Enhanced formulation of polymyxin b / trimethoprim and rifampin and methods for ophthalmic uses

Abstract

The invention provides novel pharmaceutical compositions of polymyxin B / trimethoprim and rifampin, as well as methods of their preparation and topical ophthalmic uses (e.g., treatment of ophthalmic infections).

Description

ENHANCED FORMULATION OF POLYMYXIN B / TRIMETHOPRIM AND RIFAMPIN AND METHODS FOR OPHTHALMIC USESPriority Claims and Related Patent Applications

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 530,495, filed August 3, 2023, the entire content of which is incorporated herein by reference.Technical Fields of the Invention

[0002] The invention generally relates to pharmaceuticals and methods of preparation and use thereof. More particularly, the invention provides novel pharmaceutical compositions of polymyxin B / trimethoprim and rifampin and methods of their preparation and topical ophthalmic uses (e.g., treatment of ophthalmic infections).Background of the Invention

[0003] Bacterial keratitis is a vision-threatening disease caused by a bacterial infection of the cornea that is responsible for nearly 2 million cases of blindness annually. Many Gram-positive and Gram-negative bacteria can cause bacterial keratitis including but not limited to: Staphylococcus aureus, coagulase -negative staphylococci, Streptococcus pneumoniae, Pseudomonas aeruginosa, Moraxella marcesens, Corynebacterium spp.,Proprioni bacterium spp., Klebsiella, Proteus, and Serratia. The clinical presentation of bacterial keratitis frequently includes corneal ulceration, edema, immune infiltrates, and anterior chamber inflammation regardless of the causative agent. While clinicians may obtain a microbiology culture at initial diagnosis, it may take several days for the results to identify a specific causative agent and the tests only yield a positive result in 40-60% of cases. Given the unknown causative agent at clinical presentation and the aggressive nature of bacterial keratitis, immediate and broad-spectrum ophthalmic antibiotic treatment that is effective toward both Gram-positive and Gram-negative organisms is required within days to prevent corneal perforation and / or loss of the eye. Prescribing an antibiotic which only targets either Gram-positive or Gram-negative bacteria for the treatment of bacterial keratitis is counter to established standard of care.(Whitcher et al. Corneal blindness: a global perspective. Bulletin of the World Health Organization 2001;79(3):214-21; Green et al. Cornea. 2008;27(l):22-7. Epub 2008 / 02 / 05; Cabrera-Aguas et al. Clin Exp Ophthalmol. 2022;50(5):543-62; Ting et al. Eye (Lond).2021;35(4): 1084-101; Al-Mujaini et al. Sidtan Qaboos Univ Med J. 2009;9(2): 184-95; Palioura et al. Clin Ophthalmol. 2016;10: 179-86. McLeod et al. Ophthalmology. 1996;103(l):23-8; Levey et al. Cornea. 1997;16(4):383-6.)

[0004] The fluoroquinolone class of antibiotics are the gold standard for bacterial keratitis treatment in the United States due to their broad-spectrum activity, rapid bacterial-killing kinetics, patient tolerability and low cost. In fact, there are only three FDA-approved ophthalmic solutions for managing bacterial keratitis and all are fluoroquinolones: ciprofloxacin 0.3% ophthalmic solution or ointment, ofloxacin 0.4% ophthalmic solution, and levofloxacin 1.5% ophthalmic solution.

[0005] While fluoroquinolones may present a number of side effects, more importantly, the efficacy of fluoroquinolones has declined with the rise of drug-resistant bacteria. This has resulted in increased disease severity and worse visual outcomes over the last decade. In fact, the most recently FDA approved antibiotic to treat bacterial keratitis, levofloxacin a third- generation fluoroquinolone, demonstrated resistance rates as high as 71% among S. aureus ocular isolates. (Lauren et al. US Pharmacist. 2018;(43):27-30; Lalitha et al. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America.2012;54(10): 1381 -7; Vazirani et al. Ophthalmology:. 2015; 122(10); Asbell et al. JAMA ophthalmology. 2015; 133(12).)

