Red-brown discoloration of the skin and eye conjunctiva is common during oral treatment and gradually resolves when treatment is discontinued. Oral clofazimine can also induce gastroenteritis. Preclinical models have demonstrated therapeutic benefit in Mycobacterium ulcerans-infected mice with a combination of oral rifampicin and clofazimine (Non-Patent Document 3, Non-Patent Document 4). Concomitant treatment of skin diseases with oral antibiotics can cause severe side effects, and current treatments with antibiotics have not proven effective in any form of Mycobacterium ulcerans infection. Side effects increase the urgent need and interest to develop new therapies for skin treatment. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Yotsu et al., 2018 [Non-Patent Document 2] Demange, et al., 2009 [Non-Patent Document 3] Converse et al., 2015 [Non-Patent Document 4] Converse et al., 2018 Summary of the Invention [Means for solving the problem]

[0006] Disclosed herein are methods and compositions for the treatment of skin infections, including antibiotics such as clofazimine delivered via topical ointments, creams, solutions or suspension sprays. The methods include applying a topical dose of the composition to a patient having a skin ulcer caused by a bacterial infection such as Mycobacterium ulcerans. The methods are advantageous because they facilitate treatment of the patient at a less toxic dose than oral tablet treatment. In an exemplary embodiment, a composition comprising clofazimine, a clofazimine polymorph, a clofazimine derivative or a clofazimine salt thereof, or a combination thereof, is applied directly to the ulcerated tissue of the patient's skin at the site of the ulceration to provide a therapeutic effect more rapidly, with less toxic side effects, and using a smaller amount of active agent than an orally administered composition.

[0007] In one embodiment, the method comprises administering to a patient in need of treatment a therapeutically effective dose of a clofazimine composition that is applied topically to the patient's skin. The clofazimine composition may be provided to the patient in the form of the neat drug, or a pharma- ceutically acceptable derivative, polymorph of clofazimine, or a salt thereof. In some embodiments, the clofazimine composition comprises a pharma- ceutically acceptable carrier or excipient. In certain embodiments, the clofazimine composition comprises a solution; a suspension that can be sprayed onto the ulcer; or a topical ointment, foam, or cream that can be applied directly to the ulcer tissue or applied to an adhesive tape or wrap.

[0008] In some embodiments, a method of treatment is disclosed comprising administering to a subject in need thereof a therapeutic amount of a composition comprising clofazimine and a pharma- ceutical acceptable carrier and / or excipient, wherein the bacterial infection is a Buruli or other mycobacterial infection.

[0009] In certain embodiments, the method includes applying to a subject diagnosed with a positive Mycobacterium ulcerans infection a therapeutically effective amount of a topical clofazimine composition comprising clofazimine, a pharma- ceutically acceptable derivative, a polymorph of clofazimine, or a salt of clofazimine, such as clofazimine hydrochloride, clofazimine acetate, clofazimine citrate, clofazimine phosphate, clofazimine oxalate, clofazimine sulfate, or combinations thereof, and a pharma- ceutically acceptable excipient and / or carrier, to inhibit bacterial replication on an ulcer in the patient's skin.

[0010] In one embodiment, the method of treatment comprises administering to the subject a therapeutically effective amount of a topical clofazimine composition, wherein the clofazimine, pharma- ceutically acceptable derivative, salt, or combination thereof is in an amount of about 1 mg to about 30 mg; about 1 mg to about 20 mg; about 1 mg to about 10 mg; about 3 mg to about 8 mg, or about 2 mg to about 6 mg per dose in the composition delivered in solution or suspension daily for a predetermined period of time necessary to heal the ulcer. In an embodiment, the total amount of topical antibiotic is applied one or more times daily as needed. The composition is applied to cover the entire area of ​​the ulcer.

[0011] In certain embodiments, the compositions may include pharma- ceutically acceptable excipients, and clofazimine may include up to 50 mg per dose administered to a subject in need of treatment, and is delivered to the wound or ulcer by spraying the solution or suspension using a spray or atomizing device, or by spreading and applying the clofazimine ointment or cream in a dosing tube or jar with a disposable spatula or device. In some embodiments, topical clofazimine compositions are formulated into solutions, suspensions, lotions, pastes, ointments, creams, gels, oils, bandages, aerosols, sprays, foams, powders, and / or occlusive dressings.

