A method of treating malignant fungating wound using besifloxacin

Abstract

The present disclosure relates to a method of treating malignant fungating wound (MFW) and / or the signs and symptoms of MFW in a subject in need thereof, by administering an inhibitor of DNA gyrase and / or topoisomerase and / or MD2-TLR interaction to the wound. The DNA gyrase and / or topoisomerase and / or MD2-TLR inhibitor is preferably, but not limited to, besifloxacin. It is found that the DNA gyrase and / or topoisomerase and / or MD2-TLR inhibitor results in effective neutralization / reduction of aerobic and anaerobic bacteria found in MFW site. When administered to the wound topically and / or intralesionally, the DNA gyrase and / or topoisomerase and / or MD2-TLR inhibitor, reduces malodor and pain associated with the MFW and improves quality of life. The present disclosure also relates to a pharmaceutical composition comprising a DNA gyrase and / or topoisomerase and / or MD2-TLR inhibitor, such as, besifloxacin, and a pharmaceutically acceptable excipient as well as use of these compositions in treating the signs and symptoms of MFW.

Description

A METHOD OF TREATING MALIGNANT FUNGATING WOUND USING BESIFLOXACIN CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims priority from a provisional patent application filed in USPTO having Patent Application No.63 / 660,067 filed on June 14, 2024. TECHNICAL FIELD

[0002] The present disclosure relates to a method of treating Malignant Fungating Wound (MFW) using an inhibitor of DNA Gyrase and / or topoisomerase and / or MD2-TLR modulator. Particularly, the present disclosure relates to a method of treating Malignant Fungating Wound (MFW) using Besifloxacin. The present application also provides pharmaceutical compositions comprising Besifloxacin. BACKGROUND OF THE DISCLOSURE

[0003] Malignant fungating wounds (MFW) afflict 5-14% of patients with advanced cancer (1, 2). MFWs may arise from any type of malignant tumor but common primary sites are: breast, head and neck, kidney, lung, ovary, colon, penis, skin, bladder, sarcomas, leukemia and lymphoma. MFW results from a cancerous mass that invades the epithelium and surrounding lymphatic and blood vessels, causing widespread tissue damage, tissue hypoxia and necrosis and polymicrobial proliferation of the wound bed (3).

[0004] MFW is a non-healing wound (3). Unfortunately, MFW is extremely distressing to patients given their high burden of symptoms, including extreme malodor, heavy exudate, bleeding, severe pain, leading to feeling of shame, low self-esteem, and social isolation (4, 5). Presentation of symptoms of malignant fungating wounds has become a symbol of impending death for patients and their family (1). The management of symptoms is therefore the mainstay of treatment for MFW. In a survey of nurses, 48% identified malodor as the main challenge, followed by pain and exudate control (6). As described by Souza et al, ‘odor is a constant day-to-day symptom of the patient, causing nausea and unleashing the progressive worsening of their nutritional status, in addition to afflicting the people with whom they interact, or even health professionals through direct contact’(7). The malodor associated with MFWs has a significant negative effect on quality of life and often inflicts a sense of shame due to the pervasive and pungent smell (4). Therefore, the treating symptomof malodor associated with MFW is an important clinical goal and can dramatically impact the lives of patients. Currently, there are no FDA-approved drugs to treat the symptom of malodor associated with MFW. Unfortunately, several studies have demonstrated a lack of odor improvement or wound appearance with the use of systemic antibiotics (9), the likely explanation being that the areas of necrosis prevent an effective concentration of antibiotics in the MFW due to their interrupted blood supply (10). Indeed, in a prospective double-blind crossover trial, systemic metronidazole was found to be not superior to placebo in the reduction of malodor (11).

[0005] There is an unmet need for effective methods and agents for treating MFW and its symptoms. The present disclosure attempts to address this need. SUMMARY OF THE DISCLOSURE

[0006] Addressing the aforesaid need in the art, the present disclosure provides a method of treating the signs and / or symptoms of Malignant Fungating Wound (MFW) in a subject in need thereof, comprising administering an inhibitor of DNA gyrase and / or topoisomerase and / or MD2- TLR interaction to the wound.

[0007] In some embodiments, the inhibitor of DNA gyrase and / or topoisomerase and / or MD2- TLR interaction is administered to a fungating wound, topically or intralesionally.

[0008] In some embodiments, the inhibitor of DNA gyrase and / or topoisomerase and / or MD2- TLR interaction is a fluoroquinolone molecule.

[0009] In some embodiments of the present disclosure, the fluoroquinolone molecule is besifloxacin.

[0010] In some embodiments, the inhibitor of DNA gyrase and / or topoisomerase and / or MD2- TLR interaction is administered in the form of a pharmaceutical composition.

[0011] The present disclosure also provides a method of treating Malignant Fungating Wound (MFW) using an inhibitor of DNA gyrase and / or topoisomerase and / or MD2-TLR interaction.

[0012] The present disclosure also provides the method of using an inhibitor of DNA gyrase and / or topoisomerase and / or MD2-TLR interaction to treat pain associated with malignant fungating wound.

[0013] The present disclosure also provides the method of using an inhibitor of DNA gyraseand / or topoisomerase and / or MD2-TLR interaction to treat malodor associated with malignant fungating wound.

[0014] The present disclosure also provides the method of using an inhibitor of DNA gyrase and / or topoisomerase and / or MD2-TLR interaction to improve the quality of life of patients suffering from malignant fungating wound.

[0015] The present disclosure also relates to use of a DNA gyrase and / or topoisomerase inhibitor and / or MD2-TLR interaction in manufacturing a medicament for treating Malignant Fungating Wound.

[0016] The present disclosure also relates to use of a DNA gyrase and / or topoisomerase inhibitor and / or MD2-TLR interaction in manufacturing a medicament for treating signs and / or symptoms of Malignant Fungating Wound.

[0017] The present disclosure also provides a pharmaceutical composition comprising besifloxacin and a pharmaceutically acceptable excipient.

[0018] The present disclosure also provides a use of a pharmaceutical composition comprising besifloxacin and a pharmaceutically acceptable excipient to reduce malodor and / or pain symptoms associated with MFW.

[0019] The present disclosure also provides a use of a pharmaceutical composition comprising besifloxacin and a pharmaceutically acceptable excipient to reduce bacterial counts (sign) in MFW.

[0020] The present disclosure also provides a use of a pharmaceutical composition comprising besifloxacin and a pharmaceutically acceptable excipient to improve the quality of life of patients with MFW. BRIEF DESCRIPTION OF THE ACCOMPANYING FIGURES

[0021] Figure 1 shows the binding of besifloxacin to DNA gyrase.

[0022] Figure 2 shows the binding of Besifloxacin to the hydrophobic pocket of Myeloid Differentiation Protein 2 (MD-2), which interfaces with Toll-Like Receptor (TLR).

[0023] Figure 3 shows the composition of bacterial colonies in MFW and the efficacy of VB- 1953 (Besifloxacin gel) against these bacteria.

[0024] Figure 4 shows representative photographs of malignant fungating wounds in patients with different tumor types treated with VB-1953 (besigloxacin gel) before start of treatment (baseline) and after 14 days of treatment with VB-1953 applied topically on the wound.

[0025] Figure 5 shows study design timeline illustrating treatment schedule and assessment points for pain and quality of life outcomes. DETAILED DESCRIPTION OF THE DISCLOSURE

[0026] With respect to the use of substantially any plural and / or singular terms herein, those having skill in the art can translate from the plural to the singular and / or from the singular to the plural as is appropriate to the context and / or application. The various singular / plural permutations may be expressly set forth herein for sake of clarity. The use of the expression “at least” or “at least one” suggests the use of one or more elements or ingredients or quantities, as the use may be in the embodiment of the disclosure to achieve one or more of the desired objects or results. Throughout this specification, the word “comprise”, or variations such as “comprises” or “comprising” or “containing” or “has” or “having”, or “including but not limited to” wherever used, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[0027] Reference throughout this specification to “one embodiment”, “an embodiment”, or “some embodiments” means that a particular feature, structure or characteristic described in connection with the embodiment may be included in at least one embodiment of the present disclosure. Thus, the appearances of the phrases “in one embodiment”, “in an embodiment”, or “in some embodiments” in various places throughout this specification may not necessarily all refer to the same embodiment. It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.

[0028] The term “about” as used herein encompasses variations of + / -10% and more preferably + / - 5%, as such variations are appropriate for practicing the present invention.

[0029] The present disclosure provides a method of treating MFW using an inhibitor of DNA gyrase and / or topoisomerase and / or MD2-TLR interaction.

[0030] Throughout the present disclosure, the term besifloxacin is intended to also cover salts of besifloxacin such as besifloxacin Hydrochloride or besifloxacin HCl.

[0031] The present disclosure provides a method of treating Malignant Fungating Wound (MFW) in a subject in need thereof, comprising administering an inhibitor of DNA gyrase and / or topoisomerase and / or MD2-TLR interactions to the wound. In some embodiments, the inhibitor of DNA gyrase and / or topoisomerase and / or MD2-TLR interactions is administered to the MFW topically or intralesionally. In some embodiments, the frequency of administration is once daily, twice daily, or three times daily.

[0032] The present disclosure provides a method of treating signs and / or symptoms of Malignant Fungating Wound (MFW) in a subject in need thereof, comprising administering an inhibitor of DNA gyrase and / or topoisomerase and / or MD2-TLR interactions to the wound. In some embodiments, the inhibitor of DNA gyrase and / or topoisomerase and / or MD2-TLR interactions is administered to the MFW topically or intralesionally. In some embodiments, the frequency of administration is once daily, twice daily, or three times daily.

[0033] In some embodiments, the inhibitor of DNA gyrase and / or topoisomerase and or MD2- TLR is a fluoroquinolone molecule. In some exemplary, non-limiting embodiments of the present disclosure, the fluoroquinolone molecule is besifloxacin.

[0034] In some embodiments, provided herein is a method of treating MFW in a subject in need thereof, comprising administering a fluoroquinolone molecule to the wound. In some embodiments, the fluoroquinolone molecule administered to the wound is besifloxacin. In some embodiments, administration of the fluoroquinolone molecule to the wound comprises topical or intralesional administration. In some embodiments, the frequency of administration is once daily, twice daily, or three times daily.

[0035] In some embodiments, provided herein is a method of treating signs and / or symptoms of MFW in a subject in need thereof, comprising administering a fluoroquinolone molecule to the wound. In some embodiments, the fluoroquinolone molecule administered to the wound is besifloxacin. In some embodiments, administration of the fluoroquinolone molecule to the wound comprises topical or intralesional administration. In some embodiments, the frequency of administration is once daily, twice daily, or three times daily.

[0036] The term “subject” or “patient” as used herein refers to any mammal including, without limitation, humans and other primates (e.g., chimpanzees and other apes and monkey species), farm animals (e.g., cattle, sheep, pigs, goats and horses), domestic mammals (e.g., dogs and cats), and laboratory animals (e.g., rodents such as mice, rats, and guinea pigs). In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0037] In some embodiments of the present disclosure, treating Malignant Fungating Wound comprises neutralization / reduction of aerobic and / or anaerobic bacteria at the wound site, reducing inflammation of the wound and / or reducing malodor associated with the MFW and / or improving the quality of life of patients with MFW.

[0038] In some embodiments, the inhibitor of DNA gyrase and / or topoisomerase and / or MD2- TLR interactions is administered to the wound (e.g., topically or intralesionally) in the form of a pharmaceutical composition. In some embodiments, the frequency of administration is once daily, twice daily, or three times daily.

[0039] In some embodiments, the inhibitor of DNA gyrase and / or topoisomerase is present at a concentration of about 0.5-4.5% w / w in the pharmaceutical composition, including values and ranges therebetween. For example, the inhibitor of DNA gyrase and / or topoisomerase and / or MD2-TLR interactions, such as besifloxacin, is present in the pharmaceutical composition at a concentration of about 0.5-4.5% w / w, about 0.7-4.36% w / w, about 1-4.5% w / w, about 1.09-4.0% w / w; about 1.09- 4.36% w / w, about 1.5-3.7% w / w; about 1.75-3.2% w / w; about 2-3% w / w; about 0.5% w / w; about 1.0% w / w, about 1.09% w / w, about 1.5% w / w, about 2.0% w / w; about 2.18% w / w; about 2.5% w / w; about 3.0% w / w; about 3.5% w / w; about 4.0% w / w; about 4.36% w / w; or about 4.5% w / w; including values and ranges therebetween.

[0040] In some embodiments, the pharmaceutical composition comprises the inhibitor of DNA gyrase and / or topoisomerase and / or MD2-TLR interactions and one or more excipient(s).

[0041] Accordingly, in some exemplary, non-limiting embodiments, the present disclosure provides a method of treating Malignant Fungating Wound (MFW) in a subject in need thereof, comprising administering a pharmaceutical composition comprising besifloxacin and one or more excipient(s) to the wound.

[0042] Accordingly, in some exemplary, non-limiting embodiments, the present disclosureprovides a method of treating signs and / or symptoms of Malignant Fungating Wound (MFW) in a subject in need thereof, comprising administering a pharmaceutical composition comprising besifloxacin and one or more excipient(s) to the wound.

[0043] In some non-limiting embodiments of the present disclosure, the excipient is selected from a group comprising a surfactant, a chelating agent, a solubilizing agent, a wetting agent, a detergent, a stabilizer, a whitener or an opacifier, an emulsifying agent, a foaming agent, a thickening agent, a binding agent, a moisturizing agent, a preservative, a rheology modifier, an antimicrobial agent, a cleaning agent, a flavouring agent, a fragrance, a solvent and a filler, and a combination thereof.

[0044] In some embodiments of the present disclosure, the pH of the pharmaceutical composition is about 5.5-7.0, including values and ranges therebetween.

[0045] For example, the pH of the pharmaceutical composition is about 5.5-7.0; about 6.0-7.0; about 6.0-6.5; about 5.5; about 6.0; about 6.5; or about 7.0; including values and ranges therebetween.

[0046] In some embodiments of the present disclosure, the viscosity of the pharmaceutical composition is about 3500-15000 m.Pa.S, including values and ranges therebetween.

[0047] For example, the viscosity of the pharmaceutical composition is about 3500-15000 m.Pa.S; about 4500-13000 m.Pa.S; about 6000-11000 m.Pa.S; about 7000-10000 m.Pa.S; about 8000-14000 m.Pa.S; about 3500 m.Pa.S; about 4000 m.Pa.S; about 5000 m.Pa.S; about 6000 m.Pa.S; about 7000 m.Pa.S; about 8000 m.Pa.S; about 9000 m.Pa.S; about 10000 m.Pa.S; about 11000 m.Pa.S; about 12000 m.Pa.S; about 13000 m.Pa.S; about 14000 m.Pa.S; or about 15000 m.Pa.S; including values and ranges therebetween.

[0048] In some embodiments, the methods of the present disclosure reduce the bacterial count of the MFW. The reduction in the bacterial count of the wound as referred to herein includes reduction in the bacterial count in the wound or in the exudate obtained from the wound. In some embodiments, the methods of the present disclosure reduce the bacterial count of the MFW by at least about 20%, 30%, 40%, 50%, or 60% compared to the bacterial count of the wound prior to the treatment.

[0049] In some embodiments, the methods of the present disclosure reduce the bacterial count of the MFW by about 20-99%, including values and ranges thereof, such as by about 20-75%, 20- 70%, 20-65%, 20-60%, 20-55%, 20-50%, 20-45%, 20-40%, 25-75%, 25-60%, 25-50%, 25-40%, 30-80%, 30-75%, 30-60%, 30-50%, 40-80%, 40-70%, 40-60%, 50-80%, 50-70%, or 60-99%, compared to the bacterial count prior to the treatment.

[0050] In some embodiments, the methods of the present disclosure reduce the bacterial count of the MFW by about 1.5 to 5-fold, 2 to 5-fold, 2 to 4-fold, 2.5 to 5-fold, 3 to 5-fold, or 3 to 4- fold, including values and ranges thereof, such as by about 1.5-fold, 2-fold, 2.5-fold, 3-fold, 4-fold, or about 5-fold, compared to the bacterial count prior to the treatment.

[0051] The above values for reduction in the bacterial count include reduction in the count of specific bacteria found in the MFW, such as Staphylococcus (e.g., S. aureus), Pseudomonas, Streptococcus, E. coli, Klebsiella, and anaerobic bacteria.

[0052] In some embodiments, the methods of the present disclosure reduce the odor emanating from the wound.