[0006] Due to the challenges with fluoroquinolones, clinicians often turn to off-label therapeutic agents or specialty compounded antibiotics such as fortified aminoglycosides, in combination with fortified vancomycin or a cephalosporin. While these drugs may be efficacious, variability can arise from the lack of standard formulation and may not be tolerated well by patients due to more severe side effects. Moreover, most patients and physicians lack access to a specialty compounding pharmacy, especially within the emergent timeframe of the disease, which limits these compounded antibiotics as a reliable therapy for bacterial keratitis. Furthermore, the duration of therapy for bacterial keratitis via specialty compounded antibiotics often requires frequent refills.

[0007] Additional to the availability and effectiveness of broad-spectrum antibiotic therapeutic options, any treatment of bacterial keratitis must be able to be efficiently delivered to the patient via a pharmacy and supply chain. Given the emergent nature of this disease, prescribed medications must be made available to the patient within hours of their initial diagnosis for effective and immediate treatment.

[0008] There remains an ongoing need for improved pharmaceutical formulations and methods of use for treating ophthalmic infections.Summary of the Invention

[0009] In one aspect, the invention generally relates to a kit or package comprising: an aqueous first composition comprising polymyxin B / trimethoprim (PT), or pharmaceutically acceptable salts thereof, and a surfactant or polymer, wherein the first composition is characterized by a pH in the range from about 4.0 to about 6.5; and a second composition comprising Rif and a solid state polyol (mannitol and / or sorbitol ) and optionally an antioxidant, wherein the first composition is a sterile aqueous solution, and the second composition is a sterile lyophilized solid or powdery composition.

[0010] In another aspect, the invention generally relates to a method for treating a bacterial ocular infection, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition disclosed herein.Brief Description of the Drawings

[0011] FIG. 1 shows results indicating that Surfactants reduce PT’s polymyxin B-associated rifampin destabilization.

[0012] FIG. 2 shows results indicating that 1% Polyvinyl alcohol (PVA) does not significantly impact Rifampin activity or PT + Rifampin synergy.

[0013] FIG. 3 shows results indicating that 2% PVP K30 does not significantly impact Rifampin activity or PT + Rifampin synergy.

[0014] FIG. 4 shows results indicating that Pol oxama 407 0.2% does not significantly impact Rifampin activity or PT + Rifampin synergy.

[0015] FIG. 5 shows results indicating that 1% Tyloxapol does not significantly impact Rifampin activity or PT + Rifampin synergy.

[0016] FIG. 6 shows results indicating that greater than 0.033% Polysorbate negatively impacts Rifampin activity.Detailed Description of the Invention

[0017] The present invention provides enhanced pharmaceutical formulations, efficient storage, and methods for ophthalmic uses (e. ., bacterial keratitis, surgical prophylaxis, bacterial conj unctiviti s, keratoprosthesi s) .

[0018] Pharmacies and the pharmacy supply chain must be able to (1) receive and transfer agents in a secure and durable method, (2) store component ingredients or the final products for a sufficient shelf-life, and (3) prepare any therapeutic agents quickly and repeatedly for effective and efficient delivery.

[0019] A normal course of treatment for bacterial keratitis generally starts immediately upon diagnosis and continues for a number of weeks to months. Due to the potential rapid progression of the disease, treatment is dosed as frequently as once per hour for the first few days and then tapers to 8 or 12 times per day, then 4 times per day, and eventually to once or twice a day. Given the frequency of treatment, patients apply the solution, ointment, or other therapy to the effected eye wherever they are at that time: at their home, place of employment, etc. Patients must be able to easily and effectively prepare the treatment and dose themselves in a number of different locations and scenarios. Therefore, any steps taken by the patient must be extremely straightforward and easy to use.

[0020] A significant number of peer-reviewed publications have documented and demonstrated the combination of polymyxin B / trimethoprim (PT) and rifampin (Rif) as a synergistic broad-spectrum antibiotic which rapidly kills bacteria, is effective towards established bacterial biofilms and can eradicate keratitis in animal models of Gram-positive and / or Gram-negative bacterial corneal infections. The use of polymyxin B / trimethoprim + rifampin (PT+Rif) as a synergistic antibiotic combination was disclosed in US 11,096,923 B2. (Laskey et al. Cornea. 2020 Oct;39(10): 1278-1284; Chojnacki et al. Antimicrob Agents Chemother. 2018 Dec 21;63(l):e01929-18; Chojnacki et al. Antimicrob Agents Chemother. 2019 Sep 23;63(10):e00777-19; Meijome et al. Transl Cis Sci Technol. 2022 Nov 1 ; 11(11): 12; Mei et al. Transl Vis Sci Technol. 2022 May 2;11(5):26.)