[0012] In one particular embodiment, the solution or suspension comprises a saline or alcohol-based solution. In some embodiments, a viscous additive is used to facilitate application and retention of the clofazimine, clofazimine derivative, clofazimine salt or combination thereof on the ulcerated area of ​​the skin. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] In embodiments disclosed herein, methods are provided for treating mycobacterial infections that include the use of clofazimine solutions, clofazimine suspensions for dropwise application to ulcers, sprayed directly as an aerosol, or spreadable application of clofazimine creams and clofazimine ointments for topical application directly to the ulcerated area of ​​the skin of a subject, particularly where the skin ulcer is caused by Mycobacterium ulcerans, e.g., Buruli ulcer.

[0014] In an exemplary embodiment, the method comprises reacting a compound of the general formula: [ka] and one or more pharma- ceuticals and / or carriers, the pharmaceutical composition comprising: a topical clofazimine medicament for the treatment of Buruli ulcer caused by Mycobacterium ulcerans; and

[0015] In one embodiment, the medicament or formulation comprises clofazimine, its derivatives, its salts, and / or combinations thereof, and is provided as a micronized suspension comprising a surfactant, milled particles, the milled drug particles being smaller than the aerosol droplets. In one embodiment, the topical medicament is provided in the form of a liposomal formulation, such as a lipophilic drug, such as a phospholipid, including 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and / or dipalmitoylphosphatidylcholine (DPPC) or other existing liposomes. In some embodiments, the formulation includes one or more components, such as a solvent, e.g., ethanol or propylene glycol, dextran and cyclodextrin, and a surfactant, such as polysorbate 80.

[0016] In one embodiment, there is provided a topical clofazimine formulation for treating Mycobacterium ulcerans infections comprising ultra-pure polysorbate 80 and / or one or more pharma- ceutically acceptable excipients or carriers, in which the clofazimine formulation has reduced allergic reactions, low toxicity, and low levels of peroxide compounds.

[0017] In some embodiments, the method includes a composition for a solid dispersion of clofazimine, a clofazimine salt, a clofazimine derivative, or a clofazimine polymorphic compound. In one embodiment, the term solid dispersion refers to a solid body consisting of at least two different components, one generally a hydrophilic matrix and the other a hydrophobic drug compound. In one embodiment, the solid dispersion includes a clofazimine compound, a derivative or salt thereof, and an acidic bioerodible polymeric additive, such as a PVM / MA (poly(vinyl methyl ether-maleic anhydride)) copolymer. In this embodiment, the composition has good solubility and local or systemic availability. PVM / MA is a compound approved by the FDA for use as a dentifrice and denture adhesive, and can provide local adhesion of the formulation for best results in delivery of the active compound.

[0018] In another embodiment, the method comprises administering a self-microemulsifying drug delivery system (SMEDDS). In this embodiment, the method comprises providing a patient with a composition comprising a mixture of oil, surfactant, and optionally co-solvent or co-surfactant, which spontaneously forms a stable microemulsion upon dilution with water. The microemulsion is then applied to the ulcerated skin by dropwise spreading on the area infected with Mycobacteria.

[0019] In certain embodiments, skin formulations for topical clofazimine antibiotic treatment include one or more of the following components or delivery systems: a surfactant, such as polysorbate 80; an emulsifier, such as oleic acid; a finely divided drug compound; liposomes of 2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and / or dipalmitoylphosphatidylcholine (DPPC) and / or cholesterol; poly(DL-lactide-co-glycolide) nanospheres; an aerosol propellant; a cellulose derivative; and a suspension of finely divided drug and inactive ingredients.

[0020] One embodiment is a method for treating a skin infection caused by Mycobacterium ulcerans comprising administering to a patient having a skin infection, such as a skin ulcer, a topical pharmaceutical composition comprising clofazimine, clofazimine polymorphs, clofazimine derivatives, clofazimine salts, analogs thereof, and / or combinations thereof, and one or more pharma- ceutically acceptable carriers or excipients.

