Enhanced preparation of polymyxin B / trimethoprim and rifampicin and eye application method thereof

Abstract

The present invention provides a novel pharmaceutical composition of polymyxin B / trimethoprim and rifampicin, as well as a preparation method and topical ocular application thereof (e.g., treatment of ocular infections).

Description

[0001] Priority claims and related patent applications This application claims priority to U.S. Provisional Application No. 63 / 530,495, filed August 3, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention generally relates to a drug and its preparation and use. More specifically, this invention provides a novel pharmaceutical composition of polymyxin B / trimethoprim and rifampin, its preparation method, and its topical ocular application (e.g., for the treatment of ocular infections). Background Technology

[0003] Bacterial keratitis is a serious visual impairment caused by bacterial infection of the cornea, resulting in nearly 2 million cases of blindness each year. Many Gram-positive and Gram-negative bacteria can cause bacterial keratitis, including but not limited to: gold Staphylococcus aureus, coagulase-negative staphylococci, Streptococcus pneumoniae, Pseudomonas aeruginosa, Moraxella catarrhalis, Serratia marcescens, Corynebacterium, Propionibacterium, Klebsiella, Proteus and Serratia Regardless of the causative agent, the clinical presentation of bacterial keratitis typically includes corneal ulceration, edema, immune infiltration, and anterior chamber inflammation. Although clinicians can perform microbial culture at the initial diagnosis, it often takes several days to identify the specific causative agent, and this test is positive in only 40%–60% of cases. Given that the causative agent is not yet clear at the time of clinical presentation, and bacterial keratitis deteriorates rapidly, immediate broad-spectrum ocular antibiotic treatment targeting both Gram-positive and Gram-negative bacteria is necessary to prevent corneal perforation and / or eye loss. Prescribing antibiotics targeting only one class of Gram-positive or Gram-negative bacteria for bacterial keratitis contradicts current treatment standards. (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(1):22-7. Epub2008 / 02 / 05; Cabrera-Aguas et al. Clin Exp Ophthalmol . 2022;50(5):543-62; Tinget al. Eye (Lond) . 2021;35(4):1084-101; Al-Mujaini et al. Sultan Qaboos Univ Med J . 2009;9(2):184-95; Palioura et al. Clin Ophthalmol. 2016;10:179-86.McLeod et al. Ophthalmology . 1996;103(1):23-8; Levey et al. Cornea . 1997;16(4):383-6.) Fluoroquinolone antibiotics are considered the gold standard for treating bacterial keratitis in the United States due to their broad-spectrum activity, rapid bactericidal action, good patient tolerance, and low cost. In fact, the FDA currently approves only three ophthalmic solutions for treating bacterial keratitis, all of which are fluoroquinolones: 0.3% ciprofloxacin ophthalmic solution or ointment, 0.4% ofloxacin ophthalmic solution, and 1.5% levofloxacin ophthalmic solution.

[0004] While fluoroquinolones can cause various side effects, more importantly, their effectiveness is declining due to the increasing prevalence of drug-resistant bacteria. This has led to a worsening of patients' conditions and poorer vision recovery over the past decade. In fact, levofloxacin, an antibiotic recently approved by the FDA for the treatment of bacterial keratitis, is a third-generation fluoroquinolone and has a resistance rate as high as 71% in ocular isolates of Staphylococcus aureus. (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).) Because of the aforementioned problems with fluoroquinolones, clinicians sometimes resort to off-label treatments or specially formulated antibiotics, such as enhanced aminoglycosides, in combination with enhanced vancomycin or cephalosporins. While these drugs may be effective, their efficacy can vary due to the lack of standardized formulations, and they may be poorly tolerated by patients due to more severe side effects. Furthermore, most patients and doctors do not have access to specialized pharmacy services, especially during times of emergency, making these formulated antibiotics a less reliable treatment option for bacterial keratitis. In addition, treatment with specially formulated antibiotics for bacterial keratitis often requires frequent reconstitution.

[0005] In addition to the availability and effectiveness of broad-spectrum antibiotic treatments, any treatment for bacterial keratitis must be efficiently delivered to patients through pharmacies and the supply chain. Given the urgency of the disease, prescribed medications must be provided to patients within hours of initial diagnosis to ensure effective and timely treatment.