[0021] The present invention discusses details which are required for the preparation and formulation for the delivery and treatment of ophthalmic infections including but not limited to: bacterial keratitis, surgical prophylaxis, bacterial conjunctivitis, keratoprosthesis, and others.

[0022] In one aspect, the invention generally relates to a kit or package comprising: an aqueous first composition comprising PT, or pharmaceutically acceptable salts thereof, and a surfactant or polymer, wherein the first composition is characterized by a pH in the range from about 4.0 to about 6.5; and a second composition comprising Rif and a solid state polyol (mannitol and / or sorbitol ) and optionally an antioxidant, wherein the first composition is a sterile aqueous solution, the second composition is a sterile lyophilized solid or powdery composition.

[0023] PT+Rif may be provided as a two-part formulation that is combined at point of care via a packaging system (e.g., a dual chamber bottle or eye dropper). Separating PT and Rif into two different chambers of a single dosing and packaging system enables a longer shelf-life of the non-mixed components as well as easier preparation and delivery at point of care (patient use). Additional compounds are added to each part of the active ingredient components in order to further stabilize the solution when mixed together. PT is generally provided in a solution formulation while Rif can be added in either a powder / cake or solid-state formulation for reconstitution. Sterile powders can be produced by spray drying.

[0024] In another aspect, the invention generally relates to a pharmaceutical composition comprising PT and a surfactant, wherein polymyxin B sulfate is present in the range of about 7,500 units / mL to about 12,500 units / mL; trimethoprim sulfate is present in the range of about 0.75 mg / mL to about 1.25 mg / mL; the surfactant is present in the range of about 0.5 mg / mL to about 5.0 mg / mL; and the pharmaceutical composition is a sterile aqueous solution characterized by a pH in the range from about 4.0 to about 6.5.

[0025] In yet another aspect, the invention generally relates to a pharmaceutical composition comprising Rif, mannitol and an antioxidant, wherein Rif is present in the range of about 0.2 mg / mL to about 1.0 mg / mL; mannitol is present in the range of about 10 mg / mL to about 60 mg / mL; the antioxidant is present in the range of about 0 mg / mL to about 1.0 mg / mL; and the pharmaceutical composition is a sterile lyophilized solid or powdery mixture.

[0026] In yet another aspect, the invention generally relates to a reconstituted pharmaceutical composition which is prepared from combining a composition of PT and a surfactant composition and a composition of Rif, mannitol and an antioxidant.

[0027] In yet another aspect, the invention generally relates to a method for treating a bacterial ocular infection, comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0028] In yet another aspect, the invention generally relates to use of a composition disclosed herein to treat a disease or condition (e.g., bacterial ocular infection).

[0029] The following examples are given for the purpose of illustrating the invention, but not for limiting the scope or spirit of the invention.ExamplesSolution stability

[0030] The ophthalmic formulation includes trimethoprim sulfate (1 mg / mL), polymyxin B sulfate (10,000 units / mL), and rifampin (0.5 mg / mL). A combination product of trimethoprim sulfate and polymyxin B sulfate is currently marketed (Polytrim) and is stable at room temperature. Rif is marketed as an oral capsule and as a lyophilized powder for reconstitution and IV administration. The IV solution of Rif must be used shortly after reconstitution due to the poor solution stability of the compound.