[0021] In one embodiment, the topical pharmaceutical composition comprises a solution, suspension, lotion, paste, ointment, cream, gel, oil, bandage, aerosol, spray, powder, and / or occlusive dressing.

[0022] In another embodiment, the method of treatment comprises providing a patient with a topical pharmaceutical formulation comprising a therapeutically effective dose of clofazimine, clofazimine derivatives, clofazimine salts and / or analogues in a suspension for spraying onto the ulcerated area of ​​the skin.

[0023] In an embodiment, in the method of treatment, a pharmaceutical formulation is formed for use by emulsifying one or more clofazimine derivatives, clofazimine salts and / or analogues thereof into a suspension along with one or more excipients necessary for drug solubility in the topical formulation, and mixing in a second solubility enhancer comprising a non-ionic surfactant. In this embodiment, the formulation is formed by adding a second solubility enhancer, e.g., a phospholipid, or mixture of natural phospholipids, and the topical pharmaceutical formulation comprises clofazimine, clofazimine derivatives, clofazimine salts and / or analogues in a liposomally solubilized form.

[0024] In another embodiment, the topical pharmaceutical composition contains from 0.01 to about 100 mg of clofazimine, clofazimine derivatives, clofazimine salts and / or analogues per administered dose. In embodiments where the topical pharmaceutical composition is an emulsion, the emulsifier content is <50% w / w and >20% w / w water.

[0025] In one embodiment, the content of the suspension is a topical pharmaceutical composition in either an aqueous or alcoholic medium containing a solid particulate active content of clofazimine, clofazimine derivatives, clofazimine salts and / or analogues as a pharmaceutical ingredient in the form of a gel, the gel comprising a mixture of water, acetone, alcohol, propylene glycol, and / or cellulose derivatives in any composition.

[0026] In another embodiment, when the topical pharmaceutical composition is in the form of a foam, the contents of the foam, aerosol, and / or spray include any mixture of hydrocarbon propellants, non-polar hydrocarbons, ethanol, acetone, hexadecyl alcohol, glycol ethers, polyvinylpyrrolidone, and / or polyglycols.

[0027] Compositions for treating bacterial infections of the skin, such as Buruli ulcer, are provided, the compositions comprising an emulsion or suspension having uniform droplets having a mean diameter of at most about 1 μm and / or a polydispersity index of at most about 1 D.S. In some embodiments, the therapeutic compositions are sterile and free of solid particles, including active agents, having a particle size of 1 μm or greater.

[0028] In one embodiment, the composition is a suspension of clofazimine using a finely ground form of the drug and containing polysorbate 80, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and / or dipalmitoylphosphatidylcholine (DPPC) and / or cholesterol, as well as citric acid monohydrate, edetate disodium, sodium chloride, trisodium citrate dihydrate, and water.

[0029] In another embodiment, the composition is a suspension of clofazimine with 3-7% hypertonic saline, sodium bicarbonate, bismuth, gallium or d-amino acids, for application in drops or by spray from a device.

[0030] In another embodiment, the method includes a composition having a concentration of the antibiotic clofazimine from about 1 mg / mL to about 3 mg / mL. In certain embodiments herein, the composition is formulated to have a pH of 3-10. In embodiments, the composition can include an inert buffer. In some embodiments, the topical composition can have an osmolality in the range of 200-700 mOsm / kg and an ionic strength in the range of 31-300 mM.

[0031] In one embodiment, the composition is administered topically to the skin of a patient suffering from a Mycobacterium ulcerans skin infection, a nontuberculous mycobacterial skin infection, or other bacterial skin infection. In one embodiment, the composition may be applied topically to a body surface affected by a bacterial infection in which the pathogen is susceptible to the respective antibiotic in the formulation.

[0032] In another embodiment, compositions comprising clofazimine, clofazimine derivatives, clofazimine polymorphs or clofazimine salts and / or clofazimine analogues as pharmaceutical ingredients are provided for use in a variety of ways depending on the skin or mucosal area to be treated and may be formulated as medicaments for oral, nasal, ophthalmic, pulmonary, parenteral, topical or mucosal application.