[0006] There is still a need to improve the formulation and administration of drugs used to treat eye infections. Summary of the Invention

[0007] On one hand, the present invention generally relates to a kit or package comprising a first aqueous composition comprising polymyxin B / trimethoprim (PT) or a pharmaceutically acceptable salt thereof, and a surfactant or polymer, wherein the pH of the first composition is in the range of about 4.0 to 6.5; and a second composition comprising rifampin and a solid polyol (mannitol and / or sorbitol), and optionally containing an antioxidant, wherein the first composition is a sterile aqueous solution and the second composition is a sterile lyophilized solid or powder composition.

[0008] On the other hand, the present invention generally relates to a method for treating bacterial eye infections, comprising administering a therapeutically effective amount of the pharmaceutical composition disclosed herein to a subject in need of such treatment. Attached Figure Description

[0009] Figure 1 The results showed that surfactants could alleviate the instability of rifampin in PT caused by polymyxin B.

[0010] Figure 2 The results showed that 1% polyvinyl alcohol (PVA) did not significantly affect the activity of rifampin or the synergistic effect of PT+rifampin.

[0011] Figure 3 The results showed that 2% PVP K30 did not significantly affect the activity of rifampin or the synergistic effect of PT+rifampin.

[0012] Figure 4 The results showed that 0.2% poloxamer 407 did not significantly affect the activity of rifampin or the synergistic effect of PT+rifampin.

[0013] Figure 5 The results showed that 1% tetrabutylphenol did not significantly affect the activity of rifampin or the synergistic effect of PT+rifampin.

[0014] Figure 6 The results showed that polysorbate levels above 0.033% had an adverse effect on rifampicin activity. Detailed Implementation

[0015] This invention provides an enhanced pharmaceutical formulation, an optimized storage method, and a method of ocular application (e.g., bacterial keratitis, surgical prevention, bacterial conjunctivitis, and artificial cornea).

[0016] Pharmacies and their supply chains must be able to: (1) receive and transfer formulations in a safe and secure manner; (2) store component raw materials or final products for a sufficient shelf life; and (3) rapidly and reproducibly prepare a variety of therapeutic agents to achieve effective and efficient supply.

[0017] Routine treatment for bacterial keratitis typically begins immediately after diagnosis and lasts for weeks to months. Because the disease can worsen rapidly, medication may be administered hourly for the first few days, gradually reducing to 8 or 12 times daily, then to 4 times daily, and finally to once or twice daily. Due to the need for frequent application, patients will apply the solution, ointment, or other treatments to the affected eye wherever they are, such as at home or at work. Therefore, patients need to be able to easily and effectively prepare and administer the treatment themselves in various locations and situations. Consequently, any steps required by the patient must be simple and easy to perform.

[0018] Extensive peer-reviewed literature documents and demonstrates that the combination of polymyxin B / trimethoprim (PT) and rifampin (Rif) is a synergistic broad-spectrum antibiotic capable of rapid bactericidal action, effective against established bacterial biofilms, and curative for keratitis in animal models of Gram-positive and / or Gram-negative bacterial keratitis. US Patent 11,096,923 B2 discloses the use of polymyxin B / trimethoprim + rifampin (PT+Rif) as a synergistic antibiotic combination. (Laskey et al.) Cornea . 2020 Oct;39(10):1278-1284; Chojnacki etal. Antimicrob Agents Chemother. 2018 Dec 21;63(1):e01929-18; Chojnacki et al. Antimicrob Agents Chemother . 2019 Sep 23;63(10):e00777-19; Meijome etal. Transl Vis Sci Technol . 2022 Nov 1;11(11):12; Mei et al. Transl Vis Sci Technol . 2022 May 2;11(5):26.) This invention discusses details of the preparation and formulation of pharmaceuticals for the delivery and treatment of ocular infections, including but not limited to: bacterial keratitis, surgical prophylaxis, bacterial conjunctivitis, artificial corneas, and others.

[0019] On one hand, the present invention generally relates to a kit or package comprising a first aqueous composition containing PT or a pharmaceutically acceptable salt thereof and a surfactant or polymer, wherein the pH of the first composition is about 4.0 to 6.5; and a second composition containing rifampin and a solid polyol (mannitol and / or sorbitol), and optionally containing an antioxidant, wherein the first composition is a sterile aqueous solution and the second composition is a sterile lyophilized solid or powder composition.