[0053] In some embodiments, the methods of the present disclosure reduce the malodor associated with the MFW. For example, in some embodiments, the administration of besifloxacin or a pharmaceutical composition thereof to MFWs in the subject reduces the malodor by at least about 20%, 30%, 40%, 50%, or 60% and more compared to the malodor prior to the treatment.

[0054] In some embodiments, the administration of besifloxacin or a pharmaceutical composition thereof to MFWs in the subject reduces the malodor by about 20-80%, including values and ranges thereof, such as by about 20-75%, 20-70%, 20-65%, 20-60%, 20-55%, 20-50%, 20-45%, 20-40%, 25-75%, 25-60%, 25-50%, 25-40%, 30-80%, 30-75%, 30-60%, 30-50%, 40-80%, 40-70%, 40-60%, 50-80%, 50-70%, or 60-80%, compared to the count prior to the treatment.

[0055] In some embodiments, the administration of besifloxacin or a pharmaceutical composition thereof to MFWs in the subject reduces the malodor by about 1.5 to 5-fold, 2 to 5-fold, 2 to 4-fold, 2.5 to 5-fold, 3 to 5-fold, or 3 to 4-fold, including values and ranges thereof, such as by about 1.5-fold, 2-fold, 2.5-fold, 3-fold, 4-fold, or about 5-fold, compared to the count prior to the treatment.

[0056] In some embodiments, the methods of the present disclosure reduce the pain associated with the MFW. For example, in some embodiments, the administration of besifloxacin or a pharmaceutical composition thereof to MFWs in the subject reduces the pain associated with the lesion by at least about 20%, 30%, 40%, 50%, or 60% compared to the pain associated with the lesionprior to the treatment.

[0057] In some embodiments, the administration of besifloxacin or a pharmaceutical composition thereof to MFWs in the subject reduces the pain associated with the lesion by about 20- 80%, including values and ranges thereof, such as by about 20-75%, 20-70%, 20-65%, 20-60%, 20- 55%, 20-50%, 20-45%, 20-40%, 25-75%, 25-60%, 25-50%, 25-40%, 30-80%, 30-75%, 30-60%, 30- 50%, 40-80%, 40-70%, 40-60%, 50-80%, 50-70%, or 60-80%, compared to the count prior to the treatment.

[0058] In some embodiments, the administration of besifloxacin or a pharmaceutical composition thereof to MFWs in the subject reduces the pain associated with the lesion by about 1.5 to 5-fold, 2 to 5-fold, 2 to 4-fold, 2.5 to 5-fold, 3 to 5-fold, or 3 to 4-fold, including values and ranges thereof, such as by about 1.5-fold, 2-fold, 2.5-fold, 3-fold, 4-fold, or about 5-fold, compared to the count prior to the treatment.

[0059] In some embodiments, the methods of the present disclosure reduce the inflammation of the MFW. For example, in some embodiments, the administration of besifloxacin or a pharmaceutical composition thereof to MFWs in the subject reduces the inflamed lesion by at least about 20%, 30%, 40%, 50%, or 60% compared to the inflamed lesion prior to the treatment.

[0060] In some embodiments, the administration of besifloxacin or a pharmaceutical composition thereof to MFWs in the subject reduces the inflamed lesion by about 20-80%, including values and ranges thereof, such as by about 20-75%, 20-70%, 20-65%, 20-60%, 20-55%, 20-50%, 20-45%, 20-40%, 25-75%, 25-60%, 25-50%, 25-40%, 30-80%, 30-75%, 30-60%, 30-50%, 40-80%, 40-70%, 40-60%, 50-80%, 50-70%, or 60-80%, compared to the count prior to the treatment.

[0061] In some embodiments, the administration of besifloxacin or a pharmaceutical composition thereof to MFWs in the subject reduces the inflamed lesion by about 1.5 to 5-fold, 2 to 5-fold, 2 to 4-fold, 2.5 to 5-fold, 3 to 5-fold, or 3 to 4-fold, including values and ranges thereof, such as by about 1.5-fold, 2-fold, 2.5-fold, 3-fold, 4-fold, or about 5-fold, compared to the count prior to the treatment.

[0062] In some embodiments, the methods of the present disclosure improve quality of life of the patient suffering from signs and / or symptoms of MFW.

[0063] In some embodiments, the pharmaceutical composition employed in the methods of thepresent disclosure is a topical formulation or an intralesional formulation. Accordingly, in some embodiments, the present disclosure provides a pharmaceutical composition such as a topical formulation or an intralesional formulation comprising besifloxacin and an excipient.

[0064] In some non-limiting embodiments of the present disclosure, the topical formulation is in the form of a cream, gel, ointment, lotion, spray, topical drops, emugel, soap bar, face wash or body wash.

[0065] In some embodiments, the topical formulation is a cream comprising besifloxacin and an excipient selected from a group comprising surfactant, chelating agent, solubilizing agent, wetting agent, detergent, stabilizer, emulsifying agent, foaming agent, thickening agent, binding agent, moisturizing agent, preservative, rheology modifier, antimicrobial agent, flavouring agent, fragrance, solvent, filler, or a combination thereof.

[0066] In some embodiments, the topical formulation is an ointment comprising besifloxacin and an excipient selected from a group comprising a surfactant, a chelating agent, a solubilizing agent, a wetting agent, a detergent, a stabilizer, an emulsifying agent, a foaming agent, a thickening agent, a binding agent, a moisturizing agent, a preservative, a rheology modifier, an antimicrobial agent, a flavouring agent, a fragrance, a solvent, a filler, and a combination thereof.

[0067] In some embodiments of the present disclosure, the topical formulation is a lotion comprising besifloxacin and an excipient selected from a group comprising surfactant, chelating agent, solubilizing agent, wetting agent, detergent, stabilizer, emulsifying agent, foaming agent, thickening agent, binding agent, moisturizing agent, preservative, rheology modifier, antimicrobial agent, flavouring agent, fragrance, solvent and filler, and a combination thereof.

[0068] In some embodiments, the topical formulation is a spray comprising besifloxacin and an excipient selected from a group comprising surfactant, chelating agent, solubilizing agent, wetting agent, detergent, stabilizer, emulsifying agent, foaming agent, thickening agent, binding agent, moisturizing agent, preservative, rheology modifier, antimicrobial agent, flavouring agent, fragrance, solvent, filler, and a combination thereof.

[0069] In some embodiments, the topical formulation is an emugel comprising besifloxacin and an excipient selected from a group comprising surfactant, chelating agent, solubilizing agent, wetting agent, detergent, stabilizer, emulsifying agent, foaming agent, thickening agent, binding agent,moisturizing agent, preservative, rheology modifier, antimicrobial agent, flavouring agent, fragrance, solvent, filler, and a combination thereof.

[0070] In some embodiments, the topical formulation is a soap bar comprising besifloxacin and an excipient selected from a group comprising surfactant, chelating agent, disinfectant, solubilizing agent, wetting agent, detergent, stabilizer, whitener or opacifier, emulsifying agent, foaming agent, thickening agent, binding agent, moisturizing agent, preservative, rheology modifier, antimicrobial agent, cleaning agent, flavouring agent, fragrance, solvent and filler, and a combination thereof.

[0071] In some embodiments, the topical formulation is a facewash comprising besifloxacin and an excipient selected from a group comprising surfactant, chelating agent, solubilizing agent, wetting agent, detergent, stabilizer, whitener or opacifier, emulsifying agent, foaming agent, thickening agent, binding agent, moisturizing agent, preservative, rheology modifier, antimicrobial agent, cleaning agent, flavouring agent, fragrance, solvent, filler, and a combination thereof.

[0072] In some embodiments of the present disclosure, the topical formulation is a bodywash comprising besifloxacin and an excipient selected from a group comprising surfactant, chelating agent, solubilizing agent, wetting agent, detergent, stabilizer, emulsifying agent, foaming agent, thickening agent, binding agent, moisturizing agent, preservative, rheology modifier, antimicrobial agent, cleaning agent, flavouring agent, fragrance, solvent, filler, and a combination thereof.

[0073] In some embodiments, the excipient included in the pharmaceutical compositions of the present disclosure is selected from one or more excipients disclosed in the exemplified formulations included in the Example section of the present application. Although the Example section discloses specific excipients, the present disclosure contemplates use of other excipients from that class as an alternative to the specific excipient employed in the composition.

[0074] In some embodiments of the present disclosure, the topical formulation is a gel comprising besifloxacin and an excipient selected from a group comprising a moisturizing agent, a chelating agent, a preservative, a stabilizing agent, a solubilizing agent, a thickening agent, a rheology modifier, a solvent, and a combination thereof. In some embodiments, the preservative is not included in the topical gel formulation. In some embodiments, a rheological modifier is not included in the topical gel formulation. In some embodiments, both, the preservative and the rheological modifier are not included in the topical gel formulation.

[0075] In some non-limiting embodiments of the gel formulation of the present disclosure, the moisturizing agent is glycerin; the chelating agent is edetate disodium; the preservative is phenoxyethanol; the stabilizing agent is sodium hyaluronate; the solubilizing agent is one of polyethylene glycol, diethylene glycol monoethyl ether, and a combination thereof; the thickening agent is hydroxyethyl cellulose; the rheology modifier is carbomer or sodium hyaluronate; and the solvent is water.

[0076] In some exemplary, non-limiting embodiments of the present disclosure, polyethylene glycol is polyethylene glycol 400; and carbomer is carbomer homopolymer type C.

[0077] In some embodiments of the present disclosure, the topical gel formulation comprises one of besifloxacin and besifloxacin HCl at a concentration of about 0.5% w / w to about 4.5% w / w, including values and ranges therebetween; glycerin at a concentration of about 2% w / w to about 10% w / w, including values and ranges therebetween; edetate disodium dehydrate at a concentration of about 0.1% w / w; phenoxyethanol at a concentration of about 0.1% w / w to about 0.7% w / w, including values and ranges therebetween; sodium hyaluronate at a concentration of about 0.1% w / w to about 0.5% w. / w, including values and ranges therebetween; polyethylene glycol at a concentration of about 2% w / w to about 7% w / w, including values and ranges therebetween; diethylene glycol monoethyl ether at a concentration of about 2% w / w to about 7% w / w, including values and ranges therebetween; hydroxyethyl cellulose at a concentration of about 0.6% w / w to about 1.75% w / w, including values and ranges therebetween; carbomer homopolymer type C at a concentration of about 0.1% to about 0.8% w / w, including values and ranges therebetween; and the rest is solvent. When the formulations contain besifloxacin hydrochloride at a concentration of 4.36% w / w, it is equivalent to besifloxacin 4% w / w. In some embodiments, phenoxyethanol and / or sodium hyaluronate are not present in the topical composition.

[0078] For example, besifloxacin or besifloxacin HCl is present at a concentration of about 0.5- 4.5% w / w; about 0.7-4.36% w / w, about 1-4.5% w / w, about 1.09-4% w / w; about 1.09-4.36% w / w, about 1.5-3.7% w / w; about 1.75-3.2% w / w; about 2-3% w / w; about 0.5% w / w; about 1.0% w / w, about 1.09% w / w, about 1.5% w / w, about 2.0% w / w; about 2.18% w / w; about 2.5% w / w; about 3.0% w / w; about 3.5% w / w; about 4.0% w / w; about 4.36% w / w; or about 4.5% w / w; including values and ranges therebetween; glycerin is present at a concentration of about 2-10% w / w; about 4-8% w / w; about 5-9% w / w; about 6-7% w / w; about 2% w / w; about 2.5% w / w; about 3% w / w; about 3.5% w / w; about 4% w / w; about 4.5% w / w; about 5% w / w; about 5.5% w / w; about 6% w / w; about 6.5%w / w; about 7% w / w; about 7.5% w / w; about 8% w / w; about 8.5% w / w; about 9% w / w; about 9.5% w / w; or about 10% w / w; including values and ranges therebetween; phenoxyethanol is present at a concentration of about 0.1-0.7% w / w; about 0.2-0.6% w / w; about 0.3-0.5% w / w; about 0.4-0.5% w / w; about 0.1% w / w; about 0.2% w / w; about 0.3% w / w; about 0.4% w / w; about 0.5% w / w; about 0.6% w / w; or about 0.7% w / w, including values and ranges therebetween; sodium hyaluronate is present at a concentration of about 0.1-0.5% w / w, about 0.2-0.4% w / w; about 0.3-0.4% w / w; about 0.1% w / w; about 0.2% w / w; about 0.3% w / w; about 0.4% w / w; or about 0.5% w / w, including values and ranges therebetween; polyethylene glycol is present at a concentration of about 2-7% w / w; about 3-6% w / w; about 4-5% w / w; about 2% w / w; about 2.5% w / w; about 3% w / w; about 3.5% w / w; about 4% w / w; about 4.5% w / w; about 5% w / w; about 5.5% w / w; about 6% w / w; about 6.5% w / w; or about 7% w / w, including values and ranges therebetween; diethylene glycol monoethyl ether is present at a concentration of about 2-7% w / w, about 3-6% w / w; about 4-5% w / w; about 2% w / w; about 2.5% w / w; about 3% w / w; about 3.5% w / w; about 4% w / w; about 4.5% w / w; about 5% w / w; about 5.5% w / w; about 6% w / w; about 6.5% w / w; or about 7% w / w, including values and ranges therebetween; hydroxyethyl cellulose is present at a concentration of about 0.6-1.75% w / w; about 0.7-1.5% w / w; about 0.8-1% w / w; about 0.6% w / w; about 0.7% w / w; about 0.8% w / w; about 0.9% w / w; about 1% w / w; about 1.25% w / w; about 1.5% w / w; or about 1.75% w / w; including values and ranges therebetween; and carbomer homopolymer type C is present at a concentration of about 0.1-0.8% w / w; about 0.2-0.7% w / w; about 0.3-0.6% w / w; about 0.4-0.5% w / w; about 0.1% w / w; about 0.2% w / w; about 0.3% w / w; about 0.4% w / w; about 0.5% w / w; about 0.6% w / w; about 0.7% w / w; or about 0.8% w / w; including values and ranges therebetween.

[0079] In some exemplary, non-limiting embodiments of the present disclosure, the topical gel formulation comprises besifloxacin at one of a concentration of about 1.09%, 2.18%, and 4.36% w / w; glycerin at a concentration of about 5% w / w; edetate disodium at a concentration of about 0.1% w / w; phenoxyethanol at a concentration of about 0.7% w / w; sodium hyaluronate at a concentration of about 0.2% w. / w; polyethylene glycol at a concentration of about 5% w / w; diethylene glycol monoethyl ether at a concentration of about 5% w / w; hydroxyethyl cellulose at a concentration of about 0.6% w / w; carbomer homopolymer type C at a concentration of about 0.65% w / w; and the rest is solvent.

[0080] In some exemplary, non-limiting embodiments of the present disclosure, the topical gel formulation comprises besifloxacin at one of a concentration of about 1.09% w / w and 2.18% w / w; glycerin at a concentration of about 5% w / w; edetate disodium at a concentration of about 0.1% w / w;phenoxyethanol at a concentration of about 0.7% w / w; polyethylene glycol at a concentration of about 5% w / w; diethylene glycol monoethyl ether at a concentration of about 5% w / w; hydroxyethyl cellulose at a concentration of about 0.6% w / w; carbomer homopolymer type C at a concentration of about 0.65% w / w; and the rest is solvent.

[0081] In some exemplary, non-limiting embodiments of the present disclosure, the topical gel formulation comprises besifloxacin at one of a concentration of about 1.09% and 2.18% w / w; glycerin at a concentration of about 5% w / w; edetate disodium at a concentration of about 0.1% w / w; sodium hyaluronate at a concentration of about 0.2% w / w; polyethylene glycol at a concentration of about 5% w / w; diethylene glycol monoethyl ether at a concentration of about 5% w / w; hydroxyethyl cellulose at a concentration of about 0.6% w / w; carbomer homopolymer type C at a concentration of about 0.65% w / w; and the rest is the solvent.

[0082] The present disclosure also relates to an inhibitor of DNA gyrase and / or topoisomerase and / or MD2-TLR interactions for use in treating MFW.

[0083] In some embodiments of the present disclosure, the inhibitor of DNA gyrase and / or topoisomerase and / or MD2-TLR interactions for use in treating MFW is a fluoroquinolone molecule.

[0084] In some embodiments, the fluoroquinolone molecule for use in treating MFW is besifloxacin.

[0085] Accordingly, in some exemplary, non-limiting embodiments, the present disclosure relates to besifloxacin for use in treating Malignant Fungating Wound (MFW).