[0033] In one embodiment, there is provided a process for producing an emulsion comprising clofazimine for topical use, which results in an emulsion comprising between 50%-98%, or between 60-90%, of emulsion droplets <5 Pm, with a geometric standard deviation of the emulsion droplets of <2.2, or <1.8. In one embodiment, the process for producing an emulsion produces emulsion droplets wherein the proportion of emulsion droplets <3.5 Pm is between 40%-95%, or between 50-85%.

[0034] A method for preparing a stable pharmaceutical formulation for topical administration is provided, comprising emulsifying one or more of a clofazimine compound, a clofazimine derivative, a clofazimine salt and / or an analogue thereof in a suspension together with one or more excipients required for the solubility of the drug to form a topical formulation, and mixing a second solubility enhancer comprising a non-ionic surfactant. In some embodiments, the second solubility enhancer is a phospholipid or a mixture of natural phospholipids, and the topical pharmaceutical formulation comprises clofazimine, a clofazimine derivative, a clofazimine salt and / or an analogue in a form solubilized in liposomes.

[0035] In certain embodiments, the method of producing a stable pharmaceutical formulation for topical administration further comprises a suspension of <5Pm emulsion droplets present in the suspension at 50%-98%, more preferably 60-90%, and the emulsion droplets have a geometric standard deviation of <2.2, preferably <1.8.

[0036] In another embodiment, the method for preparing a stable pharmaceutical formulation for topical administration further comprises a suspension of emulsion droplets of <3.5Pm present in an amount of 40%-95% of the total droplets in the suspension, more preferably 50-85%.

[0037] In another embodiment, a topical suspension as described above is provided that may be applied to various body surfaces as an antimycobacterial therapy for other types of infections besides ulcerated tissue. In some embodiments, a method of treating a mycobacterial infection is provided, the method comprising applying a topical antimycobacterial pharmaceutical composition to a subject having a mycobacterial infection of the skin. In one embodiment, the antimycobacterial composition may comprise a suspension or solution comprising clofazimine, a clofazimine derivative, a clofazimine polymorph, a clofazimine analog, or a combination thereof, and one or more pharma- ceutically acceptable excipients.

[0038] In yet another embodiment, a topical suspension as described above is provided for application to various body surfaces of a subject in need thereof as an anti-inflammatory therapy for other types of disease conditions of the skin. In one embodiment, a method of treating inflammation of the skin is provided, the method comprising applying a topical pharmaceutical composition to a subject having inflammation of the skin due to a mycobacterial infection of the skin or other pathogens of the skin. In one embodiment, the pharmaceutical composition may comprise a suspension or solution comprising clofazimine, a clofazimine derivative, a clofazimine polymorph, a clofazimine analog, or a combination thereof, and one or more pharma- ceutically acceptable excipients.

[0039] In one embodiment, the clofazimine solution or suspension contains from about 0.1 mg / mL to about 100 mg / mL. In some embodiments, the solution, suspension or foam containing clofazimine, clofazimine derivatives, clofazimine polymorphs, clofazimine analogs or combinations thereof is in a concentration of from about 0.2 mg / L to about 10 mg / L; and one or more pharma- ceutically acceptable carriers and / or excipients.

[0040] In another embodiment, a method is provided for treating a skin disease caused by a mycobacterial infection comprising applying to an infected skin area a topical pharmaceutical composition comprising clofazimine, a clofazimine derivative, a clofazimine analog, a clofazimine polymorph, or a combination thereof, in combination therapy with one or more antibacterial agents or antibiotics, which may be selected from rifampicin, clarithromycin, bacitracin, ciproflaxin, moxifloxacin, ethambutol, amikacin, azithromycin, and levofloxacin. In one embodiment, the one or more antibacterial agents may be formulated with the clofazimine compound or may be applied separately to the site of infection, each in a different formulation, which may be applied simultaneously with the application of clofazimine or at different intervals during treatment, by different methods such as oral tablets or capsules, or by intravenous administration. Combination therapy may facilitate treatment of the disease.

