WO2024221162A1 - Method for preventing prosthetic joint infection by using compound - Google Patents

Abstract

The present application provides a method for preventing prosthetic joint infection (PJI). The method comprises administering at least one intravenous infusion of a therapeutic agent to a subject in need, wherein the therapeutic agent comprises about 100 mg to about 500 mg of a compound represented by formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated compound thereof, and a single intravenous infusion lasts for about 20 minutes to about 3 hours.

Description

Method for preventing periprosthetic joint infection using compounds Technical Field

The present application relates to the field of biomedicine, and specifically to a method and use of a compound to prevent infection around joint prostheses.

Background Art

Artificial joint replacement, which involves surgical implantation of prostheses to replace joints that are painful and unable to function normally due to arthritis, joint diseases, osteoarthritis, rheumatoid arthritis, etc., is being widely used in clinical practice as an effective treatment method. Prosthetic joint infection (PJI) is a serious complication of total hip arthroplasty (THA) and total knee arthroplasty (TKA), which can lead to complete failure of the operation, resulting in joint dysfunction of the affected limb, and even amputation or death in severe cases. The pathogenesis of PJI is mainly related to biofilm infection, with an incidence of 0.5% to 1.2% and 0.5% to 1.6%, respectively; and with the increase in the number of patients undergoing joint replacement, the number of PJI patients is increasing. However, the treatment of PJI is quite difficult, requiring multiple surgical revisions and long-term systematic antibiotic treatment. Patients are repeatedly hospitalized and have long-term mobility problems, which seriously affects their quality of life. The medical expenses are several times or even dozens of times higher than those of patients without PJI. At the same time, cases of treatment failure are also relatively common. In view of the above reasons, avoiding the risk factors that lead to PJI before and after surgery and preventing the occurrence of PJI are undoubtedly more desirable solutions, especially for some susceptible populations. The most commonly used clinical measures to prevent periprosthetic infection include: controlling susceptibility factors and preventing the use of antibiotics. The former includes preoperative treatment of potential infectious lesions, intraoperative use of pulse irrigation of wounds and osteotomy surfaces, etc.; the latter includes preoperative prophylactic use of intravenous antibiotics, premixing antibiotics in the cement of cement-type joints, etc. For the preventive use of antibiotics, there is currently no particularly effective means, and there is still a lack of unified implementation standards or research conclusions on the timing of antibiotic use, the best course of treatment and dosage, and the route of administration. Therefore, this field urgently needs to update a precise and effective method to prevent PJI and its related biofilm infections.

Summary of the invention

In order to overcome the shortcomings of the prior art in preventing periprosthetic joint infection, the present invention provides an effective and safe prevention method, and the use of the compound represented by formula (I) for preparing an intravenous infusion therapeutic agent for preventing periprosthetic joint infection.

On the one hand, the present application provides a method for preventing periprosthetic joint infection (PJI), the method comprising intravenously infusing at least one therapeutic agent to a subject in need thereof, wherein the therapeutic agent comprises about 100 mg to about 500 mg of a compound represented by formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof, and the single intravenous infusion lasts for about 20 minutes to about 3 hours.

In some embodiments, the single intravenous infusion lasts for 60 ± 10 minutes.

In some embodiments, the therapeutic agent comprises about 200 mg to about 400 mg of the compound of formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof.

In some embodiments, the therapeutic agent comprises about 300 mg of the compound of formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof.

In some embodiments, the method comprises administering the intravenous infusion once daily or twice daily.

In some embodiments, the two daily intravenous infusions are separated by about 12 hours.

In some embodiments, the method comprises administering the intravenous infusion at least once a day for 1 to 14 days.

In some embodiments, the first day of the duration of 1 to 14 days is the day on which the subject receives artificial joint prosthesis replacement surgery.

In some embodiments, the periprosthetic joint infection is caused by a Gram-positive bacterial infection.

In some embodiments, the periprosthetic joint infection is caused by Staphylococcus aureus and/or coagulase-negative staphylococcal infection.

In some embodiments, the periprosthetic joint infection (PJI) comprises early PJI, acute hematogenous PJI, and chronic PJI.

In some embodiments, the periprosthetic joint infection is an early PJI occurring within about 3 months after the subject receives artificial joint prosthesis replacement surgery or an acute hematogenous PJI occurring within about 4 weeks after the surgery.