[0086] Accordingly, in some exemplary, non-limiting embodiments, the present disclosure relates to besifloxacin for use in treating signs and / or symptoms of Malignant Fungating Wound (MFW).

[0087] Besifloxacin acts via a dual mechanism of action by inhibiting DNA gyrase / topoisomerase IV and MD2-TLR interactions to reduce odor, inflammation and pain associated with MFW.

[0088] Binding to DNA Gyrase: Figure 1 shows the binding of besifloxacin in a unique manner to DNA Gyrase. Due to its bulky 7-membered azeprenyl group, besifloxacin binds to the quinolone binding site of the complex of DNA-DNA gyrase more strongly due to increase in van der Waal’sand hydrophobic interactions due to group. The 8-chloro group along with the fluoro group are involved in halogen bond interactions. There is an increased interaction with the DNA and less interaction with the DNA gyrases that binding is unaffected even when there is a mutation in the protein. This results in bacterial cell kill to a greater extent than metronidazole, which is currently used to kill anaerobic bacteria. Besifloxacin kills both aerobic and anaerobic bacteria.

[0089] Binding to TLR-MD2: Figure 2 shows that as an additional mechanism of action, Besifloxacin binds to the hydrophobic pocket of MD-2, which interfaces with TLR. As a result, Besifloxacin can exert an immunomodulatory effect independent of its antibacterial effect. This is critical in reducing the symptoms of MFW as the necrotic wound and cellular debris can trigger the activation of the TLR-MD2 signaling leading to tissue damage.

[0090] In some embodiments, the DNA gyrase and / or topoisomerase inhibitor for use in treating MFW and / or signs and / or symptoms of MFW is in the form of a pharmaceutical composition.

[0091] In some embodiments, the inhibitor of DNA gyrase and / or topoisomerase and / or MD2- TLR interaction is present at a concentration of about 0.5-4.5% w / w in the pharmaceutical composition.

[0092] In some embodiments of the present disclosure, the inhibitor of DNA gyrase and / or topoisomerase and / or MD2-TLR interaction is besifloxacin.

[0093] Accordingly, in some exemplary, non-limiting embodiments, the present disclosure relates to a pharmaceutical composition comprising besifloxacin and a pharmaceutically acceptable excipient for use in treating Malignant Fungating Wound (MFW) and / or signs / symptoms of MFW. In some embodiments, the pharmaceutical composition comprising besifloxacin for use in treating MFW is selected from one of a topical formulation and an intralesional formulation. The besifloxacin is present at a concentration of about 0.5% w / w to about 4.5% w / w. The composition is selected from one of a topical formulation and an intralesional formulation. The topical formulation is selected from a group comprising of a cream, gel, ointment, lotion, spray, emugel, soap bar, face wash and body wash. The topical formulation is a gel comprising besifloxacin and an excipient selected from a group comprising moisturizing agent, chelating agent, preservative, stabilizing agent, solubilizing agent, thickening agent, rheology modifier and solvent, and a combination thereof. The moisturizing agent is glycerin; the chelating agent is edetate disodium dehydrate; the preservative is phenoxyethanol; the stabilizing agent is sodium hyaluronate; the solubilizing agent is one of polyethylene glycol,diethylene glycol monoethyl ether, and a combination thereof; the thickening agent is hydroxyethyl cellulose; the rheology modifier is sodium hyaluronate or carbomer homopolymer type C; and the solvent is water.

[0094] In another exemplary, non-limiting embodiments, the present disclosure relates to the pharmaceutical composition comprising besifloxacin is present at a concentration of about 0.5% w / w to about 4.5% w / w; glycerin is present at a concentration of about 2% w / w to about 10% w / w; edetate disodium dehydrate is present at a concentration of about 0.1% w / w; phenoxyethanol is present at a concentration of about 0.1% w / w to about 0.7% w / w; sodium hyaluronate is present at a concentration of about 0.1% w / w to about 0.5% w / w; polyethylene glycol is present at a concentration of about 2% w / w to about 7% w / w; diethylene glycol monoethyl ether is present at a concentration of about 2% w / w to about 7% w / w; hydroxyethyl cellulose is present at a concentration of about 0.6% w / w to about 1.75% w / w; carbomer homopolymer type C is present at a concentration of about 0.1% to about 0.8% w / w; and the rest is solvent.

[0095] In another exemplary, non-limiting embodiments, besifloxacin is present at one of a concentration of about 1.09%, 2.18%, and 4.36% w / w; glycerin is present at a concentration of about 5% w / w; edetate disodium dehydrate is present at a concentration of about 0.1% w / w; phenoxyethanol is present at a concentration of about 0.7% w / w; sodium hyaluronate is present at a concentration of about 0.2% w / w; polyethylene glycol is present at a concentration of about 5% w / w; diethylene glycol monoethyl ether is present at a concentration of about 5% w / w; hydroxyethyl cellulose is present at a concentration of about 0.6% w / w; carbomer homopolymer type C is present at a concentration of about 0.65% w / w; and the rest is solvent.

[0096] In another exemplary, non-limiting embodiments, besifloxacin is present at one of a concentration of about 1.09% and 2.18% w / w; glycerin is present at a concentration of about 5% w / w; edetate disodium dehydrate is present at a concentration of about 0.1% w / w; phenoxyethanol is present at a concentration of about 0.7% w / w; polyethylene glycol is present at a concentration of about 5% w / w; diethylene glycol monoethyl ether is present at a concentration of about 5% w / w; hydroxyethyl cellulose is present at a concentration of about 0.6% w / w; carbomer homopolymer type C is present at a concentration of about 0.65% w / w; and rest is solvent.

[0097] In another exemplary, non-limiting embodiments, besifloxacin is present at one of a concentration of about 1.09% and 2.18% w / w; glycerin is present at a concentration of about 5% w / w;edetate disodium dehydrate is present at a concentration of about 0.1% w / w; sodium hyaluronate is present at a concentration of about 0.2% w / w; polyethylene glycol is present at a concentration of about 5% w / w; diethylene glycol monoethyl ether is present at a concentration of about 5% w / w; hydroxyethyl cellulose is present at a concentration of about 0.6% w / w; carbomer homopolymer type C is present at a concentration of about 0.65% w / w; and the rest is solvent.

[0098] The features and characteristics of the pharmaceutical composition encompassed by the present disclosure are described above. For the sake of brevity, and avoiding repetition, each of those embodiments are not being reiterated here again with respect to the specific use.

[0099] However, each of the said embodiments completely fall within the purview of the use described above.

[0100] The present disclosure also relates to use of an inhibitor of DNA gyrase and / or topoisomerase and / or MD2-TLR interactions in manufacturing a medicament for treating Malignant Fungating Wound.

[0101] Additional embodiments and features of the present disclosure will be apparent to one of ordinary skill in art based on the description provided herein. The embodiments herein provide various features and advantageous details thereof in the description. Descriptions of well- known / conventional methods and techniques are omitted so as to not unnecessarily obscure the embodiments herein. EXAMPLES

[0102] Example 1: Composition of bacterial colonies in MFW and the efficacy of Besifloxacin against these bacteria

[0103] VB-1953 (Besifloxacin 2% gel) was used in this experiment. Composition of bacteria colonizing the wounds of patients suffering from MFW was studied. As shown in Figure 3A, most of the patients with MFW had the wound colonized with aerobic bacteria, which can cause odor even in the absence of anaerobic bacteria. The addition of anaerobic bacteria increased the odor as can be observed in Figure 3B. Figure 3C shows the Minimum Inhibitory Concentration of VB-1953 against aerobic and anaerobic bacteria. The graph clearly shows that VB-1953 is highly effective against both groups of bacteria.

[0104] Example 2: Preparation of Topical Gel Formulations Comprising Besifloxacin

[0105] Different Besifloxacin containing topical gel formulations having compositions as shown in Table 1 below were prepared. Table 1: Topical Gel Formulations Ingredients Formulation 1 Formulation 2 Formulation 3 Besifloxacin 1.09 / 2.18 / 4.36 1.09 / 2.18 1.09 / 2.18 Hydrochloride Glycerin 5.00 5.00 5.00 Edetate disodium 0.10 0.10 0.10 Phenoxyethanol 0.70 0.70 0.0-0.70 Sodium 0.20 0.20 / 0.0 0.20 hyaluronate Polyethylene glycol 5.00 5.00 5.00 400 Diethylene glycol 5.00 5.00 5.00 monoethyl ether Hydroxyethyl 0.60 0.60 0.60 cellulose Carbomer homopolymer type 0.65 0.65 0.65 C q.s. to pH 6.0- q.s. to pH 6.0- q.s. to pH 6.0- Sodium hydroxide 6.5 6.5 6.5 Purified water q.s. to 100 q.s. to 100 q.s. to 100

[0106] Example 3: Topical application of VB-1953 reduces bacterial count Treatment of patients with a topical application of Besifloxacin formulation 1 from Table 1 resultedin a reduction of anaerobic bacteria and reduction of inflammation by 40-50% within 2 weeks. Topical application also allowed locally high concentration of drug with minimal systemic exposure, which allowed both once daily and twice daily application to be clinically effective.

[0107] Example 4: Other Besifloxacin Based Formulations Various besifloxacin based formulations for topical administration were prepared and are mentioned below: Table 2: Some exemplary cream formulations. Method of Phase Ingredients A B C preparation 1) All ingredients of API 0.2% 2% 5% phase A were mixed and heated at 70- 80^C Cetostearyl alcohol 10.0% - 10.0% 2) All ingredients of phase B were mixed and stirred to get Cetyl alcohol — 10.0% — uniform solution, then phase B was also heated to 70- A Stearyl alcohol — 5.0% — 80^C with continuous stirring Macrogol Cetostearyl 5.0% — 5.0% Ether 2 3) Phase A was added into phase B Span 20 — 1.0% — with continuous stirring at 70-80^C Apifil 5.0% — — 4) Ingredients ofphase C was Pemulen TR 1 — 0.5% 0.5% added into pre- formed cream at 40^C with Macrogol continuous Cetostearyl Ether stirring 20 5.0% 5.0% 5) Finally phase D B Tween 20 — 5.0% — was added to get Glycerol 5.0% 10.0% 5.0% desired pH q.s. to q.s. to Water q.s. to 100 100 100 C Preservative 0.1% 0.1% 0.1% D q.s. to q.s. to Citric acid / NaOH q.s. to pH pH pH Table 3: Some exemplary emugel formulations. Method of Phase Ingredients A B C preparation API 0.1% 1% 10% A Olive Oil 5.0% — — Castor Oil 5.0% — — 1) All ingredients of phase A was mixed Stearyl alcohol — 2.0% 2.0% and heated at 70- Oleyl alcohol — 2.0% 2.0% 80^C Liquid Paraffin — 6.0% 6.0% 2) All ingredients ofSpan 20 2.0% — — phase B was mixed and stirred to get Steareth 2 — 2.0% 2.0% uniform solution, Tween 20 8.0% — — then phase B was also heated to 70- Steareth 20 — 2.0% 2.0% 80^C with B Carbopol 1.0% 1.0% — continuous stirring Pemulen — — 0.5% 3) Phase A was added into phase B Propylene glycol 5.0% 5.0% 5.0% with continuous q.s. to q.s. to q.s. to stirring at 70-80^C Water 100% 100% 100% 4) Ingredients of C Preservative 0.1% 0.1% 0.1% phase C was added into pre-formed emulsion at 40^C with continuous stirring D Citric acid / NaOH q.s. to pH q.s. to pH q.s. to pH 5) Finally phase D was added to get desired pH Table 4: Some exemplary gel formulations. Phase Ingredients A B C Method of preparation A API 0.01% 0.5% 2% 1) Ingredients of phase A was mixed Ethanol 10.0% 5.0% 5.0% to solubilize drug B Tween 20 2.0% — 2.0%Steareth 20 — 2.0% — 2) All ingredients of phase B was Carbopol 1.0% — 1.0% mixed and stirred Pemulen — 0.5% — to get uniform solution, Propylene glycol 10.0% 20.0% 15.0% 3) Phase A was Water q.s. to q.s. to q.s. to 100% added into phase B 100% 100% with continuous C Preservative 0.1% 0.1% 0.1% stirring 4) Ingredients of phase C was D Citric acid / q.s. to pH q.s. to q.s. to pH added into pre- NaOH / TEA pH formed emulsion with continuous stirring 5) Finally phase D was added to get desired pH Table 5: Some exemplary lotion formulations. Phase Ingredients A B C Method of preparation API 0.02% 1.5% 3% 1) All ingredients of phase A was mixed Liquid paraffin 5.0% 10.0% 15.0% and heated at 70- Olive oil 1.0% 1.0% 1.0% 80^C A Glyceryl stearate 2.0% 1.0% — 2) All ingredients ofphase B was mixed and stirred to get B Tween 20 2.0% 5.0% 10.0% uniform solution, then Pemulen — 0.5% — phase B was also heated to 70-80^C Ultrez 21 1.0% — 2.0% with continuous Ethanol 5.0% 5.0% 5.0% stirring Propylene glycol 10.0% 10.0% 10.0% 3) Phase A was added into phase B q.s. to q.s. to q.s. to Water with continuous 100% 100% 100% stirring at 70-80^C C Preservative 0.1% 0.1% 0.1% 4) Ingredients of phase C was added into pre- formed lotion at 40^C with Citric acid / NaOH D q.s. q.s. to q.s. to pH continuous stirring / TEA to pH 5) Finally phase D pH was added to get desired pH

[0108] Micronized Besifloxacin Particle Dispersions (D1) Preparation: Besifloxacin was dispersed in surfactant solution (2% aqueous solution of poloxamer 407). The resulting suspension was passed through high pressure homogenizer at about 800 bar. The output dispersion was collected in a beaker and recycled 10 times to yield a dispersion of appropriately sized particles (particle size range of 2µm to 8µm). The size distribution was determined by MasterSizer (Malvern Instruments) and mean particle size found to be 4.1 μm [Dv (10)-0.8μm, Dv (90)-8.9μm].

[0109] Preparation of Gel and / Cream Formulations Loaded with Besifloxacin alone, and its combination with adapalene Gel and / Cream formulations containing besifloxacin were formulated as per the compositions shown in Table 6. These gel formulations have off-white to slightly yellow appearance with the pH of 5-5.5 and viscosity of around 5000 mPa.s. The formulations consist of besifloxacin equivalent to 1% w / w, in three different forms (1) micronized suspended besifloxacin HCl (Table 6, GL1, GL2), (2) fully solublised besifloxacin HCl (Table 6, GL4) and (3) besifloxacin particles suspended in cream formulation without sizing (CM1). In addition to stand alone besifloxacin formulation, besifloxacin was combined with the adapalene (0.1%) (Table 6, GL1) to provide a keratolytic activity in patients. Table 6: Gel and / Cream Formulations for Compositions GL1, GL2, GL3, GL4 and CM1 Sr. No. Ingredient Composition (%) GL1 GL2 GL3 GL4 CM1 1 Water q.s q.s q.s q.s q.s 2 Carbopol 940 1 1 1 3 Carbopol 980 NF 0 0 0 0.8 0.6 4 Hydroxy 0 0 0 1 0 Propyl Cellulose-H 5 Allantoin 0.2 0.2 0.2 0 0 6 Besifloxacin HCl (equivalent to 1 (D1) 1 (D1) 0 1 1 besifloxacin) 7 Adapalene 0.1 0 0 0 0 8 Triethanolamine 1 1 1 0 09 Sodium hydroxide 0 0 0 0.15 0.3 10 Glycerol 5 5 5 0 5 11 Propylene Glycol 5 5 5 0 0 12 PEG 400 5 5 5 0 0 13 Poloxamer 407 0.2 0.2 0.2 0 0 14 Sod. Lauryl 0 0 0 1.6 0 Sulphate 15 Tween 80 0 0 0 8 0 16 Tween 20 0 0 0 4 0 17 diethylene glycol 0 0 0 15 0 monoethyl ether 18 Cetyl Alcohol 0 0 0 0 2 19 Light Liquid 0 0 0 0 5 Paraffin 20 Cyclopentasiloxane 0 0 0 0 5 21 Steareth 2 0 0 0 0 2 22 Steareth 21 0 0 0 0 2 23 BHT 0 0 0 0 0.1 24 Disodium EDTA 0.1 0.1 0.1 0.05 0 25 Phenoxyethanol 0.5 0.5 0.5 0.6 0.5