[0041] (Example) Example 1 The development of clofazimine liposomal formulations is as follows: Unilamellar liposomes with a mean diameter of 100 nm and a polydispersity of 0.4-0.5 are formed by the addition of emulsifiers / solubilizers Polysorbate 80 (HX2)™ and / or alternative tensides. Polysorbate 80 (HX2)™ is added to the clofazimine compound in suspension with 0.9% NaCl solution or suspension. Polysorbate 80 (HX2)™ gives the best results for topical formulations, e.g., low allergic reactions, low toxicity, low levels of peroxide compounds. Solid clofazimine may be first dissolved in 75% acetic acid before emulsification with Polysorbate 80.

[0042] Polysorbate 80 is frequently used in pharmaceutical formulations as an emulsifier, solubilizer and stabilizer and can be added to the formulation at room temperature. The formulation is stable at room temperature and at extreme tropical temperatures of about 40°C and can be used for application until the target number of doses is reached, for example, daily topical application to an ulcer or wound until it heals. The daily concentration of antibiotic in the formulation depends on the severity of the ulcer, for example, a suspension can contain about 0.1-1.0 mg / g.

[0043] The viscosity of the formulation will vary depending on the final topical formulation. For example, the viscosity of an aerosol spray will be different from that of a gel. The formulation is stable for more than 6 months at temperatures between -20°C and 60°C.

[0044] Although certain preferred embodiments have been referred to above, it is understood that the present invention is not so limited. It is understood by those skilled in the art that various modifications may be made to the disclosed embodiments, and such modifications are intended to be within the scope of the present invention.

[0045] All publications, patent applications and patents cited herein are hereby incorporated by reference in their entirety.

[0046] (Additional Note) (Appendix 1) A topical pharmaceutical composition for the treatment of skin infections caused by Mycobacterium ulcerans comprising clofazimine, clofazimine polymorphs, clofazimine derivatives, clofazimine salts and / or analogues thereof and one or more pharma- ceutically acceptable carriers or excipients.

[0047] (Appendix 2) 2. A topical pharmaceutical composition according to claim 1, comprising a solution, suspension, lotion, paste, ointment, cream, gel, oil, bandage, aerosol, spray, powder and / or occlusive dressing.

[0048] (Appendix 3) 2. The topical pharmaceutical composition of claim 1, further comprising a therapeutically effective dose of clofazimine, clofazimine polymorphs, clofazimine derivatives, clofazimine salts and / or analogues thereof in a suspension for dropping or spraying onto ulcerated areas of the skin.

[0049] (Appendix 4) 3. The topical pharmaceutical composition according to claim 2, wherein the content of clofazimine, clofazimine polymorphs, clofazimine derivatives, clofazimine salts and / or analogues is 0.01 to about 100 mg per dose.

[0050] (Appendix 5) 5. A topical pharmaceutical composition according to any one of claims 1 to 4, comprising less than 50% w / w emulsifier and more than 20% w / w water.

[0051] (Appendix 6) 6. A topical pharmaceutical composition according to any one of claims 1 to 5, wherein the content of the suspension is an aqueous or alcoholic medium containing solid particulate active ingredient of clofazimine, clofazimine polymorphs, clofazimine derivatives, clofazimine salts and / or analogues as a pharmaceutical ingredient.

[0052] (Appendix 7) 7. The topical pharmaceutical composition according to any one of claims 1 to 6, wherein the gel contains a mixture of any composition of water, acetone, alcohol, propylene glycol and / or cellulose derivatives.

[0053] (Appendix 8) The topical pharmaceutical composition of any one of claims 1 to 7, wherein the foam, aerosol and / or spray contains a mixture of any of the compositions of claims 2 to 7, plus a hydrocarbon propellant, a non-polar hydrocarbon, ethanol, acetone, hexadecyl alcohol, glycol ethers and / or polyglycols.

[0054] (Appendix 9) 9. A topical pharmaceutical composition according to any one of claims 1 to 8, comprising an emulsion or suspension having a mean diameter of up to about 1 μm and / or a polydispersity index of up to about 1 D.S.