In some embodiments, the therapeutic agent further comprises other components selected from other drugs, pharmaceutically acceptable carriers, solvents, and buffers.

In some embodiments, the compound of formula (I) and the other components are not mixed with each other.

In some embodiments, the compound of formula (I) and one or more of the other components are mixed with each other.

In some embodiments, the method further comprises administering to the subject in need thereof an effective amount of an additional therapeutic agent.

On the other hand, the present application provides the use of a compound represented by formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance thereof in the preparation of an intravenous infusion therapeutic agent, wherein the therapeutic agent is used to prevent periprosthetic joint infection; and a unit dose of the intravenous infusion therapeutic agent contains about 100 mg to about 500 mg of a compound represented by formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance thereof, and is formulated to be suitable for administration to a subject in need thereof with a single infusion time of about 20 minutes to about 3 hours.

In some embodiments, the therapeutic agent is formulated for administration to the subject as a single infusion time of 60 ± 10 minutes.

In some embodiments, a unit dose of the therapeutic agent comprises about 200 mg to about 400 mg of a compound of formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof.

In some embodiments, a unit dose of the therapeutic agent comprises about 300 mg of the compound of formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof.

In some embodiments, the therapeutic agent comprises the unit dosage amount suitable for providing once daily or twice daily intravenous infusion.

In some embodiments, the therapeutic agent comprises the unit dosage suitable for providing twice daily intravenous infusions, and the interval between the twice daily intravenous infusions is about 12 hours.

In some embodiments, the therapeutic agent comprises the unit dosage suitable for providing intravenous infusion at least once a day for 1-14 days.

In some embodiments, the first day of the duration of 1 to 14 days is the day on which the subject receives artificial joint prosthesis replacement surgery.

In some embodiments, the periprosthetic joint infection is caused by a Gram-positive bacterial infection.

In some embodiments, the periprosthetic joint infection is caused by Staphylococcus aureus and/or coagulase-negative staphylococcal infection.

In some embodiments, the periprosthetic joint infection (PJI) comprises early PJI, acute hematogenous PJI, and chronic PJI.

In some embodiments, the periprosthetic joint infection is an early PJI occurring within about 3 months after the subject receives artificial joint prosthesis replacement surgery or an acute hematogenous PJI occurring within about 4 weeks after the surgery.

In some embodiments, the therapeutic agent further comprises other components selected from other drugs, pharmaceutically acceptable carriers, solvents, and buffers.

In some embodiments, the compound of formula (I) and the other components are not mixed with each other.

In some embodiments, the compound of formula (I) and one or more of the other components are mixed with each other.

In some embodiments, the therapeutic agent is formulated for co-administration with an effective amount of another therapeutic agent to the subject in need thereof.

DETAILED DESCRIPTION

The following is an explanation of the implementation of the present invention by means of specific embodiments. Those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification.

Definition of terms

In this application, the term "subject in need thereof" may generally include those already suffering from a disorder as well as those in whom the disorder is to be prevented, and may specifically refer to human and other mammalian subjects receiving preventive or therapeutic treatment.

In this application, the term "therapeutic agent" generally refers to a compound, mixture of compounds, composition, biomacromolecule, or extract made from biological material that is capable of inducing a desired therapeutic effect when properly administered to a subject.

In the present application, the term "pharmaceutically acceptable salt" generally refers to conventional acid- or base-addition salts that retain the biological efficacy and properties of the parent compound, such as the compound shown in formula (I). By way of example only, acid-addition salts can be formed from suitable non-toxic organic or inorganic acids, sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, aminosulfonic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoroacetic acid, etc.; base-addition salts include salts such as sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts and magnesium salts derived from inorganic bases, and salts such as primary amines, secondary amines and tertiary amines derived from organic bases. Chemical modification of (drug) compounds into salts is a well-known technique for pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, fluidity and solubility of the compounds. See, e.g., Ansel, H., et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed., 1995.

In the present application, the terms "solvate" and "solvate" are used interchangeably and generally refer to an association or complex of one or more solvent molecules and a salt-type compound of the present application. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" generally refers to a complex in which the solvent molecule is water.