[0031] Addition of a surfactant resulted in improved solution stability. Surfactants approved for ophthalmics include: octoxynol-40, nonoxyl-9, poloxamer 188, poloxamer 407, PEG-35 castor oil, PEG-40 hydrogenated castor oil, PEG-40 stearate, polysorbate 80, and tyloxapol. The surfactant levels are in the 0.05-0.3% w / w range. Approved polymers include polyvinylprrolidone (povidone, or PVP), polyvinyl alcohol (PVA), and modified celluloses. The polymer levels can be up to 2% w / w. PVA and PVP did not inhibit rifampin activity.Lyophilization

[0032] The marketed lyophilized formulation of Rif includes sodium formaldehyde sulfoxylate and NaOH to adjust pH. Sodium formaldehyde sulfoxylate may improve dissolution of the lyophilized cake by forming a salt with Rif, but it is not approved for ophthalmics.

[0033] During lyophilization experiments, it was found that adding mannitol to the lyophilized formulation (1 :1 w / w to 10: 1 w / w mannitol: rifampin) improved the reconstitution of the lyophilized cake significantly compared to a neat lyophilized rifampin cake.

[0034] An antioxidant, such as ascorbic acid (or its salts and esters) can be included in the lyophilized formulation. This may improve the solid-state stability of rifampin in the lyophilized cake or other solid-state formulation and its solution stability after reconstitution.

[0035] During excipient screening studies, the surfactant polysorbate 80 was found to inhibit the antimicrobial activity of rifampin. Surprisingly, it was found that the surfactants tyloxapol and poloxamer 407 did not inhibit rifampin activity.

[0036] Exemplary reconstituted formulation compositions:

[0037] Additional potential excipients:• Poloxamer (surfactant), 0-5 mg / mL• Povidone (viscosity modifier), 0-60 mg / mL• Polyvinyl alcohol (viscosity modifier), 0-60 mg / mL• Disodium edetate (chelating agent), 0-1 mg / mL

[0038] Likely Solid Formulation (amount per vial for 1 mL when reconstituted):• 0.5 mg rifampin• 10-50 mg mannitol• 0-1 mg ascorbic acid• 0-30 mg of povidone• 0-.5 mg of poloxamer 407 or 188• 0-60 mg of polyvinyl alcohol

[0039] FIG. 1 shows results indicating that Surfactants reduce PT’s polymyxin B-associated rifampin destabilization. Shown in panel A are the rifampin degradation profiles of rifampin, rifampin in the presence of trimethoprim, and rifampin in the presence of polymyxin B at 25°C, establishing that rifampin is destabilized in the presence of polymyxin B. Shown in panel B are the rifampin degradation profiles of rifampin, rifampin in the presence of polymyxin B, rifampin in the presence of PT (polymyxin B + trimethoprim) supplemented with polysorbate 80, and rifampin in the presence of PT (polymyxin B + trimethoprim) supplemented with tyloxapol, establishing that surfactants such as tyloxapol and polysorbate stabilize rifampin at 5°C. As shown in Figures 5 and 6, rifampin remains active in tyloxapol but loses antimicrobial activity in the presence of polysorbate.

[0040] FIG. 2 shows results indicating that 1% Polyvinyl alcohol (PVA) does not significantly impact Rifampin activity or PT + Rifampin synergy. Shown are the antimicrobial properties of increasing concentrations (0, 0.0006, 0.0012, 0.0025, 0.005, 0.01, 0.02, 0.4, 0.08, 0.16, 0.32 and 64 pg / ml) of Rifampin loaded into columns 1-12 of a microtiter plate containing media supplemented with 1% PVA and inoculated with 10,000 viable cells of the bacterial pathogen, Staphylococcus aureus. Also shown are the antimicrobial properties of increasing concentrations of PT (0, 0.26, 0.53, 1.10, 2.10, 4.20, and 8.40 pg / ml) applied to each row of the plate. In the absence of PT (row A) as little as 0.0025 pg / ml rifampin inhibits S. aureus growth (well is highlighted by green in row A). In the absence of Rifampin (column 1) as little as 0.53 pg / ml PT inhibits S. aureus growth (highlighted by green in column 1). In combination 0.0012 pg / ml rifampin and 0.26 pg / ml PT inhibits S. aureus growth (highlighted in red), establishingthat the combination of PT+rifampin displays synergistic antimicrobial activity in the presence of 1% PVA.