[0110] Method of preparation: (1) Allantoin was heated to 50°C to dissolve completely and cooled down to RT.(2) Carbopol was added to above mixture and allowed to swell for 1 to 2h. (3) Dispersion of micronized Besifloxacin and adapalene powder was added to the swelled carbopol mixture and allowed to stir for 30 min at 400rpm. (4) Then, glycerol, propylene glycol, PEG 400, poloxamer 407 were added followed by the addition of disodium EDTA solubilized in water. Phenoxyethanol was then added to the above stirring mixture. After addition of all the ingredients, the mixture was allowed to stir for 30 minutes. (5) Above mixture was neutralized with triethanolamine and stirred for 2-3h at 800 rpm. (6) Preparation of Cream Formulations (CM1) Loaded with Besifloxacin HCl Cream formulation containing suspended Besifloxacin particles were formulated as per the compositions shown in Table 6. This gel formulation had off-white to slightly yellow appearance with pH of 5-5.5 and viscosity of 3060 mPa.s. Procedure: (7) Part A: Besifloxacin was dispersed in glycerin and deionized water in the main vessel and heated to 70°C. (8) Part B: Heated in cetyl Alcohol, light liquid paraffin, cyclopentasiloxane, steareth 2, and steareth 21 and in a separate vessel to 70°C. (9) PART B was added into PART A with continuous mixing at 70°C and allowed to mix for 15 min. The batch was cooled with mixing to 45°C. (10) PART C: carbopol was swelled separately in water for 2h. (11) PART C was added into PART A / B and mixed well for 20 min. (12) Preparation of Spray Formulations Loaded with Besifloxacin Hydrochloride, Clinafloxacin or Sitafloxacin Alone and the Combinations with Adapalene Spray formulations containing besifloxacin Hydrochloride, clinafloxacin, sitafloxacin in combination with adapalene and salicylic acid were formulated as per the compositions shown in Table 7. These formulations have the pH of 4.7-5.5. The formulations consisted of actives (besifloxacin hydrochloride, clinafloxacin and sitafloxacin) equivalent to 1% w / w in different formulations (Table 7, S5, S3 and S2). In addition to stand alone formulation, anti-microbial agents were combined withkeratolytic agent such as adapalene (0.1%) to provide a keratolytic activity in patients (Table 7, S1, and S4 ). Method of preparation: (1) Water was added to a main mixing vessel followed by the addition of sodium hydroxide solution, PEG 1450, methyl gluceth-20 and glycerin in order with mixing. (2) In a separate vessel, besifloxacin hydrochloride, clinafloxacin or sitafloxacin were added in isopropyl alcohol, propylene glycol, diethylene glycol monethyl ether and ethanol mixture were mixed. All the contents of this vessel were added to the main vessel and mixed. (3) Adapalene was dissolved in N-methyl 2-pyrrolidone and added to main mixing vessel, and mixed. (4) Salicyclic acid, phenoxyethanol, and sodium hydroxide were added to adjust the pH to 5.0. (5) Fragrance was added to the stirring mixture and stirred continuously till uniform mixing. Table 7: Spray formulations for compositions S1, S2, S3, S4, S5 and S6 Composition (%) S. No. Ingredient S1 S2 S3 S4 S5 S6 1 Water q.s q.s q.s q.s q.s q.s Sodium hydroxide (18% 2 q.s q.s q.s q.s q.s q.s aq.) 3 PEG 1450 2 2 2 2 2 2 4 Methyl Gluceth-20 2.5 2.5 2.5 2.5 2.5 2.5 5 Glycerin 1 1.5 2 1 1 1.5 6 Besifloxacin 1 0 0 0 1 1 7 Clinafloxacin 0 0 1 0 0 08 Sitafloxacin 0 1 0 1 0 0 9 Adapalene 0.1 0 0 0.1 0 0 10 Isopropyl alcohol 20 20 20 20 20 0 diethylene glycol monethyl 11 1 1 1 1 1 1 ether 12 Propylene glycol 1.5 1.5 1.5 1.5 1.5 1.5 13 Ethyl alcohol 0 0 0 0 0 20 14 N-methyl 2-pyrrolidone 3 0 0 3 0 0 15 Salicylic acid 0 0 0 0 0 2 16 Sodium hydroxide q.s q.s q.s q.s q.s q.s 17 Phenoxyethanol 1 1 1 1 1 1 18 Fragrance 0.4 0.4 0.4 0.4 0.4 q.s.

[0111] Preparation of Face Wash Formulations Loaded with Besifloxacin hydrochloride, Clinafloxacin or Sitafloxacin Alone and the Combinations with Adapalene Facewash formulations containing besifloxacin, clinafloxacin, or sitafloxacin and the combination with adapalene or salicylic acid were formulated as per the compositions shown in Table 8. These facewash formulations had pH of 4.7-6 and viscosity of around 1500-5000 mPa.s. The formulations consisted of actives (besifloxacin hydrochloride, clinafloxacin or sitafloxacin) equivalent to 1%w / w in different formulations (Table 8, FW5, FW3 and FW2). In addition to stand alone formulation, anti-microbial agents were combined with keratolytic agent such as adapalene (0.1%) to provide keratolytic activity in patients (Table 8, FW1, FW4 and FW6). Method of preparation: (1) In a main mixing vessel, water was added. Then carbopol aqua SF-1 was added slowly at a low speed (70-80rpm) of mixing.(2) In the same vessel, sodium C14-16 olefin sulfonate (40%) and sodium lauryl ether sulphate (28.6%) were added while stirring. (3) The mixture was neutralized with sodium hydroxide, adjusting the pH to 6.5 to 7.0. The mixing speed was slightly increased to ensure uniform mixing. (4) Then cocamidopropylbetaine was added to above mixture with continuous stirring followed by slow additions of disodium EDTA and glycerin. (5) Besifloxacin hydrochloride, clinafloxacin, or sitafloxacin and adapalene were added to the above stirring main vessel. (6) Adapalene was dissolved in N-methyl 2-pyrrolidone and added to main mixing vessel, and mixed. (7) Then, salicylic acid, propylene glycol and PEG-7 glycerylcocoateare were added to continuous stirring main vessel. (8) Finally, pH was adjusted to 5.5 by the addition of citric acid. Table 8: Face wash for compositions FW1, FW2, FW3, FW4, FW5 and FW6 Composition (%) S. No. Ingredient FW1 FW2 FW3 FW4 FW5 FW6 1 Water q.s. q.s. q.s. q.s. q.s. q.s. 2 Carbopol aqua SF-1 6 6 6 6 6 6 Sodium C14-16 Olefin 3 35 35 35 35 35 35 Sulfonate 4 Sodium lauryl ether sulphate 2 2 2 2 2 2 5 Sodium hydroxide (18% aq.) q.s. q.s. q.s. q.s. q.s. q.s. Cocamidopropylbetaine 6 10 5 10 10 5 7 (30%)7 Disodium EDTA 0.1 0.1 0.1 0.1 0.1 0.1 8 Glycerin 5 5 5 5 5 3 9 Besifloxacin 1 0 0 0 1 1 10 Clinafloxacin 0 0 1 1 0 0 11 Sitafloxacin 0 1 0 0 0 0 12 Adapalene 0.1 0 0 0.1 0 0 13 N-methyl 2-pyrrolidone 3 0 0 3 0 0 14 Salicylic Acid 0 0 0 0 0 1 15 Propylene glycol 0 0 0 0 0 4 16 PEG-7 glycerylcocoate 1 1 1 1 1 1 17 Citric Acid (50%) q.s. q.s. q.s. q.s. q.s. q.s.

[0112] Preparation of Soap Bars Loaded with Besifloxacin hydrochloride, Clinafloxacin or Sitafloxacin Alone and the Combinations with Adapalene Method of preparation: Soap bars containing besifloxacin, clinafloxacin or sitafloxacin were formulated as per the compositions shown in Table 9. The soap bars consisted of Besifloxacin hydrochloride equivalent to 1%w / w (Table 9, SB5), clinafloxacin equivalent to 1%w / w (Table 9, SB3), sitafloxacin equivalent to 1%w / w (Table 9, SB2). In addition to stand alone besifloxacin formulation, besifloxacin was combined with adapalene (0.1%) (Table 9, SB1) and salicylic acid (Table 9, SB6) to provide both anti-microbial and keratolytic activity to patients suffering from acne. Similarly, another formulation contained clinafloxacin in combination with adapalene (Table 9, SB4). Method of preparation: (1) Sodium palmitate was blended with remaining ingredients in the mixer.(2) The mass was passed through the roll mill and plodder followed by billeting and stamping at a temperature between 35°C-40°C. Table 9: Soap bars for compositions SB1, SB2, SB3, SB4, and SB6 Composition (%) S. No. Ingredient SB1 SB2 SB3 SB4 SB5 SB6 1 Sodium palmitate 94.2 94.2 94.2 94.2 94.2 94.2 Sodium lauryl ether 2 2 2 2 2 2 2 sulphate 3 Polyquaternium-39 1 1 1 1 1 1 4 Methyl Gluceth-20 1 1 1 1 1 1 5 Titanium dioxide 0.5 0.5 0.5 0.5 0.5 0 6 Besifloxacin 1 0 0 0 1 1 7 Clinafloxacin 0 0 1 1 0 0 8 Sitafloxacin 0 1 0 0 0 0 9 Adapalene 0.1 0 0 0.1 0 0 10 Salicylic acid 0 0 0 0 0 0.1 11 Oleyl oleate 0.5 0.5 0.5 0.5 0.5 0.5 BHT (Butylated 12 0.01 0.01 0.01 0.01 0.01 0.01 HydroxyToluene)

[0113] Preparation of Body Wash Containing Besifloxacin Hydrochloride, Clinafloxacin or Sitafloxacin Alone and the Combinations with Adapalene Method of preparation: Body wash formulations containing besifloxacin, clinafloxacin orsitafloxacin and adapalene or salicylic acid were formulated as per the compositions shown in Table 10. The body wash formulations consisted of besifloxacin equivalent to 1%w / w (Table 10, BW5), sitafloxacin equivalent to 1%w / w (Table 10, BW2) and clinafloxacin equivalent to 1%w / w (Table 10, BW3). In addition to stand alone besifloxacin formulation, besifloxacin was combined with the adapalene (0.1%) and salicylic acid (2%) (Table 10, BW1, BW6), to provide both anti-acne and keratolytic activity in acne patients. Similarly, another formulation contained clinafloxacin in combination with adapalene (Table 10, BW4). Table 10: Body Wash for Compositions BW1, BW2, BW3, BW4, BW5 and BW6 S. No. Ingredient Composition (%) BW1 BW2 BW3 BW4 BW5 BW6 1 Water q.s. q.s. q.s. q.s. q.s. q.s. 2 Disodium EDTA 0.1 0.1 0.1 0.1 0.1 0.1 3 Carbopolaqua SF-1 1 1 1 1 1 1 Ammonium lauryl 4 30 30 30 30 30 30 sulphate (30%) 5 Propylene glycol 5 5 5 5 5 5 6 Besifloxacin 1 0 0 0 1 1 7 Clinafloxacin 0 0 1 1 0 0 8 Sitafloxacin 0 1 0 0 0 0 9 Adapalene 0.1 0 0 0.1 0 0.1 10 N-methyl 2-pyrrolidone 3 0 0 3 0 3 11 Ethanol 4 4 4 4 4 4 12 Propyl paraben 0.03 0.03 0.03 0.03 0.03 0.0313 Methyl gluceth-10 0.3 0.3 0.3 0.3 0.3 0.3 Disodium laureth 14 2 2 2 2 2 2 sulfosuccinate (39%) 15 Fragrance 0.5 0.5 0.5 0.5 0.5 0.5 16 Triethanolamine q.s. q.s. q.s. q.s. q.s. q.s. Method of preparation: (1) In main mixing vessel, disodium EDTA was dissolved in water. (2) Carbpol aqua SF-1 was added to the main vessel. (3) It was stirred for 10 min followed by the addition of ammonium lauryl sulphate. Propylene glycol, besifloxacin hydrochloride, clinafloxacin, or sitafloxacin were added to above mixture with continuous stirring. (4) Adapalene was dissolved in N-methyl 2-pyrrolidone and added to main mixing vessel, followed by its mixing. (5) While stirring remaining ingredients were added to the above mixture. (6) Finally, neutralization was done with triethanolamine and pH was adjusted to 5.5-6.0.

[0114] Preparation of Lotion Formulations Loaded with Besifloxacin Hydrochloride, Clinafloxacin or Sitafloxacin Alone and the Combinations with Adapalene Lotion formulations containing besifloxacin were formulated as per the compositions shown in Table 11. These lotions had pH of 4.7-5.5 and viscosity of around 2500-6000 mPa.s. The lotions consisted of besifloxacin equivalent to 1%w / w (Table 11, L5), sitafloxacin equivalent to 1% w / w L2) and clinafloxacin equivalent to 1%w / w (L3). In addition to stand alone formulation, besifloxacin was combined with the adapalene (0.1%) (L1) or salicylic acid (Table 11, L6) to provide keratolytic activity in patients. Similarly, another formulation contained clinafloxacin in combination with adapalene (Table 11, L4).Table 11: Lotion Formulations for Compositions L1, L2, L3, L4 and L5 Composition (%) S. No. Ingredient L1 L2 L3 L4 L5 L6 1 Water q.s q.s q.s q.s q.s q.s 2 Disodium EDTA 0.05 0.05 0.05 0.05 0.05 0.05 3 Carbopol aqua SF-1 1 1 1 1 1 1 4 Petrolatum 1 1 1 1 1 1 5 Cyclomethicone 0.5 0.5 0.5 0.5 0.5 0.5 6 Sorbitan stearate 1.4 1.4 1.4 1.4 1.4 1.4 7 Polysorbate 60 0.6 0.6 0.6 0.6 0.6 0.6 8 Methyl gluceth-20 1 1 1 1 1 1 9 Cetyl alcohol 1.6 1.6 1.6 1.6 1.6 1.6 10 Tocopheryl acetate 0.25 0.25 0.25 0.25 0.25 0.25 11 Besifloxacin 1 0 0 0 1 1 12 Clinafloxacin 0 0 1 1 0 0 13 Sitafloxacin 0 1 0 0 0 0 14 Adapalene 0.1 0 0 0.1 0 0 15 N-methyl 2-pyrrolidone 3 0 0 3 0 0 16 Salicylic acid 0 0 0 0 0 1 17 Propylene glycol 2 2 2 2 2 218 Glycerin 8 8 8 8 8 8 19 Ethanol 2 2 2 2 2 2 20 Phenoxyethanol 1 1 1 1 1 1 21 Sodium hydroxide q.s q.s q.s q.s q.s q.s Method of preparation: (1) In main mixing vessel, disodium EDTA was dissolved in water. When it was fully dissolved, mixing speed was set at 100 rpm. (2) Carbopol aqua SF-1 was slowly dispersed into water and stirring was continued until complete mixing. (3) The mixture was heated to 70°C. (3) Petrolatum, cyclomethicone, polysorbate 60, sorbitan strearate, cetyl alcohol were melted in a separate beaker and added to above mixture. The stirring speed was kept at 200 rpm. (4) The mixture was allowed to cool at 35-40°C with constant stirring at 200 rpm. (5) Tocopheryl acetate was added to the above mixture after the temperature reached 35- 40°C. (6) Besifloxacin hydrochloride, clinafloxacin or sitafloxacin were added to the above mixture by dispersing in water. (7) Adapalene was dissolved in N-methyl 2-pyrrolidone and added to main mixing vessel, followed by its mixing at 250 rpm. (8) Salicylic acid was dissolved in ethanol, propylene glycol and glycerol and added to main mixing vessel. (9) Phenoxyethanol was added to the above mixture with constant stirring at 250 rpm. (10) The whole mixture was neutralized with sodium hydroxide and mixed for 30 min.