In the present application, the term "prodrug" generally refers to the prodrug substance that can be metabolized to form a substance having the structure of the compound of the present application after being administered to a subject; the term "metabolite" generally refers to the substance obtained by the metabolism of the compound of the present application after being administered to a subject, and the prodrugs and metabolites contained in such derivatives are included in the scope of the invention of the present application.

In the present application, the terms "deuterated substance" and "deuterated compound" are used interchangeably, and generally refer to a new compound obtained after one or more hydrogen atoms in an organic compound are replaced by deuterium atoms.

In the present application, the term "appearance..." generally refers to a subject or an observed person showing clinical signs related to a specific disease, for example, in the present application, it may refer to showing clinical signs related to early, acute hematogenous or chronic periprosthetic joint infection.

In this application, the term "drug" generally refers to a molecule with a desired biological effect. The drug can be preventive or therapeutic. The drug may include, but is not limited to: protein molecules, including but not limited to peptides, polypeptides, proteins, including post-translationally modified proteins, fusion proteins, antibodies, etc.; small molecules (less than 1000 Daltons), including inorganic or organic compounds; nucleic acid molecules, including but not limited to double-stranded or single-stranded DNA, or double-stranded or single-stranded RNA (such as antisense (molecules), RNAi, etc.), intron sequences, triple-helix nucleic acid molecules and aptamers; or vaccines (such as Lister and non-Lister vaccines). The drug can be obtained from any known organism (including but not limited to: animals, plants, bacteria, fungi and protozoa or viruses) or synthetic molecule libraries.

In the present application, the term "pharmaceutically acceptable carrier" generally refers to one or more non-toxic materials that do not interfere with the effectiveness of the biological activity of the active ingredient. Such preparations can conventionally contain salts, buffers, preservatives, compatible carriers, and optionally other therapeutic agents. Such pharmaceutically acceptable preparations can also include compatible solid or liquid fillers, diluents or encapsulated materials suitable for administration to people. Other envisioned carriers, excipients, and/or additives that can be used in the formulations described herein may include, for example, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, lipids, protein excipients (such as serum albumin, gelatin, casein), salt-forming counterions (such as sodium), etc. These and other known pharmaceutical carriers, excipients and/or additives suitable for use in the formulations described herein are known in the art, for example, as listed in "Remington: The Science & Practice of Pharmacy", 21st edition, Lippincott Williams & Wilkins (2005) and "Physician's Desk Reference", 60th edition, Medical Economics, Montvale, New Jersey (2005). Suitable pharmaceutically acceptable carriers can be routinely selected for the desired or required mode of administration, solubility and/or stability.

In this application, the term "mixing" generally refers to the process of combining one or more compounds, cells, molecules, etc. in the same area. This can be done, for example, in a test tube, a petri dish, or any container that allows mixing of one or more compounds, cells or molecules.

In this application, the term "unit dose" when used to refer to the compounds of the present invention generally refers to substantially discrete units suitable as unitary dosages for subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the necessary diluents, such as carriers or excipients.

In the present application, the term "comprising" generally refers to including the features explicitly specified, but not excluding other elements. The terms "above" and "below" generally refer to the case where the number is inclusive.

In this application, the term "selected from" generally refers to including selected objects and all combinations thereof. For example, "selected from (:) A, B and C" means including all combinations of A, B and C, for example, A, B, C, A+B, A+C, B+C or A+B+C.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present application provides a method for preventing periprosthetic joint infection (PJI), the method comprising intravenously infusing at least one therapeutic agent to a subject in need thereof, the therapeutic agent comprising about 100 mg to about 500 mg of a compound represented by formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance thereof, and the single intravenous infusion lasts for about 20 minutes to about 3 hours,

For example, the therapeutic agent may contain about 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg or 500mg. Further, in some embodiments, the therapeutic agent may comprise about 200mg to about 400mg of the compound shown in formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance. For example, the therapeutic agent may contain about 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg of the compound of formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance. Exemplarily, the therapeutic agent may contain about 300 mg of the compound shown in formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance.