[0020] PT+Rif can be formulated as a two-component formulation that is combined at the point of use via a packaging system (e.g., a two-chamber vial or eye dropper). Separating PT and Rif into two different chambers within the same dosing packaging system extends the shelf life of the unmixed components and facilitates on-site reconstitution and delivery (for patient use). Additional compounds can be added to the portions containing the active ingredient to further stabilize the solution after mixing. PT is typically supplied as a solution, while Rif can be added as a powder / cake or solid formulation for reconstitution. Sterile powders can be prepared via spray drying.

[0021] On the other hand, the present invention generally relates to a pharmaceutical composition comprising PT and a surfactant, wherein polymyxin B sulfate is approximately 7500 units / mL to 12500 units / mL; trimethoprim sulfate is approximately 0.75 mg / mL to 1.25 mg / mL; the surfactant is approximately 0.5 mg / mL to 5.0 mg / mL; and the pharmaceutical composition is a sterile aqueous solution with a pH of approximately 4.0 to 6.5.

[0022] In another aspect, the present invention generally relates to a pharmaceutical composition comprising rifampin, mannitol and an antioxidant, wherein the rifampin is about 0.2 mg / mL to 1.0 mg / mL; the mannitol is about 10 mg / mL to 60 mg / mL; the antioxidant is about 0 mg / mL to 1.0 mg / mL; and the pharmaceutical composition is a sterile lyophilized solid or powder mixture.

[0023] On the other hand, the present invention generally relates to a reconstituted pharmaceutical composition prepared by mixing a composition of PT and a surfactant with a composition of Rif, mannitol and an antioxidant.

[0024] In another aspect, the present invention generally relates to a method for treating bacterial eye infections, comprising administering to a subject in need a therapeutically effective amount of the pharmaceutical composition disclosed herein.

[0025] In another respect, the present invention generally relates to the use of the compositions disclosed herein in the treatment of diseases or conditions (e.g., bacterial eye infections).

[0026] The following examples are for illustrative purposes only and are not intended to limit the scope or spirit of the invention.

[0027] Example Solution stability The ophthalmic formulation contains trimethoprim sulfate (1 mg / mL), polymyxin B sulfate (10,000 units / mL), and rifampin (0.5 mg / mL). The combination of trimethoprim sulfate and polymyxin B sulfate is currently marketed (Polytrim) and is stable at room temperature. Rifampin is available as oral capsules and as a lyophilized powder for reconstitution and intravenous administration. Due to the poor solution stability of rifampin compounds, its intravenous solution must be used as soon as possible after reconstitution.

[0028] The addition of surfactants improves solution stability. Approved surfactants for ocular use include: octyloxyl-40, nonoxyl-9, poloxamer 188, poloxamer 407, PEG-35 castor oil, PEG-40 hydrogenated castor oil, PEG-40 stearate, polysorbate 80, and tetrabutylphenol. The surfactant concentration is 0.05-0.3% w / w. Approved polymers include polyvinylpyrrolidone (polyvinyl alcohol, or PVP), polyvinyl alcohol (PVA), and modified cellulose. Polymer concentrations can be up to 2% w / w. PVA and PVP do not inhibit the activity of rifampin.

[0029] freeze drying method Commercially available rifampicin lyophilized formulations contain sodium formaldehyde sulfoxylate and sodium hydroxide to adjust the pH. Sodium formaldehyde sulfoxylate can improve the solubility of lyophilized blocks by forming a salt with rifampicin, but it is not approved for use in the eyes.

[0030] During the freeze-drying experiment, it was found that adding mannitol (mannitol:rifampicin ratio of 1:1 w / w to 10:1 w / w) to the freeze-dried formulation significantly improved the reconstitution effect of the freeze-dried blocks compared with pure rifampicin freeze-dried blocks.

[0031] Antioxidants, such as ascorbic acid (or its salts and esters), can be added to lyophilized formulations. This improves the solid-state stability of rifampin in lyophilized blocks or other solid formulations, as well as its solution stability after reconstitution.