[0041] FIG. 3 shows results indicating that 2% PVP K30 does not significantly impact Rifampin activity or PT + Rifampin synergy. Shown are the antimicrobial properties of increasing concentrations (0, 0.0006, 0.0012, 0.0025, 0.005, 0.01, 0.02, 0.4, 0.08, 0.16, 0.32 and 64 pg / ml) of Rifampin loaded in columns 1-12 of a microtiter plate containing media supplemented with 2% PVP K30 and inoculated with 10,000 viable cells of the bacterial pathogen, Staphylococcus aureus. Also shown are the antimicrobial properties of increasing concentrations of PT (0, 0.26, 0.53, 1.10, 2.10, 4.20, and 8.40 pg / ml) applied to each row of the plate. In the absence of PT (row A) as little as 0.0025 pg / ml rifampin inhibits S. aureus growth (well is highlighted by green in row A). In the absence of Rifampin (column 1) as little as 0.53 pg / ml PT inhibits . aureus growth (highlighted by green in column 1). In combination 0.0012 pg / ml rifampin and 0.53 pg / ml PT inhibits . aureus growth (highlighted in red), establishing that the combination of PT+rifampin displays synergistic antimicrobial activity in the presence of 2% PVP K30.

[0042] FIG. 4 shows results indicating that Poloxama 407 0.2% does not significantly impact Rifampin activity or PT + Rifampin synergy. Shown are the antimicrobial properties of increasing concentrations (0, 0.0006, 0.0012, 0.0025, 0.005, 0.01, 0.02, 0.4, 0.08, 0.16, 0.32 and 64 pg / ml) of Rifampin loaded in columns 1-12 of a microtiter plate containing media supplemented with 0.2% Poloxama 407 and inoculated with 10,000 viable cells of the bacterial pathogen, Staphylococcus aureus. Also shown are the antimicrobial properties of increasing concentrations of PT (0, 0.26, 0.53, 1.10, 2.10, 4.20, and 8.40 pg / ml) applied to each row of the plate. In the absence of PT (row A) as little as 0.005 pg / ml rifampin inhibits S. aureus growth (well is highlighted by green in row A). In the absence of Rifampin (column 1) as little as 1.06 pg / ml PT inhibits A aureus growth (highlighted by green in column 1). In combination 0.0012 pg / ml rifampin and 0.53 pg / ml PT inhibits S. aureus growth (highlighted in red), establishing that the combination of PT+rifampin displays synergistic antimicrobial activity in the presence of 0.2% Poloxama 407.

[0043] FIG. 5 shows results indicating that 1% Tyloxapol does not significantly impact Rifampin activity or PT + Rifampin synergy. Shown are the antimicrobial properties of increasing concentrations (0, 0.0006, 0.0012, 0.0025, 0.005, 0.01, 0.02, 0.4, 0.08, 0.16, 0.32 and64 pg / ml) of Rifampin loaded in columns 1-12 of a microtiter plate containing media supplemented with 1% Tyloxapol and inoculated with 10,000 viable cells of the bacterial pathogen, Staphylococcus aureus. Also shown are the antimicrobial properties of increasing concentrations of PT (0, 0.26, 0.53, 1.10, 2.10, 4.20, and 8.40 pg / ml) applied to each row of the plate. In the absence of PT (row A) as little as 0.005 pg / ml rifampin inhibits S. aureus growth (well is highlighted by green in row A). In the absence of Rifampin (column 1) as little as 1.06 pg / ml PT inhibits S. aureus growth (highlighted by green in column 1). In combination 0.0012 pg / ml rifampin and 0.53 pg / ml PT inhibits 5. aureus growth (highlighted in red), establishing that the combination of PT + rifampin displays synergistic antimicrobial activity in the presence of 1% Tyloxapol.