For example, the single infusion time that the intravenous infusion can last for about 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes (1 hour), 70 minutes, 80 minutes, 90 minutes, 100 minutes, 110 minutes, 120 minutes (2 hours), 130 minutes, 140 minutes, 150 minutes, 160 minutes, 170 minutes or 180 minutes (3 hours). Further, in some embodiments, the single intravenous infusion can last for 60±10 minutes. For example, the single infusion time that the intravenous infusion can last for about 50 minutes, 51 minutes, 52 minutes, 53 minutes, 54 minutes, 55 minutes, 56 minutes, 57 minutes, 58 minutes, 59 minutes, 60 minutes, 61 minutes, 62 minutes, 63 minutes, 64 minutes, 65 minutes, 66 minutes, 67 minutes, 68 minutes, 69 minutes or 70 minutes.

In some embodiments, the method may include once daily intravenous infusion; in other embodiments, the method may include twice daily intravenous infusion. For example, the method may include twice daily intravenous infusion, and the interval between the two daily intravenous infusions is about 12 hours.

In some embodiments, the method includes at least one intravenous infusion per day, and lasts for 1 day to 14 days. For example, the intravenous infusion at least once a day can last for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days or 14 days. For example, the method may include performing one intravenous infusion per day during the continuous period of 1 day to 14 days, and the intravenous infusion may be performed at the same time period or at different time periods every day. For example, the method may include performing two intravenous infusions per day during the continuous period of 1 day to 14 days, and the interval between the two intravenous infusions may be about 12 hours, and the intravenous infusion may be performed at the same time period or at different time periods every day. For example, the first day of the continuous period of 1 day to 14 days is the day when the subject receives artificial joint prosthesis replacement surgery.

The pathogenic bacteria spectrum of periprosthetic joint infection is complex and may be caused by a single pathogen or a mixed infection of multiple pathogens. In some embodiments, the subject may be a subject suffering from periprosthetic joint infection caused by Gram-positive bacteria. For example, the subject may be a subject suffering from periprosthetic joint infection caused by Staphylococcus aureus and/or coagulase-negative Staphylococcus. The subject of periarticular infection of prosthesis. Specifically, the coagulase-negative staphylococcus can be selected from Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus xylinus, Staphylococcus haemolyticus, Staphylococcus capitis, Staphylococcus warneri, Staphylococcus mimicus, Staphylococcus xylosus and Staphylococcus apes. In the present application, the gram-positive bacteria can also include its resistant strains, for example, the resistant strains can be single-resistant to rifamycin (for example, rifampicin), single-resistant to quinolone or quinolones, or double-resistant to rifamycin and quinolones. For example, the resistant strains may also be resistant to other antibiotics, including resistance to macrolide drugs such as clarithromycin, azithromycin, roxithromycin, etc.; resistance to nitroimidazole drugs such as metronidazole, ornidazole, premanid, delamanid, etc.; resistance to aminoglycoside drugs such as streptomycin, amikacin, etc.; resistance to β-lactam drugs such as methicillin, ampicillin, amoxicillin, etc.; resistance to tetracycline drugs such as tetracycline, tigecycline, minocycline, etc.; resistance to oxazolidinone drugs such as linezolid, tedizolid, etc.; resistance to nitrofuran drugs such as furazolidone; resistance to polypeptide drugs such as vancomycin and polymyxin; resistance to diarylquinoline drugs such as bedaquiline and clofazimine, etc. In the present application, the diagnosis of whether the subject suffers from periprosthetic joint infection can be made through diagnostic methods and diagnostic criteria known in the art, combined with the subject's detailed medical history and physical examination, serology, microbiology, pathology and imaging examination results.

In some embodiments, the periprosthetic joint infection (PJI) comprises early PJI, acute hematogenous PJI, and chronic PJI. Due to the complexity and variability of the disease and pathogenic mechanism of PJI, there is no unified standard for the diagnosis and classification of PJI in this field. However, based on the clinical characteristics of PJI and the time of infection, the commonly used classification methods include the Tsukayama method (Tsukayama DT, Estrada R, Gustilo RB. Infection after total hip arthroplasty. A study of the treatment of one hundred and six infections[J]. J Bone Joint Surg Am, 1996, 78(4):512-523; and Tsuk ayama DT, Goldberg VM, Ky le R. Diagnosi s and management of infection after total knee arthroplasty[J]. J Bone Joint Surg Am, 1996, 78(4):512-523). Am,2003,85A(1):75-80.), Zimmerli method (Zimmerli W,Trampuz A,Ochsner PE.Prosthetic-joint infections[J].N Engl J Med,2004,351(16):1645-1654.), Coventry method (Coventry MB.Treatment of infections occur ing in total hip surgery. Orthop Clin North Am 1975; 6:991-1003.) and Barrett method (Barrett L, Atkins B. The clinical presentation of prosthetic joint infection. J Antimicrob Chemother. 2014 Sep; 69Suppl 1: i25-7.), etc. For example, Zimmerli et al. define PJI occurring within 3 months after artificial joint prosthesis replacement surgery as early PJI infection, PJI occurring within 3 to 24 months after the surgery as delayed or mid-term PJI infection, and PJI occurring after 24 months after the surgery as late infection. For example, the periprosthetic joint infection can also be an acute hematogenous PJI occurring within about 4 weeks after the surgery.