[0055] (Appendix 10) 10. A topical pharmaceutical composition according to any one of claims 1 to 9, which is sterile and does not contain solid particles of an active agent having a particle size of 1 μm or more.

[0056] (Appendix 11) 11. A topical pharmaceutical composition according to any one of claims 1 to 10, which is a suspension of clofazimine formed using a finely ground form of the drug, and which uses for application polysorbate 80, dipalmitoylphosphatidylcholine (DPPC) and / or 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and / or cholesterol as well as citric acid monohydrate, disodium edetate, sodium chloride, trisodium dehydrate and water.

[0057] (Appendix 12) 12. A topical pharmaceutical composition according to any one of claims 1 to 11, which is a suspension of clofazimine and comprises hypertonic saline 3-7%, sodium bicarbonate, bismuth, gallium or a d-amino acid.

[0058] (Appendix 13) 13. A topical pharmaceutical composition according to any one of claims 1 to 12, comprising an antibiotic at a concentration of 1 mg / mL.

[0059] (Appendix 14) 14. The topical pharmaceutical composition according to any one of claims 1 to 13, having a pH of 3 to 10.

[0060] (Appendix 15) 15. A topical pharmaceutical composition according to any one of claims 1 to 14, comprising an inert buffer.

[0061] (Appendix 16) 16. The topical pharmaceutical composition according to any one of claims 1 to 15, having an osmotic pressure in the range of 200 to 700 mOsm / kg and an ion concentration in the range of 31 to 300 mM.

[0062] (Appendix 17) A topical pharmaceutical composition described in any one of claims 1 to 16, administered topically to the skin of a patient suffering from a Mycobacterium ulcerans skin infection, a nontuberculous mycobacterial skin infection or another bacterial skin infection.

[0063] (Appendix 18) 18. The topical pharmaceutical composition according to any one of claims 1 to 17, which is applied topically to a body surface affected by a bacterial infection in which the pathogen is susceptible to the respective antibiotic in the formulation.

[0064] (Appendix 19) 19. Use of a composition according to any one of claims 1 to 18, formulated as an oral, nasal, ophthalmic, pulmonary, parenteral, topical or mucosal medicament.

[0065] (Appendix 20) A method for producing a stable pharmaceutical formulation comprising emulsifying one or more of a clofazimine compound, a clofazimine derivative, a polymorph, a clofazimine salt and / or an analogue thereof in a suspension together with one or more excipients required for the solubility of the drug to form a topical formulation, and mixing a second solubility enhancer comprising a non-ionic surfactant to form emulsion droplets.

[0066] (Appendix 21) 21. The method of claim 20, wherein the second solubility enhancing agent is a phospholipid or a mixture of natural phospholipids, and the topical pharmaceutical formulation comprises clofazimine, clofazimine derivatives, clofazimine salts and / or analogues in a liposomally solubilized form.

[0067] (Appendix 22) 21. The method of claim 20, wherein the stable pharmaceutical formulation further comprises emulsion droplets of <5Pm present in the suspension at a rate of 50%-98%, more preferably 60-90%, and the geometric standard deviation of the emulsion droplets is <2.2, preferably <1.8.

[0068] (Appendix 23) 22. The method according to claim 21, wherein the emulsion droplets of <3.5 Pm are present in the suspension in a proportion of 40% to 95%, more preferably 50 to 85%.

Claims

1. A topical pharmaceutical composition for the treatment of skin infections caused by Mycobacterium ulcerans, comprising clofazimine, clofazimine polymorphs, clofazimine derivatives, clofazimine salts and / or analogues thereof, and one or more pharmaceutically acceptable carriers or excipients.

2. 10. The topical pharmaceutical composition of claim 1, comprising a solution, suspension, lotion, paste, ointment, cream, gel, oil, bandage, aerosol, spray, powder and / or occlusive dressing.

3. 10. The topical pharmaceutical composition of claim 1, further comprising a therapeutically effective dose of clofazimine, clofazimine polymorphs, clofazimine derivatives, clofazimine salts and / or analogs thereof in a suspension for dripping or spraying onto ulcerated areas of the skin.