[0044] FIG. 6 shows results indicating that greater than 0.033% Polysorbate negatively impacts Rifampin activity: Less than 22.5 ug / ml BAC has no impact on Rifampin activity, whereas greater than 45 ug / ml exhibits antibacterial activity. Shown are the antimicrobial properties of 0.005 pg / ml rifampin (loaded in columns 1-12 of a microtiter plate containing media and inoculated with 10,000 viable cells of the bacterial pathogen, Staphylococcus aureus) in the presence of 0, 0.0001, 0.0003, 0.0006, 0.0017, 0.0033, 0.0075, 0.015, 0.033, 0.075, 0.15, and 0.3% polysorbate. Also shown are the antimicrobial properties of 0.005 pg / ml rifampin in the presence of 0, 0.703, 1.406, 2.813, 5.625, 11.25, 22.5 and 45 pg / ml Benzalkonium Chloride (rows). Results show that 0.005 pg / ml rifampin displays antimicrobial effects and inhibits the growth of 5. aureus in the presence of < 0.033% polysorbate (highlighted in green), whereas higher concentrations of polysorbate interfere with the antimicrobial effects of rifampin. Further, polysorbate-associated inactivation of rifampicin occurs in the presence of < 22.5 pg / ml of the common ophthalmic preservative benzalkonium chloride. Finally, < 22.5% benzalkonium chloride has no effect on the effect of rifampin.

[0045] The described features, structures, or characteristics of Applicant’s disclosure may be combined in any suitable manner in one or more embodiments. In the description, herein, numerous specific details are recited to provide a thorough understanding of embodiments of the invention. One skilled in the relevant art will recognize, however, that Applicant’s composition and / or method may be practiced without one or more of the specific details, or with other methods, components, materials, and so forth. In other instances, well-known structures,materials, or operations are not shown or described in detail to avoid obscuring aspects of the disclosure.

[0046] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural reference, unless the context clearly dictates otherwise.

[0047] The term “comprising”, when used to define compositions and methods, is intended to mean that the compositions and methods include the recited elements, but do not exclude other elements. The term “consisting essentially of’, when used to define compositions and methods, shall mean that the compositions and methods include the recited elements and exclude other elements of any essential significance to the compositions and methods. For example, “consisting essentially of’ refers to administration of the pharmacologically active agents expressly recited and excludes pharmacologically active agents not expressly recited. The term consisting essentially of does not exclude pharmacologically inactive or inert agents, e g., pharmaceutically acceptable excipients, carriers or diluents. The term “consisting of’, when used to define compositions and methods, shall mean excluding trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.

[0048] Unless specifically stated or obvious from context, as used herein, the term “about” is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01 % of the stated value. Unless otherwise clear from context, all numerical values provided herein can be modified by the term about.

[0049] The terms “disease”, “disorder” and “condition” are used interchangeably unless indicated otherwise.

[0050] As used herein, the terms "effective amount" or "therapeutically effective amount" refer to that amount of compound(s) or pharmaceutical composition described herein that is sufficient to effect the intended application including, but not limited to, disease treatment, as illustrated below.

[0051] The therapeutically effective amount can vary depending upon the intended application, or the subject and disease condition being treated, e.g., the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the weight and age of the patient, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that will induce a particular response. The specific dose will vary depending on, for example, the particular compounds chosen, the species of subject and their age / existing health conditions or risk for health conditions, the dosing regimen to be followed, the severity of the disease, whether it is administered in combination with other agents, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0052] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described.Methods recited herein may be carried out in any order that is logically possible, in addition to a particular order disclosed.Incorporation by Reference

[0053] References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made in this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material explicitly set forth herein is only incorporated to the extent that no conflict arises between that incorporated material and the present disclosure material. In the event of a conflict, the conflict is to be resolved in favor of the present disclosure as the preferred disclosure.Equivalents

[0054] The representative examples are intended to help illustrate the invention, and are not intended to, nor should they be construed to, limit the scope of the invention. Indeed, various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including the examples and the references to the scientific and patent literature included herein. The examples contain important additional information, exemplification andguidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

What is Claimed is:CLAIMS1. A kit or package comprising: an aqueous first composition comprising polymyxin B / trimethoprim, or pharmaceutically acceptable salts thereof, and a surfactant, wherein the first composition is characterized by a pH in the range from about 4.0 to about 6.5; and a second composition comprising rifampin and mannitol and optionally an antioxidant, wherein the first composition is a sterile aqueous solution, and the second composition is a sterile lyophilized solid or powdery composition.