In some embodiments, the therapeutic agent further comprises other drugs, pharmaceutically acceptable carriers, solvents and buffers. Other components of the flushing liquid. For example, in the therapeutic agent, the compound of formula (I) and the other components are not mixed with each other. For example, the compound of formula (I) and the other components are not mixed with each other, which may mean that the compound of formula (I) and the other components are placed in different containers and/or devices, respectively. For example, the compound of formula (I) and the other components are not mixed with each other, which may mean that the container or device for placing the compound of formula (I) in the therapeutic agent, and the container or device for placing the other components are placed in different storage spaces and/or different storage conditions, respectively. For example, the compound of formula (I) and the other components are not mixed with each other, which may mean that the compound of formula (I) and the other components in the therapeutic agent are stored in specific measurement units in their respective containers and/or devices. For example, the compound of formula (I) and the other components are not mixed with each other, which may mean that the compound of formula (I) and the other components are mixed only before using the therapeutic agent, and the mixing process may include using a mixing device contained or not contained in the therapeutic agent, transferring the compound of formula (I) or other components to a container or device containing another component for mixing, and/or transferring both the compound of formula (I) and the other components to another container or device for mixing.

In some embodiments, the therapeutic agent comprises other components selected from other drugs, pharmaceutically acceptable carriers, solvents and buffers, and the compound of formula (I) is mixed with one or more of the other components. For example, the compound of formula (I) is mixed with one or more of the other components, which may refer to the compound of formula (I) and one or more of the other components being mixed and placed in the same container or device. For example, the compound of formula (I) is mixed with one or more of the other components, which may refer to the compound of formula (I) and one or more of the other components being mixed and then stored in the same or different containers or devices in specific measurement units. For example, the compound of formula (I) is mixed with one or more of the other components, which may refer to the compound of formula (I) and one or more of the other components being mixed, and then further mixing is required before the therapeutic agent is used (for example, it is necessary to shake vigorously to fully mix them).

In some embodiments, the method further comprises administering an effective amount of other therapeutic agents to the subject in need. For example, the method further comprises administering an effective amount of other therapeutic agents to the subject by injection (mainly non-intravenous route, for example, intramuscular injection and/or subcutaneous injection), oral administration, intracavitary administration, enteral administration and/or transdermal absorption. For example, the other therapeutic agents may be selected from antibacterial agents, anesthetics, analgesics, sedatives, hormone drugs, anti-inflammatory drugs, anticoagulants, platelet aggregation inhibitors, antipyretics, cell membrane permeation agents and muscle relaxants.

On the other hand, the present application provides the use of a compound represented by formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance thereof in the preparation of an intravenous infusion therapeutic agent, wherein the therapeutic agent is used to prevent periprosthetic joint infection; and a unit dose of the intravenous infusion therapeutic agent contains about 100 mg to about 500 mg of a compound represented by formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance thereof, and is formulated to be suitable for administration to a subject in need thereof with a single infusion time of about 20 minutes to about 3 hours.

For example, the unit dose of the therapeutic agent contains the compound of formula (I) and/or its pharmaceutically acceptable salt, hydrate, The solvate, prodrug, metabolite or deuterated form may be about 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg or 500 mg. Furthermore, in some embodiments, the unit dose of the therapeutic agent may include about 200 mg to about 400 mg of the compound shown in formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance. For example, the unit dose of the therapeutic agent may include about 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg of the compound of formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance. Illustratively, a unit dose of the therapeutic agent may contain about 300 mg of the compound of formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof.