[0032] In excipient screening studies, it was found that the surfactant polysorbate 80 inhibited the antimicrobial activity of rifampin. Surprisingly, the surfactants tetrabutylphenol and poloxamer 407 did not inhibit the antimicrobial activity of rifampin.

[0033] Exemplary reconstituted pharmaceutical compositions: Other optional 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 Possible solid formulations (dosage per vial reconstituted to 1 mL): ●0.5 mg rifampin ●10-50 mg mannitol ●0-1 mg ascorbic acid ●0-30 mg povidone ● 0-5 mg poloxamer 407 or 188 ● 0-60 mg polyvinyl alcohol Figure 1 The results showed that surfactants could alleviate the rifampicin instability caused by polymyxin B in PT. Figure 1 A shows the degradation curves of rifampin in the presence of trimethoprim and rifampin B at 25°C, indicating that rifampin is unstable in the presence of polymyxin B. Figure 1 B shows the degradation curves of rifampin, rifampin in the presence of polymyxin B, rifampin in the presence of PT (polymyxin B + trimethoprim) with added polysorbate 80, and rifampin in the presence of PT (polymyxin B + trimethoprim) with added tetrabutylphenol alcohol, indicating that surfactants such as tetrabutylphenol alcohol and polysorbate esters can stabilize rifampin at 5°C. Figure 5 and Figure 6 As shown, rifampin retains its activity in the presence of tetrabutylphenol, but loses its antimicrobial activity in the presence of polysorbate.

[0034] Figure 2The results showed that 1% polyvinyl alcohol (PVA) did not significantly affect the activity of rifampin or the synergistic effect of PT + rifampin. The antimicrobial properties are illustrated in the figure below, showing the antimicrobial properties of different concentrations (0, 0.0006, 0.0012, 0.0025, 0.005, 0.01, 0.02, 0.4, 0.08, 0.16, 0.32, and 64 µg / ml) of rifampin added to columns 1-12 of a microplate containing medium supplemented with 1% PVA and inoculated with 10,000 live pathogenic cells, namely Staphylococcus aureus. The figure also shows the antimicrobial properties of different concentrations of PT (0, 0.26, 0.53, 1.10, 2.10, 4.20, and 8.40 µg / ml) applied to each row of the plate. In the absence of PT (row A), only 0.0025 µg / ml rifampicin was sufficient to inhibit the growth of Staphylococcus aureus (this well in row A is highlighted in green). In the absence of rifampicin (column 1), only 0.53 µg / ml PT was sufficient to inhibit the growth of Staphylococcus aureus (highlighted in green in column 1). When used in combination, 0.0012 µg / ml rifampicin and 0.26 µg / ml PT were sufficient to inhibit the growth of Staphylococcus aureus (highlighted in red), indicating that the combination of PT and rifampicin has synergistic antimicrobial activity in the presence of 1% PVA.

[0035] Figure 3 The results showed that 2% PVP K30 did not significantly affect the activity of rifampin or the synergistic effect of PT + rifampin. The antimicrobial properties are illustrated in the figure below, showing the antimicrobial properties of different concentrations (0, 0.0006, 0.0012, 0.0025, 0.005, 0.01, 0.02, 0.4, 0.08, 0.16, 0.32, and 64 µg / ml) of rifampin added to columns 1-12 of a microplate containing medium supplemented with 2% PVP K30 and inoculated with 10,000 live pathogenic cells, namely Staphylococcus aureus. The figure also shows the antimicrobial properties of different concentrations of PT (0, 0.26, 0.53, 1.10, 2.10, 4.20, and 8.40 µg / ml) applied to each row of the plate. In the absence of PT (row A), only 0.0025 µg / ml rifampicin was sufficient to inhibit the growth of Staphylococcus aureus (this well in row A is highlighted in green). In the absence of rifampicin (column 1), only 0.53 µg / ml PT was sufficient to inhibit the growth of Staphylococcus aureus (highlighted in green in column 1). When used in combination, 0.0012 µg / ml rifampicin and 0.53 µg / ml PT were sufficient to inhibit the growth of Staphylococcus aureus (highlighted in red), indicating that the combination of PT and rifampicin has synergistic antimicrobial activity in the presence of 2% PVP K30.