2. The kit or package of claim 1, wherein polymyxin B is polymyxin B sulfate.

3. The kit or package of claim 1 or 2, wherein trimethoprim is trimethoprim sulfate.

4. The kit or package of any one of claims 1-3, wherein the surfactant is selected from tyloxapol and poloxamer 407.

5. The kit or package of any one of claims 1-3, wherein the surfactant is tyloxapol.

6. The kit or package of any one of claims 1-5, wherein the second composition comprises ascorbic acid, or a salt or ester thereof, as an antioxidant.

7. The kit or package of claim 6, wherein the antioxidant is sodium ascorbate.

8. The kit or package of any one of claims 1-7, one or both of the first and second compositions further comprises an antimicrobial agent.

9. The kit or package of claim 8, wherein the antimicrobial agent is benzalkonium chloride.

10. The kit or package of any one of claims 1 -9, one or both of the first and second compositions further comprises an osmolyte.

11. The kit or package of claim 10, wherein the osmolyte is glycerin.

12. The kit or package of any one of claims 1-11, wherein the first and / or the second composition further comprises one or more pharmaceutically acceptable excipient, carrier, or diluent.

13. A pharmaceutical composition comprising polymyxin B / trimethoprim and a surfactant, wherein polymyxin B is present in the range of about 7,500 units / mL to about 12,500 units / mL; trimethoprim is present in the range of about 0.75 mg / mL to about 1.25 mg / mL; the surfactant is present in the range of about 0.5 mg / mL to about 5.0 mg / mL; and the pharmaceutical composition is a sterile aqueous solution characterized by a pH in the range from about 4.0 to about 6.5.

14. The pharmaceutical composition of claim 13, wherein polymyxin B is present in the range of about 9,000 units / mL to about 11,000 units / mL; trimethoprim is present in the range of about 0.9 mg / mL to about 1.1 mg / mL; and the surfactant is present in the range of about 1.0 mg / mL to about 3.0 mg / mL.

15. The pharmaceutical composition of claim 13 or 14, wherein polymyxin B is polymyxin B sulfate.

16. The pharmaceutical composition of any one of claims 13-15, wherein trimethoprim is trimethoprim sulfate.

17. The pharmaceutical composition of any one of claims 13-16, wherein the surfactant is selected from tyloxapol and poloxamer 407.

18. The pharmaceutical composition of any one of claims 13-17, wherein the surfactant is tyloxapol.

19. The pharmaceutical composition of any one of claims 13-18, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipient, carrier, or diluent.

20. A pharmaceutical composition comprising rifampin, mannitol and an antioxidant, wherein rifampin is present in the range of about 0.2 mg / mL to about 1.0 mg / mL; mannitol is present in the range of about 10 mg / mL to about 60 mg / mL; the antioxidant is present in the range of about 0 mg / mL to about 1.0 mg / mL; and the pharmaceutical composition is a sterile lyophilized solid or powdery mixture.

21. The pharmaceutical composition of claim 20, wherein rifampin is present in the range of about 0.4 mg / mL to about 0.6 mg / mL; mannitol is present in the range of about 15 mg / mL to about 50 mg / mL; and the antioxidant is present in the range of about 0.1 mg / mL to about 1.0 mg / mL.

22. The pharmaceutical composition of claim 20 or 21, wherein the antioxidant is ascorbic acid, or a salt or ester thereof.

23. The pharmaceutical composition of claim 22, wherein the antioxidant is sodium ascorbate.

24. The pharmaceutical composition of any one of claims 13-23, further comprising an antimicrobial agent.

25. The pharmaceutical composition of claim 24, wherein the antimicrobial agent is benzalkonium chloride.

26. The pharmaceutical composition of any one of claims 13-25, further comprising an osmolyte.

27. The pharmaceutical composition of claim 26, wherein the osmolyte is glycerin.

28. The pharmaceutical composition of any one of claims 13-27, wherein the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipient, carrier, or diluent.

29. A pharmaceutical composition comprising the composition of any one of claims 13-19 and the composition of any one of claims 20-28.

30. A method for treating a bacterial ocular infection, comprising administering to a subject in need thereof a therapeutically effective amount of the composition of any one of claims 13-19 and / or the composition of any one of claims 20-28.31 . Use of the composition of any one of claims 13-19 and / or the composition of any one of claims 20-28 for treating a disease or condition.

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