[0115] Approaches used for the solublization of Besifloxacin HydrochlorideSurfactants are known to solubilize hydrophobic substances by reducing the interfacial tension. In addition to surfactants, co-solvents or co-surfactants also help in solubilization of poorly water- soluble compounds by increasing the wetting property or reducing the interfacial tension of the hydrophobic molecule. Besifloxacin was solubilized using surfactants such as sodium lauryl sulfate, tween 80, tween 20 and span 80, and cosolvents / cosurfactants in the delivery vehicles. The presence of the sodium lauryl sulfate greatly enhanced the aqueous solubility of the besifloxacin hydrochloride and used for preparation of topical formulation (Table 12, SC1, SC2 and SC5). The co-solvents such as propylene glycol monocaprylate and diethylene glycol monoethyl ether were used for the preparation of cream formulations (Table 12, SC3 and SC4). Table 12: Fully solubilized besifloxacin cream formulations Composition (1% w / w) S. No. Ingredients SC1 SC2 SC3 SC4 SC5 1 Besifloxacin hydrochloride 1.09 1.09 1.09 1.09 1.09 2 Sodium Lauryl sulfate 2 2 2 2 5 3 Cetyl alcohol 2 0 0 0 5 4 Tween 80 0 3 0 3 0 5 Tween 20 0 1.5 0 0 0 6 Stearyl alcohol 3 0 0 0 0 7 Propylene glycol mono caprylate 0 0 3 0 0 8 PEG-8 capriccaprylate glyceride 0 0 5 0 0 9 Propylene Glycol 0 0 0 0 1 Diethylene glycol mono- 10 0 0 0 15 0 ethyl ether11 Steareth-21 2 3 3 0 2 12 Cyclopentasiloxane 4 0 4 3 8 13 Phenoxy ethanol 0.5 0.5 0.5 0.5 0.5 Sodium Hydroxide (10% in 14 1 1 1 1 2 water) 15 Carbomer homopolymer type C 0.20 0.80 0.15 0.8 0 16 Carbopol Ultrez 10 0 0 0 0 0.3 17 Water q. s. q. s. q. s. q. s. q. s.

[0116] Preparation of Suspended Drug Loaded Gel Formulations with Minimal Solubilization-reprecipitation of the Drug Preparation of drug-loaded (suspended form) gel via a conventional method usually leads to exposure of the drug to a wide range of pH conditions, which may lead to, in some instances, solubilization of the drug, and then reprecipitation. This solubilization-reprecipitation phenomenon in most cases leads to change in original particle size, impurity profile or crystal pattern, or others. As an example, besifloxacin.HCl (which shows pH dependent solubility) displayed this solubilization-reprecipitation phenomenon, where pH of about 4.5 or below solubilized the drug to a significant and variable extent. The solubilized besifloxacin then, upon increase in pH (during formulation preparation), reprecipitated, which may result in one or more unwanted changes. In order to circumvent this issue, a modified approach was employed to prepare different suspended drug-loaded formulations. Table 13 and the Method of Preparation below details the gel composition and preparation with negligible or minimal drug solubilization-reprecipitation. These gel formulations had off-white appearance with pH of 5.0-6.0 and approx. viscosity of about 3000 to about 5500 mPa.s measured by Viscometer (RheolabQC, C-LTD 80 / QC, Anton Paar). Table 13: Besifloxacin.HCl Suspended Gel Formulations for Compositions GL5, GL6, GL7Composition (%w / w) Chemical Name GL5 GL6 GL7 Besifloxacin.HCl Equivalent to 1 1.5 2 Besifloxacin Allantoin 0.2 0.2 0.2 Carbomer homopolymer type C 0.85 0.85 0.85 Diethylene glycol monoethyl 5 5 0 ether Edetate disodium dehydrate 0.1 0.1 0.1 Glycerin 5 5 5 Phenoxyethanol 0.7 0.7 0.7 Polyethylene glycol 400 5 5 5 Sodium hyaluronate 0.4 0.4 0.4 q.s. to q.s. to q.s. to adjust Sodium hydroxide solution* adjust pH adjust pH pH Purified water q.s. q.s. q.s. Phase A: Purified water, Edetate disodium dehydrate, Allantoin, Carbomer homopolymer type C Phase B: Purified water, Sodium hyaluronate Phase C: Phenoxyethanol, Sodium hydroxide solution Phase D: Glycerin, Besifloxacin.HCl (Equivalent to Besifloxacin), Purified water, Sodium hydroxide solution Phase E: Polyethylene glycol 400, Diethylene glycol monoethyl ether, Phase F: Sodium hydroxidesolution Method of Preparation: In a main mixing vessel, edetate disodium and allantoin were dissolved in water. Then carbomer homopolymer type C and hyaluronate sodium were added and allowed to swell at 200 rpm for 60 min. Then phenoxyethanol was added to the carbomer mixture. Then, pH of the mixture was raised to 6.0 with sodium hydroxide solution. In a separate vessel, glycerin and besifloxacin.HCl were dispersed with continuous mixing at 300 rpm for 10 min. Dilute solution of sodium hydroxide was added drop-wise to the separate vessel to adjust pH to 5.5. The contents of the above mixture were added to the main mixing vessel with stirring at 200 rpm for 2 hours. Finally, polyethylene glycol and diethylene glycol monoethyl ether were added to the main mixing vessel and mixed for further 20 min. White-to-pale yellow gel was obtained.

[0117] Preparation of Suspended Drug Loaded Cream Formulation by Avoiding Re- precipitation of Drug Cream formulations containing suspended besifloxacin were prepared, with minimal solubilization- reprecipitation, as per the compositions shown in Table 14. These cream formulations had off-white appearance with pH of 5.0-6.0 and approx. viscosity of about 3000 to about 4000 mPa.s (measured by Viscometer (RheolabQC, C-LTD 80 / QC), Anton Paar). The formulations were then tested against susceptible and resistant strains of acne. Table 14: Besifloxacin.HCl Suspended Cream Formulations for Compositions CM2, CM3 and CM4 Composition (% w / w) Ingredients CM 2 CM 3 CM 4Besifloxacin.HCl equivalent 1 1.5 2 to besifloxacin Butylated Hydroxytoluene 0.1 0.1 0.1 Carbopol 980 (2%) 30 35 40 Cetyl alcohol 1 1 1 Cyclopentasiloxane 5 5 5 Glycerin 5 5 5 Light liquid paraffin 3 3 3 Phenoxyethanol 0.5 0.5 0.5 Sodium hydroxide solution 2 2 2 Span 80 1 0 1 Steareth 2 2 2 1 Steareth 21 2 2 1 Stearyl alcohol 1 1 1 Purified water q.s. to 100 q.s. to 100 q.s. to 100 Phase A: Cyclomethicone, Span 80, Cetyl alcohol, Stearyl alcohol, Light liquid paraffin, Steareth 2, Steareth 21 Phase B: Glycerin, Besifloxacin.HCl equivalent to besifloxacin, Purified water, Sodium hydroxide solution Phase C: Butylated Hydroxytoluene, Phenoxyethanol, Carbopol 980 (2%) Method of Preparation: In main mixing vessel, besifloxacin was dispersed in glycerol and water with continuous mixingat 300 rpm for 10 minutes. Dilute solution of sodium hydroxide was added drop-wise to the main mixing vessel to adjust pH to about 5.5 and heated to 70°C. In a separate vessel, cyclomethicone, span 80, cetyl alcohol, stearyl alcohol, light liquid paraffin, steareth 2 and steareth 21 were heated together to 70°C. Heated mixture of oil phase was added with continuous mixing to the main mixing vessel at 70°C, 200 rpm and allowed to mix for 15 min. The content of the main mixing vessel was allowed to air-cool with mixing to 45°C. Carbopol was allowed to swell in water for 2 h and its pH was adjusted to about 5.5 to 6 with sodium hydroxide solution, which was then added to the main mixing vessel and mixed. Remaining components butylated hydroxytoluene and phenoxyethanol were added to the main mixing vessel and mixed for 20 min. The cream’s pH was adjusted to about 5.5 to 6.0 with sodium hydroxide, if required.

[0118] Preparation of Formulations Containing Combination of Actives (soluble anti- microbial and suspended keratolytic agent) Gel formulations containing a combination of soluble besifloxacin.HCl and suspended adapalene were prepared as per the compositions shown in Table 15. These gel formulations had pale yellowappearance with pH of around 4.5 and viscosity in the range of 3000 to 5000 mPa.s (measured b yV i s c o m e t e r ( R h e o l ab Q C , C L T D 80 / Q C ) , A n t o n P a a r ). The formulations containingsoluble besifloxacin equivalent to 1-2% w / w and partially or fully suspended adapalene equivalent to 0.1% w / w were prepared to provide anti-acne, keratolytic and anti-inflammatory effects in patients. Table 15: Besifloxacin.HCl (soluble) and Adapalene (suspended) Containing Gel Formulations for Compositions SL1, SL2 and SL3 Composition (% w / w) Ingredients SL1 SL2 SL3Besifloxacin.HCl Equivalent 1 1.5 2 to Besifloxacin Adapalene 0.1 0.1 0.1 Allantoin 0.2 0.2 0.2 Diethylene glycol monoethyl 11 20 23.5 ether Edetate disodium dihydrate 0.1 0.1 0.1 Glycerin 5 5 5 Hyaluronate Sodium 0.3 0 0.3 Hydroxy ethylcellulose 0.9 1.2 0.9 Phenoxyethanol 0.7 0.7 0.7 Poloxamer 0.2 0.2 0.2 Polyethylene glycol 400 6 7 7 q.s. to q.s. to q.s. to Purified water 100 100 100 Phase A: Purifiedwater, Allantoin, Edetate disodium dihydrate, Hydroxy ethylcellulose Phase B: Purified water, Hyaluronate Sodium Phase C: Purified water, Glycerin, Besifloxacin.HCl Equivalent to Besifloxacin, Adapalene, Poloxamer Polyethylene glycol 400, Diethylene glycol monoethyl ether, Phenoxyethanol. Method of Preparation: In a main mixing vessel, edetate disodium dihydrate and allantoin were dissolved in water at 400 rpm for about 10 minutes.Hydroxyethyl cellulose (HEC) was added in portions to the main mixing vessel at very high speed (about 400-500 rpm). HEC was allowed to swell for 1 h with stirring at about 100-150 rpm. In a separate vessel, hyaluronate sodium was added and allowed to swell for 15-30 minutes, followed by addition to the main mixing vessel. In a separate vessel, glycerin and besifloxacin.HCl were dispersed in water and mixed with glass rod. Then, diethylene glycol monoethyl ether and polyethylene glycol 400 were added to besifloxacin dispersion and mixed. This dispersion was added to main mixing vessel, and allowed to stir at about 100-150 rpm for about 5 minutes. Phenoxyethanol was then added to the main mixing vessel, and mixed at 100-150 rpm until any polymer lumps disappeared completely and clear gel was obtained. Adapalene was dispersed in aqueous solution of poloxamer and added to the main mixing vessel, resulting in white-to-pale yellow opaque gel containing soluble besifloxacin and suspended adapalene.

[0119] Preparation of Suspended Drug Loaded Cream Formulation without use of polymer as a viscosity modifier According to published literature there may be physical and / or chemical interaction between Carbomer and fluoroquinolones. Therefore, there may be a need to prepare formulations without Carbomer or Carbomer-like-polymers to avoid any incompatibility issues during the product shelf life. Towards this, an alternative cream formulation, without use of the Carbomer or any other polymer, was prepared. Cream formulation compositions and procedure are given in Table 16. Table 16. Besifloxacin.HCl Suspended Cream Formulations for Compositions CM5 Ingredients Composition (% w / w) Besifloxacin 1 Butylatedhydroxy 0.1 tolueneCetyl alcohol 2 Cyclopentasiloxane 5 Glycerin 5 Mineral Oil 3 Phenoxyethanol 0.7 Polyoxyl 2 Stearyl 2 Ether Polyoxyl 21 Stearyl 2 Ether Stearyl alcohol 2 Sodium hydroxide q.s. to pH > 5.5 Purified Water q.s. to 100.0 Phase A: Cetyl alcohol, Stearyl alcohol, Mineral Oil, Cyclopentasiloxane, Polyoxyl 2 Stearyl Ether, Polyoxyl 21 Stearyl Ether Phase B: Glycerin, Besifloxacin, Phase C: Sodium hydroxide, Purified Water Phase D: Butylatedhydroxy toluene, Phenoxyethanol Phase E: Sodium hydroxide Method of Preparation Phase B: Glycerol and API were mixed together in main mixing vessel, Phase C: Sodium Hydroxide and water were mixed together and added slowly into phase B in the main mixing vessel and the contents heated to 60-65°C, Phase A excipients were mixed together and heated at 60-65°C, followed by adding to the main mixing vessel with continuous overhead stirring at about 600 rpm,The contents of the main mixing vessel were then allowed to cool to about 40°C. To this mixture contents of Phase D were added and mixed for 15 min, Finally, pH of the formulation was adjusted to 5.5 - 6.0 using phase E.

[0120] Use of Different Polymers for Viscosity Regulation of Formulations Containing Solubilized Besifloxacin.HCl The purpose of gel formulations to be prepared was to have acceptable viscosities, while the active drug remains in soluble form. This becomes challenging, when the pH required for drug solubilizing or stabilizing a solubilized drug is outside the normal range of about 5.0 to about 7.0 for topical products. For example, besifloxacin.HCl goes in solution, of course with proper choice of excipients, when the pH is adjusted to below 5.0, for example in the range 4.0-4.5. Not many polymers (without affecting gel sensorial parameters) were found to be able to furnish acceptable viscosities to the gel formulations, in this pH range.

[0121] Different polymers (and their different grades) like carbomer, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium hyaluronate, and other polymers were used to prepare gels with acceptable viscosities, wherein the active drug was desired to be in a solubilized state.

[0122] Gel formulation containing soluble besifloxacin.HCl was attempted to prepare using Carbomer as per the composition and procedure given in Table 17. Although the drug could be solubilized at pH 4.5, the Carbomer used in required amount was not able to impart acceptable viscosity to the formulation. The resulting formulation had viscosity about 1000- 1800 mPa.s (measured by Viscometer (RheolabQC, C-LTD 80 / QC), Anton Paar). Table 17. Besifloxacin HCl Solubilized Gel Formulation Prepared Using Carbomer for Compositions SL4 Phase Ingredients Composition (% w / w) Glycerin 5.0 A Besifloxacin.HCl equivalent to 1 BesifloxacinPurified Water q.s. to 100.0 Carbomer Homopolymer Type C 0.9 Allantoin 0.2 B Edetate Disodium Dihydrate 0.1 (EDTA) Phenoxyethanol 0.7 Sodium Hyaluronate 0.4 Polyethylene glycol 400 6 C Diethylene glycol monoethyl ether 11 Method of preparation: 1) Phase A: Glycerol and besifloxacin were mixed together in a separate vessel, 2) Phase B: In a main mixing vessel, allantoin and EDTA were solubilized in water with stirring at 200 rpm, then carbomer was sprinkled over it slowly and allowed to swell for 45 min, 3) Sodium hyaluronate was sprinkled into the above mixture and allowed to swell for 15 min, followed by addition of Phenoxyethanol and mixing, 4) Phase A was transferred into the main mixing vessel with continuous stirring at 200 rpm, and mixed for 30 min, 5) Polyethylene glycol 400 and diethylene glycol monoethyl ether were added to the main mixing vessel and mixed for 15 min at 150 rpm 6) Hydroxypropyl Cellulose and Hydroxypropyl Methyl Cellulose are widely used in oral and topical pharmaceutical formulations and available in number of different grades that can furnish wide viscosity ranges. Formulations containing solubilized besifloxacin were prepared using hydroxypropyl cellulose or hydroxypropyl methyl cellulose as viscosity modifiers (Table 18). Although acceptable viscosities of about 3000 mPa.s (measured by Viscometer (RheolabQC, C-LTD 80 / QC), Anton Paar) were observed using both the polymers, the sensorials were not acceptable.Table 18. Besifloxacin.HCl Solubilized Gel Formulations Prepared Using Hydroxypropyl Cellulose and Hydroxypropyl Methyl Cellulose for Compositions SL5 and SL6 Phase Ingredients Compositions (% w / w) SL5 SL6 Glyceroin 5.0 5.0 A Besifloxacin.HCl 1.09 1.09 Purified Water q.s. to 100.0 q.s. to 100.0 Hydroxypropyl Cellulose 1.5 0 Hydroxypropyl Methyl 0 1 Cellulose B Allantoin 0.2 0.2 Edetate Disodium Dihydrate 0.1 0.1 (EDTA) Phenoxyethanol 0.7 0.7 Sodium Hyaluronate 0.4 0.4 Polyethylene Glycol 400 6 6 C Diethylene glycol monoethyl 11 11 ether Method of Preparation: 1) Phase A: Glycerin and besifloxacin hydrochloride were mixed together in a separate vessel, 2) Phase B: In a main mixing vessel, allantoin and Edetate Disodium Dihydrate were solubilizedin water with stirring at 200 rpm, then hydroxypropyl cellulose or hydroxypropyl methyl cellulose was sprinkled over it slowly and allowed to swell for 45 minutes, 3) Sodium hyaluronate was sprinkled into the above mixture and allowed to swell for 15 minutes, followed by addition of phenoxyethanol, 4) Phase A was slowly added into the main mixing vessel with continuous stirring at 200 rpm, and mixed for 30 min, 5) Polyethylene glycol 400 and Diethylene glycol monoethyl ether were added to the main mixing vessel and mixed for 15 min at 150 rpm 6) Hydroxyethyl cellulose is another widely used excipient in oral and topical pharmaceutical formulations and available in a number of different viscosity grades. Formulation containing solubilized besifloxacin.HCl was prepared using hydroxyethyl cellulose as viscosity modifier (Table 19). Using this polymer, the prepared gel could display good sensorials, at pH of about 4.5, along with other parameters like acceptable viscosity and soluble drug. Table 19. Besifloxacin.HCl Solubilized Gel Formulations Prepared Using Hydroxyethyl Cellulose for Compositions SL7, SL8 and SL9 Composition (% w / w) Ingredients SL7 SL8 SL9 Besifloxacin.HCl 1.09 1.09 1.09 Allantoin 0.2 0.2 0.2 Diethylene glycol monoethyl ether 11 13 11 Edetate Disodium Dihydrate 0.1 0.1 0.1 (EDTA) Glycerin 5 5 5 Hydroxy ethyl cellulose 0.9 1 1.1 Phenoxyethanol 0.7 0.7 0.7Polyethylene Glycol400 6 7 6 Sodium hyaluronate 0.3 0.3 0.3 Purified Water q. s. to 100 q. s. to 100 q. s. to 100 Phase A: Purified water, Allantoin, Edetate Disodium Dihydrate (EDTA), Hydroxy ethyl cellulose Phase B: Purified water, Sodium hyaluronate Phase C: Purified Water, Glycerin, Besifloxacin.HCl, Polyethylene Glycol 400, Diethylene glycol monoethyl ether, Phenoxyethanol Method of Preparation 1) In a main mixing vessel, EDTA and allantoin were dissolved in water at 400 rpm for 10 min. 2) Then, hydroxy ethyl cellulose was sprinkled to the main mixing vessel at very high speed (around 400-500 rpm) and allowed to swell for 1 h at 100-150 rpm. 3) In a separate vessel, sodium hyaluronate was taken and allowed to swell with water for 15- 30 minutes. Then, added to the main mixing vessel. 4) In another vessel, glycerin and besifloxacin HCl were dispersed in water and mixed with glass rod. To this dispersion, diethylene glycol monoethyl ether and polyethylene glycol 400 were added and mixed. 5) Above dispersion was added to the main mixing vessel, and allowed to stir at 100- 150 rpm for 5 min. 6) Finally, phenoxyethanol was added to the main mixing vessel, and mixed at 100-150 rpm until polymer lumps disappeared, if any and clear gel was obtained.