[0036] Figure 4 The results showed that 0.2% poloxamer 407 did not significantly affect the activity of rifampin or the synergistic effect of PT + rifampin. The antimicrobial properties are illustrated in the figure below, showing the antimicrobial properties of different concentrations (0, 0.0006, 0.0012, 0.0025, 0.005, 0.01, 0.02, 0.4, 0.08, 0.16, 0.32, and 64 µg / ml) of rifampin added to columns 1-12 of a microplate containing medium supplemented with 0.2% poloxamer 407 and inoculated with 10,000 live pathogenic cells, namely Staphylococcus aureus. The figure also shows the antimicrobial properties of different concentrations of PT (0, 0.26, 0.53, 1.10, 2.10, 4.20, and 8.40 µg / ml) applied to each row of the plate. In the absence of PT (row A), only 0.005 µg / ml rifampin was sufficient to inhibit the growth of Staphylococcus aureus (this well in row A is highlighted in green). In the absence of rifampin (column 1), only 1.06 µg / ml PT was sufficient to inhibit the growth of Staphylococcus aureus (highlighted in green in column 1). When used in combination, 0.0012 µg / ml rifampin and 0.53 µg / ml PT were sufficient to inhibit the growth of Staphylococcus aureus (highlighted in red), indicating that the combination of PT and rifampin has synergistic antimicrobial activity in the presence of 0.2% poloxamer 407.

[0037] Figure 5The results showed that 1% tetrabutylphenol did not significantly affect the activity of rifampin or the synergistic effect of PT + rifampin. The antimicrobial properties are illustrated in the figure below: different concentrations (0, 0.0006, 0.0012, 0.0025, 0.005, 0.01, 0.02, 0.4, 0.08, 0.16, 0.32, and 64 µg / ml) of rifampin were added to columns 1-12 of a microplate containing medium supplemented with 1% tetrabutylphenol and inoculated with 10,000 live pathogenic cells, namely Staphylococcus aureus. The figure also shows the antimicrobial properties of different concentrations of PT (0, 0.26, 0.53, 1.10, 2.10, 4.20, and 8.40 µg / ml) applied to each row of the plate. In the absence of PT (row A), only 0.005 µg / ml rifampin was sufficient to inhibit the growth of Staphylococcus aureus (this well in row A is highlighted in green). In the absence of rifampin (column 1), only 1.06 µg / ml PT was sufficient to inhibit the growth of Staphylococcus aureus (highlighted in green in column 1). When used in combination, 0.0012 µg / ml rifampin and 0.53 µg / ml PT were sufficient to inhibit the growth of Staphylococcus aureus (highlighted in red), indicating that the combination of PT and rifampin has synergistic antimicrobial activity in the presence of 1% tetrabutylphenol.

[0038] Figure 6The results showed that polysorbate concentrations above 0.033% adversely affected rifampicin activity: BAC concentrations below 22.5 µg / ml did not affect rifampicin activity, while BAC concentrations above 45 µg / ml exhibited antimicrobial activity. The figure illustrates the following antimicrobial properties: antimicrobial properties of 0.005 µg / ml rifampicin (added to columns 1-12 of a microplate containing culture medium and inoculated with 10,000 live pathogenic cells, i.e., 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. The figure also shows the antimicrobial properties of 0.005 µg / ml rifampin in the presence of benzalkonium chloride (each row). The results indicate that 0.005 µg / ml rifampin exhibits antimicrobial activity and inhibits the growth of Staphylococcus aureus in the presence of ≤0.033% polysorbate (highlighted in green), while higher concentrations of polysorbate weaken the antimicrobial activity of rifampin. Furthermore, polysorbate still inactivates rifampin in the presence of the commonly used ophthalmic preservative benzalkonium chloride at ≤22.5 µg / ml. Finally, ≤22.5% benzalkonium chloride has no effect on the activity of rifampin.

[0039] The features, structures, or characteristics described in the applicant's disclosure may be combined in any suitable manner in one or more embodiments. Numerous specific details are set forth herein to provide a thorough understanding of embodiments of the invention. However, those skilled in the art will recognize that the applicant's compositions and / or methods may be practiced without one or more specific details, or using other methods, components, materials, etc. In other instances, well-known structures, materials, or operations have not been shown or described in detail to avoid obscuring aspects of this disclosure.