4. 3. The topical pharmaceutical composition of claim 2, wherein the amount of clofazimine, clofazimine polymorphs, clofazimine derivatives, clofazimine salts and / or analogs is from 0.01 to about 100 mg per dose.

5. 5. A topical pharmaceutical composition according to claim 4, wherein the content of emulsifier is less than 50% w / w and more than 20% w / w water.

6. 6. The topical pharmaceutical composition of claim 5, wherein the suspension contains an aqueous or alcoholic medium containing a solid particulate active ingredient of clofazimine, clofazimine polymorphs, clofazimine derivatives, clofazimine salts and / or analogs as a pharmaceutical ingredient.

7. 7. The topical pharmaceutical composition of claim 6, wherein the gel ingredients comprise a mixture of water, acetone, alcohol, propylene glycol and / or cellulose derivatives in any composition.

8. 8. The topical pharmaceutical composition of claim 7, wherein the foam, aerosol and / or spray contents comprise a mixture of any of the compositions of claims 2 to 7 with the addition of a hydrocarbon propellant, a non-polar hydrocarbon, ethanol, acetone, hexadecyl alcohol, a glycol ether and / or a polyglycol.

9. 9. The topical pharmaceutical composition of claim 8, comprising an emulsion or suspension having an average diameter of at most about 1 μm and / or a polydispersity index of at most about 1 D.S.

10. 10. The topical pharmaceutical composition of claim 9, which is sterile and does not contain solid particles of active agent having a particle size of 1 μm or greater.

11. 11. The topical pharmaceutical composition of claim 10, which is a suspension of clofazimine formed using a finely ground drug, and for application, uses polysorbate 80, dipalmitoylphosphatidylcholine (DPPC) and / or 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and / or cholesterol, as well as citric acid monohydrate, edetate disodium, sodium chloride, trisodium dehydrate, and water.

12. 12. The topical pharmaceutical composition of claim 11, which is a suspension of clofazimine and comprises 3-7% hypertonic saline, sodium bicarbonate, bismuth, gallium, or a d-amino acid.

13. 13. The topical pharmaceutical composition of claim 12, comprising an antibiotic at a concentration of 1 mg / mL.

14. 14. The topical pharmaceutical composition of claim 13, having a pH of 3 to 10.

15. 15. The topical pharmaceutical composition of claim 14, comprising an inert buffer.

16. 16. The topical pharmaceutical composition of claim 15, having an osmolality in the range of 200 to 700 mOsm / kg and an ionic strength in the range of 31 to 300 mM.

17. 17. The topical pharmaceutical composition of claim 16, which is administered topically to the skin of a patient suffering from a Mycobacterium ulcerans skin infection, a nontuberculous mycobacterial skin infection, or another bacterial skin infection.

18. 18. The topical pharmaceutical composition of claim 17, which is applied topically to a body surface affected by a bacterial infection in which the pathogen is susceptible to each of the antibiotics in the formulation.

19. 20. Use of the composition of claim 18 formulated as an oral, nasal, ophthalmic, pulmonary, parenteral, topical, or mucosal medicament.

20. A method for producing a stable pharmaceutical formulation comprising emulsifying one or more of a clofazimine compound, a clofazimine derivative, a polymorph, a clofazimine salt and / or an analogue thereof into a suspension together with one or more additives necessary for the solubility of the drug to form a topical formulation, and mixing a second solubility enhancer comprising a non-ionic surfactant to form emulsion droplets.

21. 21. The method of claim 20, wherein the second solubility-enhancing agent is a phospholipid or a mixture of natural phospholipids, and the topical pharmaceutical formulation comprises clofazimine, clofazimine derivatives, clofazimine salts and / or analogs in liposomally solubilized form.

22. 21. The method of claim 20, wherein the stable pharmaceutical formulation further comprises <5Pm emulsion droplets present in the suspension in an amount of 50% to 98%, more preferably 60 to 90%, and wherein the emulsion droplets have a geometric standard deviation of <2.2, preferably <1.

8.

23. 22. The method of claim 21, wherein the emulsion droplets of <3.5 Pm are present in the suspension in a proportion of 40% to 95%, more preferably 50 to 85%.