[0123] Preparation of Gel Formulations Loaded with Different Concentrations of Suspended Besifloxacin.HCl to Observe the Effect on Viscosities of Formulations Containing Hydroxyethyl Cellulose Gel formulations containing different concentrations of besifloxacin hydrochloride were formulatedusing hydroxyethyl cellulose as thickening agent as per the compositions shown in Table 20. Table 20: Gel Formulations with Different Concentrations of Suspended Besifloxacin.HCl Using Hydroxyethyl Cellulose for Compositions GL09, GL10, GL11, GL12 and GL13 Composition (% w / w) Chemical Name GL09 GL10 GL11 GL12 GL13 Besifloxacin.HCl (Equivalent 0 1 2 4 8 to Besifloxacin) Allantoin 0.2 0 0 0.2 0.2 Diethylene glycol monoethyl 5 5 5 5 5 ether Edetate disodium 0.1 0.1 0.1 0.1 0.1 dehydrate (EDTA) Glycerin 5 5 5 5 5 Hydroxy ethyl cellulose 0.9 0.9 0.9 0.9 0.9 Phenoxyethanol 0.7 0.7 0.7 0.7 0.7 Polyethylene glycol 400 5 5 5 5 5 Sodium hyaluronate 0.4 0.4 0.4 0.4 0.4 q. s. q. s. q. s. q. s. q. s. Sodium hydroxide solution to pH to pH to pH to pH to pH 5.5 5.5 5.5 5.5 5.5 Purified water q.s. q.s. q.s. q.s. q.s. Phase A: Purified water, Edetate disodium dihydrate (EDTA), Allantoin, Hydroxy ethyl cellulosePhase B: Purified water, Sodium hyaluronate Phase C: Phenoxyethanol, Sodium hydroxide solution Phase D: Glycerin, Besifloxacin.HCl (Equivalent to Besifloxacin), Purified water, Sodium hydroxide solution Phase E: Polyethylene glycol 400, Diethylene glycol monoethyl ether Phase F: Sodium hydroxide solution Method of Preparation: In a main mixing vessel, edetate disodium and allantoin were dissolved in water. Then hydroxyethyl cellulose was added in portion to the main mixing vessel while stirring at 100 rpm using over-head stirrer. Gelling agent was allowed to swell at 100 rpm for 30 min to get proper hydration. Hydrated hyaluronate sodium was added to main mixing vessel and mixed. Then phenoxyethanol was added to the mixture. Then, pH of the mixture was raised to 6.0 with sodium hydroxide solution. In a separate vessel, glycerin and besifloxacin.HCl were dispersed with continuous mixing at 300 rpm for 10 min. Dilute solution of sodium hydroxide was added drop-wise to the separate vessel to adjust pH to 5.5. The contents of the above mixture were added to the main mixing vessel with stirring at 200 rpm for 2 hours. Finally, polyethylene glycol and diethylene glycol monoethyl ether were added to the main mixing vessel and mixed for further 20 min. White-to-pale yellow gel was obtained.

[0124] Preparation of Gel Formulations Loaded with Different Concentrations of Suspended Besifloxacin.HCl to Observe the Effect on Viscosities of Formulations Containing Carbomer Gel formulations containing different concentrations of besifloxacin hydrochloride were formulated as per the compositions shown in Table 21. These formulations were formulated with carbomer to observe the effect of concentration of besifloxacin.HCl on viscosities.Table 21: Gel Formulations with Different Concentrations of Suspended Besifloxacin.HCl Using Carbomer for Compositions GL14, GL15, GL16 and GL17 Composition (%w / w) Chemical Name GL14 GL15 GL16 GL17 Besifloxacin.HCl (Equivalent 0 1 1.5 10 to Besifloxacin) Allantoin 0.2 0 0.2 0.2 Carbomer homopolymer type C 0.85 0.85 0.85 0.85 Diethylene glycol monoethyl 5 5 5 5 ether Edetate disodium 0.1 0.1 0.1 0.1 dehydrate (EDTA) Glycerin 5 5 5 5 Phenoxyethanol 0.7 0.7 0.7 0.7 Polyethylene glycol 400 5 5 5 5 Sodium hyaluronate 0.4 0.4 0.4 0.4 q.s. to q.s. to q.s. to q.s. to Sodium hydroxide solution pH pH 5.5 pH 5.5 pH 5.5 5.5 Purified water q.s. q.s. q.s. q.s. Phase A: Purified water, Edetate disodium dehydrate (EDTA), Allantoin, Carbomer homopolymer type C Phase B: Purified water, Sodium hyaluronatePhase C: Phenoxyethanol, Sodium hydroxide solution Phase D: Glycerin, Besifloxacin.HCl Equivalent to Besifloxacin, Purified water, Sodium hydroxide solution Phase E: Polyethylene glycol 400, Diethylene glycol monoethyl ether Phase F: Sodium hydroxide solution Method of Preparation: In a main mixing vessel, edetate disodium and allantoin were dissolved in water. Then carbomer homopolymer type C and hyaluronate sodium were added and allowed to swell at 200 rpm for 60 minutes. Then phenoxyethanol was added to the carbomer mixture. Then, pH of the mixture was raised to 6.0 with sodium hydroxide solution. In a separate vessel, glycerin and besifloxacin.HCl were dispersed with continuous mixing at 300 rpm for 10 min. Dilute solution of sodium hydroxide was added drop-wise to the separate vessel to adjust pH to 5.5. The contents of the above mixture were added to the main mixing vessel with stirring at 200 rpm for 2 h. Finally, polyethylene glycol and diethylene glycol monoethyl ether were added to the main mixing vessel and mixed for further 20 min. White-to-pale yellow gel was obtained.

[0125] Preparation of Gel Formulations Containing Suspended Nadifloxacin, Prulifloxacin, Ulifloxacin, Besifloxacin.HCl and Combinations with Adapalene; Prepared using Hydroxyethyl Cellulose as Thickening Agent Gel formulations containing suspended nadifloxacin, prulifoxacin, ulifloxacin and besifloxacin were formulated alone and in combination with adapalene as per the compositions shown in Table 22. These formulations had pH of 5.5-6 and viscosity of around 4000 – 6000 mPa.s.

[0126] Table 22. Gel Formulations Loaded with Nadifloxacin, Prulifloxacin, Ulifloxacin and Combination with Adapalene (Compositions GA1, GA2, GA3, GA4 and GA5)Composition (% w / w) Chemical Name GA1 GA2 GA3 GA4 GA5 Adapalene 0 0 0 0.1 0.1 Besifloxacin.HCl equivalent 0 0 0 0 1 to besifloxacin Nadifloxacin 1 0 0 0 0 Prulifloxacin 0 1 0 1 0 Ulifloxacin 0 0 1 0 0 Allantoin 0 0.2 0.2 0.2 0.2 Citric acid solution 0.15 0.15 0.15 0.15 0.15 Diethylene glycol monoethyl 5 5 5 5 5 ether Edetate disodium dehydrate 0.1 0.1 0.1 0.1 0.1 Glycerin 5 5 5 5 5 Hyaluronate Sodium 0.2 0.2 0.2 0.2 0.2 Hydroxy ethyl cellulose 1.2 1.2 1.2 1.2 1.2 Phenoxyethanol 0.7 0.7 0.7 0.7 0.7 Poloxamer 407 0 0 0 0.2 0.2 Polyethylene glycol 400 5 5 5 5 5 Sodium hydroxide solution q.s. q.s. q.s. q.s. q.s. Purified water q.s. q.s. q.s. q.s. q.s.Phase A: Purified water, Edetate disodium dihydrate, Allantoin, Hydroxy ethyl cellulose Phase B: Purified water, Hyaluronate Sodium Phase C: Glycerin, Besifloxacin.HCl equivalent to besifloxacin, Nadifloxacin, Prulifloxacin, Ulifloxacin, Purified water, Sodium hydroxide solution Phase D: Purified water, Poloxamer 407, Adapalene Phase E: Polyethylene glycol 400, Diethylene glycol monoethyl ether Phase F: Phenoxyethanol Phase G: Citric acid solution, Sodium hydroxide solution Method of Preparation: Stepwise procedure to prepare gel is mentioned below- In a main mixing vessel, edetate disodium and allantoin were dissolved in water. Then hydroxyethyl cellulose and hylauronate sodium were added and allowed to swell at 100 rpm for 60 min. Then phenoxyethanol was added to the above mixture. pH of the mixture was raised to 6.0 with sodium hydroxide solution. In a separate vessel, glycerin and besifloxacin.HCl were dispersed with continuous mixing at 300 rpm for 10 minutes. Dilute solution of sodium hydroxide was added drop-wise to the separate vessel to adjust pH to 5.5. The contents of the above mixture were added to the main mixing vessel with stirring at 200 rpm for 2 h. In a separate vessel, adapalene was dispersed in aqueous solution of poloxamer 407. This adapalene dispersion was transferred to the main mixing vessel. Finally, polyethylene glycol and diethylene glycol monoethyl ether were added to the main mixing vessel and mixed for further 20 min. White-to-pale yellow gel was obtained.

[0127] Preparation of Gel Formulations Containing Combination of Suspended Besifloxacin.HCl and Adapalene; Prepared using Carbomer as Rheology Modifier Gel formulation containing suspended besifloxacin in combination with adapalene was prepared asper the compositions shown in Table 23. The formulation had pH of 5.5-6 andviscosity of around4063 mPa.s at shear rate of 25 s-1.Table 23. Gel Formulations Loaded with Suspended Besifloxacin.HCl in Combination with Adapalene for Compositions GL19 Composition (% Chemical Name w / w) GL19 Besifloxacin.HCl equivalent 1 to besifloxacin Adapalene 0.1 Allantoin 0.2 Carbomer homopolymer type 0.85 C Diethylene glycol monoethyl 5 ether Edetate disodium dehydrate 0.1 Glycerin 5 Hyaluronate sodium 0.4 Phenoxyethanol 0.7 Poloxamer 407 0.2 Polyethylene glycol 400 5 Sodium hydroxide solution q.s. Purified water q.s. to 100 Phase A: Purified water, Edetate disodium dihydrate, Allantoin, Carbomer homopolymer type CPhase B: Purified water, Hyaluronate sodium Phase C: Sodium hydroxide solution Phase D: Glycerin, Besifloxacin.HCl equivalent to besifloxacin, Purified water, Sodium hydroxide solution Phase E: Purified water, Poloxamer 407, Adapalene Phase F: Polyethylene glycol 400, Diethylene glycol monoethyl ether Phase G: Phenoxyethanol Phase H: Sodium hydroxide solution Method of Preparation: In a main mixing vessel, edetate disodium and allantoin were dissolved in water. Then carbomer and hylauronate sodium were added and allowed to swell at 100 rpm for 120 min. Phenoxyethanol was added to the above mixture. Then, pH of the mixture was raised to 6.0 with sodium hydroxide solution. In a separate vessel, glycerin and besifloxacin.HCl were dispersed with continuous mixing at 300 rpm for 10 min. Dilute solution of sodium hydroxide was added drop-wise to the separate vessel to adjust pH to 5.5. The contents of the above mixture were added to the main mixing vessel with stirring at 200 rpm for 2 h. In a separate vessel, adapalene was dispersed in aqueous solution of poloxamer 407. This adapalene dispersion was transferred to the main mixing vessel. Finally, polyethylene glycol and diethylene glycol monoethyl ether were added to the main mixing vessel and mixed for further 20 minutes. White-to-pale yellow gel was obtained.

[0128] Gel formulations containing besifloxacin hydrochlorideGel formulations containing besifloxacin hydrochloride were prepared using carbomer as gelling agent as per the compositions shown in Table 24. The gel formulations with acceptable viscosities (3500-15000 m.Pa.s) and pH range (5.5 to 6.0) were obtained. Table 24 Composition (% w / w) Chemical Name GL20 GL21 Besifloxacin.HCl (Equivalent to 1 2 Besifloxacin) Diethylene glycol monoethyl ether 5 0 Edetate disodium dehydrate 0.1 0.05 (EDTA) Allantoin 0.2 0.5 Glycerin 5 5 Carbopol 980 0 1.2 Carbopol 940 1.0 0 Propylene Glycol 0 8 Poloxamer 407 0 0.2 Phenoxyethanol 0.7 0 Polyethylene glycol 400 5 5 Methyl paraben 0 0.3 Propyl paraben 0 0.03 Triethanolamine q.s. q.s. Purified water q.s. q.s. Method of Preparation:1) In a main mixing vessel, edetate disodium, allantoin and poloxamer were dissolved in water, followed by addition of carbomer while stirring at 200 rpm using over-head stirrer. Gelling agent was allowed to swell at 200 rpm for 2h. 2) Phenoxyethanol or parabens was / were added to the above mixture. Then, pH of the mixture was raised to 5.5 - 6.0 using triethanolamine solution. 3) In a separate vessel, glycerin and besifloxacin.HCl were dispersed with continuous mixing at 500 rpm for 20 minutes. Dilute solution of triethanolamine was added drop- wise to adjust pH to 5.5 to 6.0. 4) The contents of the above mixture were added to the main mixing vessel with stirring at 200 rpm for 2 hours. 5) Finally, polyethylene glycol, propylene glycol and diethylene glycol monoethyl ether 6) were added to the main mixing vessel at a stirring rate of 200rpm for further 20min. 7) If needed, pH for this mixture was further adjusted to 5.5 to 6.0 using triethanolamine and the mixture is stirred for 2h to obtain white-to-pale yellow gel.