[0040] In this specification and the appended claims, the singular forms “a,” “the,” and “the” include plural references unless the context clearly indicates otherwise.

[0041] When the term "comprising" is used to define a composition and method, it means that the composition and method include the listed elements, but does not exclude other elements. When the term "consisting essentially of" is used to define a composition and method, it means that the composition and method include the listed elements and excludes other elements that are of any substantial significance to the composition and method. For example, "consisting essentially of" means the application of a pharmacologically active agent that is explicitly listed, and excludes pharmacologically active agents that are not explicitly listed. The term "consisting essentially of" does not exclude pharmacologically inactive or inert agents, such as pharmaceutically acceptable excipients, carriers, or diluents. When the term "consisting of" is used to define a composition and method, it means the exclusion of trace elements of other components and substantial method steps. The embodiments defined by the above transitional terms are all within the scope of this invention.

[0042] Unless otherwise expressly stated or obvious from the context, the term "about" as used herein shall be understood to mean a normal tolerance range in the art, such as 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. All numerical values ​​provided herein may be modified by the term "about" unless otherwise clearly stated from the context.

[0043] Unless otherwise stated, the terms “disease,” “symptom,” and “condition” are used interchangeably.

[0044] As used herein, the terms “effective amount” or “therapeutic effective amount” refer to an amount of compound or pharmaceutical composition described herein sufficient to achieve the intended application, including but not limited to the treatment of diseases as described below.

[0045] Therapeutic effective doses can vary depending on the intended application or the subject and the disease condition being treated, such as the desired biological endpoint, the pharmacokinetic properties of the compound, the disease being treated, the route of administration, and the patient's weight and age. A person skilled in the art can readily determine the therapeutically effective dose. This term also applies to doses capable of inducing a specific response. Specific doses will vary depending on, for example, the specific compound used, the subject's species and age / pre-existing health condition or risk of developing a health condition, the dosing regimen followed, the severity of the disease, whether it is administered in combination with other agents, the timing of administration, the tissue of administration, and the physical delivery system used.

[0046] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While the contents of this disclosure may be practiced or tested using methods and materials similar to or equivalent to those described herein, preferred methods and materials are described hereafter. Except for the specific order disclosed, the methods described herein may be performed in any logically feasible order.

[0047] By incorporating via reference This disclosure references and mentions other documents, such as patents, patent applications, patent publications, journals, books, papers, and online content. All of the aforementioned documents are incorporated herein by reference in their entirety for all purposes. If any of the cited materials or portions thereof conflict with any existing definitions, statements, or other disclosures expressly provided herein, they will be incorporated only if there is no conflict between the cited materials and this disclosure. In the event of a conflict, the conflict will be resolved in a manner favorable to this application, and the disclosure favorable to this application will be considered the preferred embodiment.

[0048] equivalent The representative embodiments are intended to help illustrate the invention and are not intended to limit the scope of the invention, nor should they be construed as limiting the scope of the invention. In fact, in addition to the embodiments shown and described herein, various modifications and further embodiments of the invention will be readily apparent to those skilled in the art from the entirety of this document, including the embodiments and references to scientific and patent literature. These embodiments contain important additional information, examples, and guidance applicable to different embodiments of the invention and their equivalents.

Claims

1. A kit or package, characterized in that, include: A first aqueous composition comprising polymyxin B / trimethoprim, or a pharmaceutically acceptable salt thereof, and a surfactant; wherein the pH of the first composition is approximately 4.0-6.5; and The second composition includes rifampin and mannitol, and optionally contains an antioxidant; Wherein, the first composition is a sterile aqueous solution, and the second composition is a sterile lyophilized solid or powder composition.

2. The kit or package according to claim 1, characterized in that, The polymyxin B mentioned is polymyxin B sulfate.

3. The kit or package according to any one of claims 1 or 2, characterized in that, The trimethoprim is trimethoprim sulfate.

4. The kit or package according to any one of claims 1-3, characterized in that, The surfactant is selected from tetrabutylphenol and poloxamer 407.

5. The kit or package according to any one of claims 1-3, characterized in that, The surfactant is tetrabutylphenol alcohol.

6. The kit or package according to any one of claims 1-5, characterized in that, The second composition includes ascorbic acid or its salt or ester as an antioxidant.