[0129] Gel formulations containing besifloxacin hydrochloride having hydroxyethyl cellulose and sodium hyaluronate as gelling agents Gel formulations containing besifloxacin hydrochloride were prepared using hydroxyethyl cellulose and sodium hyaluronate as gelling agents as per the compositions shown in Table 25. The gel formulations with acceptable viscosities (3500-15000 m.Pa.s) and pH range (5.5 to 7.0) were obtained. Table 25 Composition (% w / w) Chemical Name GL22 GL23 GL24 GL25 GL26 Besifloxacin.HCl (Equivalent to 142 1 2Besifloxacin) Diethylene glycol monoethyl ether 5 55 5 5Edetate disodium dehydrate (EDTA) 0.1 0.10.1 0.1 0.1Glycerin 5 55 5 5Hydroxyethyl cellulose 0.9 1.21.5 1.75 1.5Phenoxyethanol 0.7 0.70.7 0.7 0.7Polyethylene glycol 400 5 55 5 5Sodium hyaluronate 0.4 0.20.2 0 0Sodium hydroxide solution q.s. q.s.q.s. q.s. q.s.Purified water q.s. q.s.q.s. q.s. q.s.Method of Preparation: 1) In a main mixing vessel, edetate disodium was dissolved in water, followed by addition of hydroxyethyl cellulose (HEC) while stirring at 200 rpm using over-head stirrer. HEC was allowed to swell at 200 rpm for 2h. 2) In a separate vessel, sodium hyaluronate was allowed to swell in water under stirring for 1 hr. After the completion of swelling of both the thickening agents, swelled sodium hyaluronate was added to the main mixing vessel. 3) Phenoxyethanol and diethylene glycol monoethyl ether were added to the above mixture. Then, pH of the mixture was raised to 5.5 - 6.0 using sodium hydroxide solution. 4) In a separate vessel, glycerin and besifloxacin.HCl were dispersed with continuous mixing at 500 rpm for 20 minutes. Dilute solution of sodium hydroxide was added drop- wise to adjust pH to 5.5 to 6.0. 5) The contents of the above mixture were added to the main mixing vessel with stirring at 200 rpm for 2 hours. 6) Finally, polyethylene glycol was added to the main mixing vessel at a stirring rate of 200rpm for further 20min.7) If needed, pH of this mixture was further adjusted to 5.5 to 7.0 using sodium hydroxidesolution and the mixture was stirred for 2h to obtain white-to-pale yellow gel.

[0130] Gel formulations containing besifloxacin hydrochloride with different combinations of carbomer, hydroxyethyl cellulose and sodium hyaluronate as gelling agents Gel formulations containing besifloxacin hydrochloride were prepared using different combinations of carbomer, hydroxyethyl cellulose and sodium hyaluronate as gelling agents as per the compositions shown in Table 26. The gel formulations with acceptable viscosities (3500-15000 m.Pa.s)and pH range (5.5 to 7.0) were obtained. Table 26 Composition (% w / w) Chemical Name GL27 GL28 GL29 GL30 GL31 Besifloxacin.HCl (Equivalent to 1 1 2 4 1 Besifloxacin) Diethylene glycol monoethyl ether 5 5 5 5 5 Edetate disodium dehydrate 0.1 0.1 0.1 0.1 0.1 (EDTA) Glycerin 5 5 5 5 5 Hydroxyethyl cellulose 1.5 1.5 0.5 1.0 0.8 Carbomer 0.7 0.3 1.2 0.4 0.8Phenoxyethanol 0.7 0.7 0.7 0.7 0.7 Polyethylene glycol 400 5 5 5 5 5 Sodium hyaluronate 1.0 0.2 0 0.2 0.4 Sodium hydroxide solution q.s. q.s. q.s. q.s. q.s. Purified water q.s. q.s. q.s. q.s. q.s. Method of Preparation: 1) In a main mixing vessel, edetate disodium was dissolved in water, followed by addition of carbomer and / or hydroxyethyl cellulose (HEC) while stirring at 200 rpm using over- head stirrer. Carbomer and HEC were allowed to swell at 200 rpm for 2h. 2) In avessel, sodium hyaluronate was allowed to swell in water under stirring for 1 hr. After the completion of swelling of both the thickening agents, swelled sodium hyaluronate was added to the main mixing vessel. 3) Phenoxyethanol and diethylene glycol monoethyl ether were added to the above mixture. Then, pH of the mixture was raised to 5.5 - 6.0 using sodium hydroxide solution. 4) In a separate vessel, glycerin and besifloxacin.HCl were dispersed with continuous mixing at 500 rpm for 20 minutes. Dilute solution of sodium hydroxide was added drop- wise to adjust pH to 5.5 to 6.0. 5) The contents of the above mixture were added to the main mixing vessel with stirring at 200 rpm for 2 hours. 6) Finally, polyethylene glycol was added to the main mixing vessel at a stirring rate of 200rpm for further 20 min. 7) If needed, pH of this mixture was further adjusted to 5.5 to 7.0 using sodium hydroxide solution and the mixture was stirred for 2h to obtain white-to-pale yellow gel.

[0131] VT1953 comprises a dual DNA gyrase-Topoisomerase and MD2-TLR inhibitor. Thesafety and efficacy of VT-19532% topical gel is tested in an open-label, investigator-initiated phase 2 clinical trial (CTRI / 2024 / 05 / 066875).

[0132] Male or female patients aged ≥9 with a diagnosis of malodorous malignant fungating wounds (MFW) resulting from different cancer types (Table 27) corresponding to 0,1 and 2 on the 6-point TELER odor scale, ECOG performance status of ≤3 and anticipated survival of ≥3 months were eligible.

[0133] Table 27 discloses patients with different types of cancers who developed MFW. All these patients were treated with VB-1953, and uniformly reported improvements in quality of life, reduction in malodor and pain associated with MFW. Diagnosis of cancer Stage of cancer Wound dimension Buccal Mucosa Stage 3 9.62 sq.cm Buccal Mucosa Stage 3 15 sq.cm Tongue Stage 4 15.90 sq.cm Buccal mucosa Stage 4 28.26 sq.cm Retromolar trigone mass Stage 3 23.75 sq.cm Buccal mucosa Stage 4 2 sq.cm Breast Stage 3 2.83 Sq.cm Breast Stage 3 23.74 sq.cm Buccal Mucosa Stage 2 21 sq.cm Vulva Stage 4 8.32q cm

[0134] The Table 27 presents clinical data from patients diagnosed with various types and stages of cancer who developed malignant fungating wounds (MFWs) and were subsequently treated with VB-1953. The types of cancer include buccal mucosa, tongue, retromolar trigone mass, breast, and vulva, with cancer stages ranging from Stage 2 to Stage 4. Wound dimensions among these patients varied widely, from as small as 2.00 sq. cm to as large as 28.26 sq. cm, indicating a broad spectrum of lesion sizes. Despite this variability in both cancer type and wound size, all patients uniformly reported improvements following treatment with VB-1953. These improvements were specifically noted in reduction in malodor, reduction in pain, and improvement in quality of life (QOL). The consistent clinical benefits observed across diverse cancer types and stages underscore the potentialof VB-1953 as a broadly effective therapeutic option for managing MFWs. The data further supports its role in enhancing the comfort and wellbeing of patients suffering from advanced cancers with cutaneous manifestations.

[0135] VT-1953 (7.5g) was applied twice daily to wounds for 14 days. The primary endpoint was the difference in the mean score of malodor associated with MFW using a TELER (Treatment Evaluation by A.A. Le Roux's method) Scale on Day 14 compared to baseline. The TELER scale has been shown as Table 28. Table 28 discloses difference in the mean score of malodor associated with MFW using a TELER Scale on Day 14 compared to baseline Score Descriptors 0 Malodor detected upon entering room (>3m or >10ft) with dressing on 1 Malodor detected at >2m<3m (between 6-10ft) distance from patient with dressing on 2 Malodor detected at ~1m or arm’s length to the patient with dressing on 3 Malodor detected in close proximity (<1m or arm’s length) after exposing / removal of the dressing 4 Mild odor detected in close proximity (<1m or arm’s length) after exposing / removal of the dressing 5 No odor

[0136] Figure 4 shows representative photographs of malignant fungating wounds in patients with different tumor types treated with VB-1953 (besigloxacin gel) before start of treatment (baseline) and after 14 days of treatment with VB-1953 applied topically on the wound.

[0137] Figure 5 shows study design timeline illustrating treatment schedule and assessment points for pain and quality of life outcomes.

[0138] Exploratory endpoints included the differences in the mean score of pain associated with MFW (by pts) using a 10-point Visual Analog Scale (VAS) on days 7 and 14 compared to BL and the mean score of QOL associated with MFW (by pts) using 5-point VAS on days 7 and 14 compared to baseline. The study plan has been shown in Figure 5. The results are summarized in the Table 29.

[0139] The Figure 5 illustrates the study design timeline used to evaluate the efficacy and safetyof a treatment over a 14-day period, with particular focus on patient-reported outcomes such as pain and quality of life (QOL). The timeline is structured across three key milestones: Day 1, Day 7, and Day 14. On Day 1, participants underwent screening and enrolment, during which baseline data for pain, QOL, and other clinical parameters were recorded. The first application of the treatment was also administered on this day. From Day 1 onward, daily application of the treatment was maintained consistently throughout the 14-day period.

[0140] On Day 7, a mid-study evaluation was conducted to assess efficacy and safety, with input from both the investigator and the patient. During this assessment, the Visual Analog Scale (VAS) scores for pain (0–10 scale) and QOL (0–5 scale) were collected to measure changes from the baseline. The treatment continued daily beyond this interim check.

[0141] On Day 14, the final study evaluation took place, again involving both the investigator and the patient. This end-of-study assessment served to determine the cumulative effect of the treatment on patient outcomes. The same VAS tools were used to quantify improvements or changes in pain and QOL relative to the baseline and Day 7 scores. Overall, the figure effectively communicates the structured approach taken in this clinical study to monitor the trajectory of treatment effects over time, ensuring systematic data collection and meaningful endpoint analysis.

[0142] Table 29 summarizes results for malodor, pain, and quality of life (QOL) outcomes across baseline, Day 7, and Day 14. Mean Mean Baseline Day 7 difference difference ndpoint (Mean ± (Mean ± Day 7 – Day 14 E Day 14 – Bas (Mean ± SD) SD) eline Baseline (95% CI), p SD) (95% CI), p value value Malodor (0- 1.25 (0.38 to 3.12 (2.30 to High– 5- 0.62 ± 0.92 1.88 ± 1.36 2 3.75 ± 0.46 3.95), Low) .12), 0.011 <0.001 Pain (0-Low -1.75 (-2.34 -3.25 (-4.32 – 10-High) 6.75 ± 1.28 5.00 ± 1.31 to -1.16), 3.50 ± 1.31 to -2.18), <0.001 <0.001 QOL (0- 0.12 ± 0.35 1.12 ± 0.64 1.0 2.75 (2.16 to Low– 5- 0 (0.55 to 1.45), 0. 2.88 ± 0.64 3.34), High) 001 <0.001

[0143] The results summarized in Table 29 demonstrate statistically significant improvements across all measured clinical endpoints—malodor, pain, and quality of life (QOL)—from baseline to Days 7 and 14, reflecting the therapeutic efficacy of the treatment under investigation.

[0144] At baseline, the mean malodor score was 0.62 ± 0.92 on a 5-point scale (where 0 indicates high malodor and 5 indicates low malodor). By Day 7, this score increased to 1.88 ± 1.36, representing a mean difference of 1.25 (95% CI: 0.38 to 2.12; p = 0.011). This improvement continued, with the mean score reaching 3.75 ± 0.46 by Day 14, corresponding to a highly significant mean difference of 3.12 (95% CI: 2.30 to 3.95; p < 0.001) compared to baseline.

[0145] Pain levels, assessed using a 10-point Visual Analog Scale (VAS) where higher scores indicate greater pain, showed a marked reduction over the course of the study. The mean baseline score was 6.75 ± 1.28. By Day 7, this dropped to 5.00 ± 1.31, yielding a significant mean reduction of -1.75 (95% CI: -2.34 to -1.16; p < 0.001). On Day 14, the pain score further decreased to 3.50 ± 1.31, with a mean change from baseline of -3.25 (95% CI: -4.32 to -2.18; p < 0.001), indicating a progressive and clinically meaningful reduction in patient-reported pain.

[0146] Quality of Life (QOL) was assessed using a 5-point scale where higher scores denote better quality of life. At baseline, the QOL score was low (0.12 ± 0.35), but showed a notable increase to 1.12 ± 0.64 by Day 7 (mean difference of 1.00; 95% CI: 0.55 to 1.45; p = 0.001). This positive trend continued, with the score rising to 2.88 ± 0.64 on Day 14, representing a substantial and statistically significant improvement of 2.75 points (95% CI: 2.16 to 3.34; p < 0.001).

[0147] Overall, the results summarized in Table 28 suggests that the treatment was effective in reducing malodor and pain, while significantly enhancing the quality of life of the patients within a short 14-day period.

[0148] There were no treatment-emergent side effects and no severe local skin reactions. The results summarized in Table 29 indicates that VT-1953 has a favorable safety profile, significantly decreased malodor and pain, and improved the QOL of patients with malignant fungating wound. These results support VT-1953 as a promising option for the symptomatic management of MFW.

[0149] The foregoing description of the specific embodiments fully reveals the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and / or adapt for various applications such specific embodiments without departing from the generic concept, and,therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments.

[0150] It is to be understood that the phraseology or terminology employed herein is for the purpose of description and not of limitation. Therefore, while the embodiments in this disclosure have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein.

[0151] As used herein, the term ‘comprising’ when placed before the recitation of steps in a method means that the method encompasses one or more steps that are additional to those expressly recited, and that the additional one or more steps may be performed before, between, and / or after the recited steps. For example, a method comprising steps a, b, and c encompasses a method of steps a, b, x, and c, a method of steps a, b, c, and x, as well as a method of steps x, a, b, and c. Furthermore, the term “comprising” when placed before the recitation of steps in a method does not (although it may) require sequential performance of the listed steps, unless the content clearly dictates otherwise. For example, a method comprising steps a, b, and c encompasses, for example, a method of performing steps in the order of steps a, c, and b, the order of steps c, b, and a, and the order of steps c, a, and b, etc.

[0152] Numerical ranges stated in the form ‘from x to y’ include the values mentioned and those values that lie within the range of the respective measurement accuracy as known to the skilled person. If several preferred numerical ranges are stated in this form, of course, all the ranges formed by a combination of the different end points are also included.

[0153] As regards the embodiments characterized in this specification, it is intended that each embodiment be read independently as well as in combination with another embodiment. For example, in case of an embodiment 1 reciting 3 alternatives A, B and C, an embodiment 2 reciting 3 alternatives D, E and F and an embodiment 3 reciting 3 alternatives G, H and I, it is to be understood that the specification unambiguously discloses embodiments corresponding to combinations A, D, G; A, D, H; A, D, I; A, E, G; A, E, H; A, E, I; A, F, G; A, F, H; A, F, I; B, D, G; B, D, H; B, D, I; B, E, G; B, E, H; B, E, I; B, F, G; B, F, H; B, F,I; C, D, G; C, D, H; C, D, I; C, E, G; C, E, H; C, E, I; C, F, G; C, F, H; C, F, I, unless specifically mentioned otherwise.

[0154] Throughout this specification, the term ‘a combination thereof’, ‘combinations thereof’or ‘any combination thereof’ or ‘any combinations thereof’ are used interchangeably and are intended to have the same meaning, as regularly known in the field of patent disclosures.

[0155] Any discussion of documents, acts, materials, devices, articles and the like that has been included in this specification is solely for the purpose of providing a context for the disclosure. It is not to be taken as an admission that any or all of these matters form a part of the prior art base or were common general knowledge in the field relevant to the disclosure as it existed anywhere before the priority date of this application.

[0156] While considerable emphasis has been placed herein on the particular features of this disclosure, it will be appreciated that various modifications can be made, and that many changes can be made in the preferred embodiments without departing from the principles of the disclosure. These and other modifications in the nature of the disclosure or the preferred embodiments will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the disclosure and not as a limitation.

[0157] All references, articles, publications, general disclosures etc. cited herein are incorporated by reference in their entireties for all purposes. However, mention of any reference, article, publication etc. cited herein is not, and should not be taken as, an acknowledgment or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world.

[0158] While specific language has been used to describe the invention, any limitations arising on account of the same are not intended. As would be apparent to a person skilled in the art, various working modifications may be made to the method in order to implement the inventive concept as taught herein.

[0159] The figures and the foregoing description give examples of embodiments. Those skilled in the art will appreciate that one or more of the described elements may well be combined into a single functional element. Alternatively, certain elements may be split into multiple functional elements. Elements from one embodiment may be added to another embodiment. For example, order of processes described herein may be changed and are not limited to the manner described herein. Moreover, the actions of any flow diagram need not be implemented in the order shown; nor do all of the acts need to be necessarily performed. Also, those acts that are not dependent on other acts maybe performed in parallel with the other acts. The scope of embodiments is by no means limited by these specific examples.

Claims

WE CLAIM:

1. A method of treating Malignant Fungating Wound (MFW), comprising administering an inhibitor of DNA gyrase and / or topoisomerase and / or MD2-TLR interactions to a wound in a subject.

2. The method as claimed in claim 1, wherein the inhibitor of DNA gyrase and / or topoisomerase and / or MD2 / TLR interaction is administered to the wound topically and / or intralesionally.

3. The method as claimed in claims 1 or 2, wherein the inhibitor of DNA gyrase and / or topoisomerase and / or MD2-TLR interactions is a fluoroquinolone.

4. The method as claimed in claim 3, wherein the fluoroquinolone is besifloxacin.

5. The method as claimed in claim 1, wherein the inhibitor of DNA gyrase and / or topoisomerase is administered in a form of a pharmaceutical composition.

6. The method as claimed in claim 5, wherein the inhibitor of DNA gyrase and / or topoisomerase is present at a concentration of about 0.5-4.5% w / w in the pharmaceutical composition.

7. The method as claimed in claim 6, wherein the inhibitor of DNA gyrase and / or topoisomerase is besifloxacin.

8. The method as claimed in claims 5-7, wherein the pharmaceutical composition is selected from one of a topical formulation and an intralesional formulation.

9. The method as claimed in claim 8, wherein the topical formulation is selected from a group comprising of a cream, a gel, an ointment, a lotion, a spray, an emugel, a soap bar, a face wash and a body wash.

10. The method as claimed in claim 8 or 9, wherein the topical formulation is a gel comprising besifloxacin and an excipient selected from a group comprising of a moisturizing agent, a chelating agent, a preservative, a stabilizing agent, a solubilizing agent, a thickening agent, a rheology modifier and a solvent, and a combination thereof.

11. The method as claimed in claim 10, wherein the moisturizing agent is glycerin; thechelating agent is edetate disodium dehydrate; the preservative is phenoxyethanol; the stabilizing agent is sodium hyaluronate; the solubilizing agent is one of polyethylene glycol, diethylene glycol monoethyl ether, and a combination thereof; the thickening agent is hydroxyethyl cellulose; the rheology modifier is one of carbomer homopolymer type C and sodium hyaluronate; and the solvent is water.

12. The method as claimed in claim 10 or 11, wherein besifloxacin is present at a concentration of about 0.5% w / w to about 4.5% w / w; glycerin is present at a concentration of about 2% w / w to about 10% w / w; edetate disodium dehydrate is present at a concentration of about 0.1% w / w; phenoxyethanol is present at a concentration of about 0.1% w / w to about 0.7% w / w; sodium hyaluronate is present at a concentration of about 0.1% w / w to about 0.5% w. / w; polyethylene glycol is present at a concentration of about 2% w / w to about 7% w / w; diethylene glycol monoethyl ether is present at a concentration of about 2% w / w to about 7% w / w; hydroxyethyl cellulose is present at a concentration of about 0.6% w / w to about 1.75% w / w; carbomer homopolymer type C is present at a concentration of about 0.1% to about 0.8% w / w; and the rest is solvent.

13. The method as claimed in claim 10 or 11, wherein besifloxacin is present at one of a concentration of about 1.09%, 2.18%, and 4.36% w / w; glycerin is present at a concentration of about 5% w / w; edetate disodium dehydrate is present at a concentration of about 0.1% w / w; phenoxyethanol is present at a concentration of about 0.7% w / w; sodium hyaluronate is present at a concentration of about 0.2% w / w; polyethylene glycol is present at a concentration of about 5% w / w; diethylene glycol monoethyl ether is present at a concentration of about 5% w / w; hydroxyethyl cellulose is present at a concentration of about 0.6% w / w; carbomer homopolymer type C is present at a concentration of about 0.65% w / w; and the rest is solvent.

14. The method as claimed in claim 11, wherein besifloxacin is present at one of the concentration of about 1.09% w / w and 2.18% w / w; glycerin is present at a concentration of about 5% w / w; edetate disodium dehydrate is present at a concentration of about 0.1% w / w; phenoxyethanol is present at a concentration of about 0.7% w / w; polyethylene glycol is present at a concentration of about 5% w / w; diethylene glycol monoethyl ether is present at a concentration of about 5% w / w; hydroxyethyl cellulose is present at a concentration of about 0.6% w / w; carbomer homopolymer type C is present at a concentration of about 0.65% w / w; and the rest is solvent.

15. The method as claimed in claim 12, wherein besifloxacin is present at one of the concentration of about 1.09% and 2.18% w / w; glycerin is present at a concentration of about 5% w / w; edetate disodium dehydrate is present at a concentration of about 0.1% w / w; sodium hyaluronate is present at a concentration of about 0.2% w / w; polyethylene glycol is present at a concentration of about 5% w / w; diethylene glycol monoethyl ether is present at a concentration of about 5% w / w; hydroxyethyl cellulose is present at a concentration of about 0.6% w / w; carbomer homopolymer type C is present at a concentration of about 0.65% w / w; and the rest is the solvent.

16. The method as claimed in claims 5-15, wherein the pH of the pharmaceutical composition is about 5.5-7.

17. The method as claimed in claims 5-15, wherein the viscosity of the pharmaceutical composition is about 3500-15000 m.Pa.S.

18. The method as claimed in claims 1-17, wherein the inhibitor of DNA gyrase and / or topoisomerase is administered to the wound as one of once, twice, and thrice daily.

19. The method as claimed in claims 1-18, wherein the method reduces the bacterial count of the MFW by one of about 20-99% and by about 1.5 to 5-fold.

20. The method as claimed in claims 1-19, wherein the method reduces the odor emanating from MFW.

21. The method as claimed in claims 1-20, wherein the method reduces the inflamed lesion in the subject by about 20-80%.

22. The method as claimed in claims 1-21, wherein the subject is a mammal.

23. An inhibitor of DNA gyrase and / or topoisomerase and / or MD2-TLR for use in treating signs and / or symptoms of Malignant Fungating Wound (MFW).

24. The DNA gyrase and / or topoisomerase and / or MD2-TLR inhibitor for use as claimed in claim 23, wherein the DNA gyrase and / or topoisomerase and / or MD2-TLR inhibitor is a fluoroquinolone.

25. The DNA gyrase and / or topoisomerase and / or MD2-TLR inhibitor for use as claimed in claim 24, wherein the fluoroquinolone is besifloxacin.

26. The DNA gyrase and / or topoisomerase and / or MD2-TLR inhibitor for use as claimed in claims 23-25, wherein the DNA gyrase and / or topoisomerase and or MD2-TLR inhibitor is in the form of a pharmaceutical composition.

27. The DNA gyrase and / or topoisomerase and / or MD2-TLR inhibitor for use as claimed in claim 26, wherein the DNA gyrase and / or topoisomerase inhibitor is present at a concentration of about 0.5-4.5% w / w in the pharmaceutical composition.

28. The DNA gyrase and / or topoisomerase inhibitor for use as claimed in claim 27, wherein the DNA gyrase and / or topoisomerase inhibitor is besifloxacin.

29. The DNA gyrase and / or topoisomerase and / or MD2-TLR inhibitor for use as claimed in claims 26-28, wherein the pharmaceutical composition is selected from one of a topical formulation and / or an intralesional formulation.

30. The DNA gyrase and / or topoisomerase and / or MD2-TLR inhibitor for use as claimed in claim 29, wherein the topical formulation is selected from a group comprising of a cream, a gel, an ointment, a lotion, liquid drops, a spray, an emugel, a soap bar, a face wash and a body wash.

31. The DNA gyrase and / or topoisomerase and / or MD2-TLR inhibitor for use as claimed in claim 30, wherein the topical formulation is the gel comprising besifloxacin and an excipient is selected from a group comprising a moisturizing agent, a chelating agent, a preservative, a stabilizing agent, a solubilizing agent, a thickening agent, a rheology modifier and a solvent, and a combination thereof.

32. The DNA gyrase and / or topoisomerase and / or MD2-TLR inhibitor for use as claimed in claim 31, wherein the moisturizing agent is glycerin; the chelating agent is edetate disodium dehydrate; the preservative is phenoxyethanol; the stabilizing agent is sodium hyaluronate; the solubilizing agent is one of polyethylene glycol, diethylene glycol monoethyl ether, and a combination thereof; the thickening agent is hydroxyethyl cellulose; the rheology modifier is one of carbomer homopolymer type C and sodium hyaluronate; and the solvent is water.

33. The DNA gyrase and / or topoisomerase and / or MD2-TLR inhibitor for use as claimed in claim 32, wherein besifloxacin is present at a concentration of about 0.5% w / w to about 4.5% w / w; glycerin is present at a concentration of about 2% w / w to about 10% w / w; edetate disodium dehydrate is present at a concentration of about 0.1% w / w; phenoxyethanol is present at aconcentration of about 0.1% w / w to about 0.7% w / w; sodium hyaluronate is present at a concentration of about 0.1% w / w to about 0.5% w / w; polyethylene glycol is present at a concentration of about 2% w / w to about 7% w / w; diethylene glycol monoethyl ether is present at a concentration of about 2% w / w to about 7% w / w; hydroxyethyl cellulose is present at a concentration of about 0.6% w / w to about 1.75% w / w; carbomer homopolymer type C is present at a concentration of about 0.1% to about 0.8% w / w; and the rest is solvent.

34. The DNA gyrase and / or topoisomerase and / or MD2-TLR inhibitor for use as claimed in claim 32, wherein besifloxacin is present at one of a concentration of about 1.09%, 2.18%, and 4.36% w / w; glycerin is present at a concentration of about 5% w / w; edetate disodium dehydrate is present at a concentration of about 0.1% w / w; phenoxyethanol is present at a concentration of about 0.7% w / w; sodium hyaluronate is present at a concentration of about 0.2% w / w; polyethylene glycol is present at a concentration of about 5% w / w; diethylene glycol monoethyl ether is present at a concentration of about 5% w / w; hydroxyethyl cellulose is present at a concentration of about 0.6% w / w; carbomer homopolymer type C is present at a concentration of about 0.65% w / w; and the rest is solvent.

35. The DNA gyrase and / or topoisomerase and / or MD2-TLR inhibitor for use as claimed in claim 32, wherein besifloxacin is present at one of a concentration of about 1.09% and 2.18% w / w; glycerin is present at a concentration of about 5% w / w; edetate disodium dehydrate is present at a concentration of about 0.1% w / w; phenoxyethanol is present at a concentration of about 0.7% w / w; polyethylene glycol is present at a concentration of about 5% w / w; diethylene glycol monoethyl ether is present at a concentration of about 5% w / w; hydroxyethyl cellulose is present at a concentration of about 0.6% w / w; carbomer homopolymer type C is present at a concentration of about 0.65% w / w; and the rest is solvent.

36. The DNA gyrase and / or topoisomerase and / or MD2-TLR inhibitor for use as claimed in claim 32, wherein besifloxacin is present at one of a concentration of about 1.09% and 2.18% w / w; glycerin is present at a concentration of about 5% w / w; edetate disodium dehydrate is present at a concentration of about 0.1% w / w; sodium hyaluronate is present at a concentration of about 0.2% w / w; polyethylene glycol is present at a concentration of about 5% w / w; diethylene glycol monoethyl ether is present at a concentration of about 5% w / w; hydroxyethyl cellulose is present at a concentration of about 0.6% w / w; carbomer homopolymer type C is present at a concentration of about 0.65% w / w; and the rest is solvent.

37. Use of a DNA gyrase and / or topoisomerase and / or MD2-TLR inhibitor in manufacturing a medicament for treating Malignant Fungating Wound.

38. A pharmaceutical composition comprising besifloxacin and a pharmaceutically acceptable excipient.

39. The pharmaceutical composition as claimed in claim 38, wherein besifloxacin is present at a concentration of about 0.5% w / w to about 4.5% w / w.

40. The pharmaceutical composition as claimed in claim 38 or 39, wherein the composition is selected from one of a topical formulation and / or an intralesional formulation.

41. The pharmaceutical composition as claimed in claim 40, wherein the topical formulation is selected from a group comprising of a cream, a gel, an ointment, a lotion, a spray, a emugel, liquid drops, a soap bar, a face wash, and a body wash.

42. The pharmaceutical composition as claimed in claims 38-41, wherein the topical formulation is a gel comprising besifloxacin and an excipient is selected from a group comprising of a moisturizing agent, a chelating agent, a preservative, a stabilizing agent, a solubilizing agent, a thickening agent, a rheology modifier and a solvent, and a combination thereof.

43. The pharmaceutical composition as claimed in claim 41, wherein the moisturizing agent is glycerin; the chelating agent is edetate disodium dehydrate; the preservative is phenoxyethanol; the stabilizing agent is sodium hyaluronate; the solubilizing agent is one of polyethylene glycol, diethylene glycol monoethyl ether and a combination thereof; the thickening agent is hydroxyethyl cellulose; the rheology modifier is one of sodium hyaluronate and carbomer homopolymer type C; and the solvent is water.

44. The pharmaceutical composition as claimed in claim 42 or 43, wherein besifloxacin is present at a concentration of about 0.5% w / w to about 4.5% w / w; glycerin is present at a concentration of about 2% w / w to about 10% w / w; edetate disodium dehydrate is present at a concentration of about 0.1% w / w; phenoxyethanol is present at a concentration of about 0.1% w / w to about 0.7% w / w; sodium hyaluronate is present at a concentration of about 0.1% w / w to about 0.5% w / w; polyethylene glycol is present at a concentration of about 2% w / w to about 7% w / w; diethylene glycol monoethyl ether is present at a concentration of about 2% w / w to about7% w / w; hydroxyethyl cellulose is present at a concentration of about 0.6% w / w to about 1.75% w / w; carbomer homopolymer type C is present at a concentration of about 0.1% to about 0.8% w / w; and the rest is solvent.

45. The pharmaceutical composition as claimed in claim 44, wherein besifloxacin is present at one of a concentration of about 1.09%, 2.18%, and 4.36% w / w; glycerin is present at a concentration of about 5% w / w; edetate disodium dehydrate is present at a concentration of about 0.1% w / w; phenoxyethanol is present at a concentration of about 0.7% w / w; sodium hyaluronate is present at a concentration of about 0.2% w / w; polyethylene glycol is present at a concentration of about 5% w / w; diethylene glycol monoethyl ether is present at a concentration of about 5% w / w; hydroxyethyl cellulose is present at a concentration of about 0.6% w / w; carbomer homopolymer type C is present at a concentration of about 0.65% w / w; and the rest is solvent.

46. The pharmaceutical composition as claimed in claim 43, wherein besifloxacin is present at one of a concentration of about 1.09% and 2.18% w / w; glycerin is present at a concentration of about 5% w / w; edetate disodium dehydrate is present at a concentration of about 0.1% w / w; phenoxyethanol is present at a concentration of about 0.7% w / w; polyethylene glycol is present at a concentration of about 5% w / w; diethylene glycol monoethyl ether is present at a concentration of about 5% w / w; hydroxyethyl cellulose is present at a concentration of about 0.6% w / w; carbomer homopolymer type C is present at a concentration of about 0.65% w / w; and rest is solvent.

47. The pharmaceutical composition as claimed in claim 43, wherein besifloxacin is present at one of a concentration of about 1.09% and 2.18% w / w; glycerin is present at a concentration of about 5% w / w; edetate disodium dehydrate is present at a concentration of about 0.1% w / w; sodium hyaluronate is present at a concentration of about 0.2% w / w; polyethylene glycol is present at a concentration of about 5% w / w; diethylene glycol monoethyl ether is present at a concentration of about 5% w / w; hydroxyethyl cellulose is present at a concentration of about 0.6% w / w; carbomer homopolymer type C is present at a concentration of about 0.65% w / w; and the rest is solvent.

48. A method of reducing malodor associated with fungating wound using a pharmaceutical composition comprising besifloxacin and a pharmaceutically acceptable excipient.

49. The pharmaceutical composition as claimed in claim 48, wherein besifloxacin is present at a concentration of about 0.5% w / w to about 4.5% w / w.

50. A method of reducing pain associated with a fungating wound using a pharmaceutical composition comprising besifloxacin and a pharmaceutically acceptable excipient.

51. The pharmaceutical composition as claimed in claim 50, wherein besifloxacin is present at a concentration of about 0.5% w / w to about 4.5% w / w.

52. A method of improving quality of life of patients with fungating wound using a pharmaceutical composition comprising besifloxacin and a pharmaceutically acceptable excipient.

53. The pharmaceutical composition as claimed in claim 52, wherein besifloxacin is present at a concentration of about 0.5% w / w to about 4.5% w / w.

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