7. The kit or package according to claim 6, characterized in that, The antioxidant is sodium ascorbate.

8. The kit or package according to any one of claims 1-7, characterized in that, At least one of the first composition and the second composition further comprises an antimicrobial agent.

9. The kit or package according to claim 8, characterized in that, The antimicrobial agent is benzalkonium chloride.

10. The kit or package according to any one of claims 1-9, characterized in that, At least one of the first composition and the second composition further comprises a osmosis regulator.

11. The kit or package according to claim 10, characterized in that, The osmotic regulator is glycerin.

12. The kit or package according to any one of claims 1-11, characterized in that, The first composition and / or the second composition further comprise one or more pharmaceutically acceptable excipients, carriers, or diluents.

13. A pharmaceutical composition, characterized in that, Including polymyxin B / trimethoprim and surfactants, Among them, polymyxin B is approximately 7500 units / mL to 12500 units / mL; The concentration of trimethoprim is approximately 0.75 mg / mL to 1.25 mg / mL; The surfactant is approximately 0.5 mg / mL to 5.0 mg / mL; and The pharmaceutical composition is a sterile aqueous solution with a pH value of approximately 4.0 to 6.

5.

14. The pharmaceutical composition according to claim 13, characterized in that, Polymyxin B is approximately 9000 units / mL to 11000 units / mL; The trimethoprim is approximately 0.9 mg / mL to 1.1 mg / mL; and The surfactant is approximately 1.0 mg / mL to 3.0 mg / mL.

15. The pharmaceutical composition according to claim 13 or 14, characterized in that, The polymyxin B mentioned is polymyxin B sulfate.

16. The pharmaceutical composition according to any one of claims 13-15, characterized in that, The trimethoprim is trimethoprim sulfate.

17. The pharmaceutical composition according to any one of claims 13-16, characterized in that, The surfactant is selected from tetrabutylphenol and poloxamer 407.

18. The pharmaceutical composition according to any one of claims 13-17, characterized in that, The surfactant is tetrabutylphenol alcohol.

19. The pharmaceutical composition according to any one of claims 13-18, characterized in that, The pharmaceutical composition further includes one or more pharmaceutically acceptable excipients, carriers, or diluents.

20. A pharmaceutical composition, characterized in that, Including rifampin, mannitol, and antioxidants, Rifampin concentration ranges from approximately 0.2 mg / mL to 1.0 mg / mL. Mannitol is approximately 10 mg / mL to 60 mg / mL; The antioxidant is approximately 0 mg / mL to 1.0 mg / mL; Furthermore, the pharmaceutical composition is a sterile lyophilized solid or a powder mixture.

21. The pharmaceutical composition according to claim 20, characterized in that, Rifampin concentration is approximately 0.4 mg / mL to 0.6 mg / mL; Mannitol is approximately 15 mg / mL to 50 mg / mL; The antioxidant is approximately 0.1 mg / mL to 1.0 mg / mL.

22. The pharmaceutical composition according to claim 20 or 21, characterized in that, The antioxidant is ascorbic acid or its salt or ester.

23. The pharmaceutical composition according to claim 22, characterized in that, The antioxidant is sodium ascorbate.

24. The pharmaceutical composition according to any one of claims 13-23, characterized in that, The pharmaceutical composition further includes an antimicrobial agent.

25. The pharmaceutical composition according to claim 24, characterized in that, The antimicrobial agent is benzalkonium chloride.

26. The pharmaceutical composition according to any one of claims 13-25, characterized in that, The pharmaceutical composition further includes an osmosis regulator.

27. The pharmaceutical composition according to claim 26, characterized in that, The osmotic regulator is glycerin.

28. The pharmaceutical composition according to any one of claims 13-27, characterized in that, The pharmaceutical composition further includes one or more pharmaceutically acceptable excipients, carriers, or diluents.

29. A pharmaceutical composition, characterized in that, Includes the compositions of any one of claims 13-19 and any one of claims 20-28.

30. A method for treating bacterial eye infections, characterized in that, This includes administering to a subject in need 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. An application characterized in that, It refers to the use of the composition according to any one of claims 13-19 and / or the composition according to any one of claims 20-28 in the treatment of diseases or conditions.

Images