For example, the single infusion time of the intravenous infusion may be about: 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes (1 hour), 70 minutes, 80 minutes, 90 minutes, 100 minutes, 110 minutes, 120 minutes (2 hours), 130 minutes, 140 minutes, 150 minutes, 160 minutes, 170 minutes or 180 minutes (3 hours). Further, in some embodiments, the therapeutic agent is formulated to be suitable for being administered to the subject with a single infusion time of 60 ± 10 minutes. For example, the single infusion time of the intravenous infusion may be about: 50 minutes, 51 minutes, 52 minutes, 53 minutes, 54 minutes, 55 minutes, 56 minutes, 57 minutes, 58 minutes, 59 minutes, 60 minutes, 61 minutes, 62 minutes, 63 minutes, 64 minutes, 65 minutes, 66 minutes, 67 minutes, 68 minutes, 69 minutes or 70 minutes.

In some embodiments, the therapeutic agent may include the unit dose suitable for providing intravenous infusion once a day; in other embodiments, the therapeutic agent may include the unit dose suitable for providing intravenous infusion twice a day. For example, the therapeutic agent may include the unit dose suitable for providing intravenous injection twice a day, and the interval between the two intravenous infusions per day is about 12 hours.

In some embodiments, the therapeutic agent comprises the unit dose suitable for providing at least 1 intravenous infusion per day for 1-14 days. For example, the therapeutic agent comprises the unit dose suitable for providing at least 1 intravenous infusion per day, and can last for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days or 14 days. For example, the therapeutic agent may comprise the unit dose suitable for providing 1 intravenous infusion per day during the continuous period of 1 day to 14 days, and the intravenous infusion may be performed at the same time period or at different time periods each day. For example, the therapeutic agent may comprise the unit dose suitable for providing 2 intravenous infusions per day during the continuous period of 1 day to 14 days. The interval between the two intravenous infusions can be about 12 hours, and the intravenous infusion can be performed at the same time period or at different time periods every day. For example, the first day of the 1-14-day continuous period is the day on which the subject receives artificial joint prosthesis replacement surgery.

In some embodiments, the joint prosthesis peri-infection is caused by gram-positive bacteria infection. For example, the joint prosthesis peri-infection can be a subject of the joint prosthesis peri-infection caused by Staphylococcus aureus and/or coagulase-negative staphylococci infection. Specifically, the coagulase-negative staphylococcus can be selected from Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus xylinus, Staphylococcus haemolyticus, Staphylococcus capitis, Staphylococcus warneri, Staphylococcus mimicus, Staphylococcus xylosus and Staphylococcus apes. In the present application, the gram-positive bacteria may also include its resistant strains, for example, the resistant strains may be resistant to rifamycin (for example, rifampicin) single resistance, quinolone or quinolones single resistance or rifamycin and quinolones double resistance. For example, the resistant strains may also be resistant to other antibiotics, including resistance to macrolide drugs such as clarithromycin, azithromycin, roxithromycin, etc.; resistance to nitroimidazole drugs such as metronidazole, ornidazole, premanid, delamanid, etc.; resistance to aminoglycoside drugs such as streptomycin, amikacin, etc.; resistance to β-lactam drugs such as methicillin, ampicillin, amoxicillin, etc.; resistance to tetracycline drugs such as tetracycline, tigecycline, minocycline, etc.; resistance to oxazolidinone drugs such as linezolid, tedizolid, etc.; resistance to nitrofuran drugs such as furazolidone; resistance to polypeptide drugs such as vancomycin and polymyxin; resistance to diarylquinoline drugs such as bedaquiline and clofazimine, etc. In the present application, the diagnosis of whether the subject suffers from periprosthetic joint infection can be made through diagnostic methods and diagnostic criteria known in the art, combined with the subject's detailed medical history and physical examination, serology, microbiology, pathology and imaging examination results.

In some embodiments, the periprosthetic joint infection (PJI) comprises early PJI, acute hematogenous PJI and chronic PJI. For example, PJI occurring within 3 months after artificial joint prosthesis replacement surgery is defined as early PJI infection, PJI occurring within 3 months to 24 months after the surgery is defined as delayed or mid-term PJI infection, and PJI occurring after 24 months after the surgery is defined as late infection (Zimmerli et al., 2004). For example, the periprosthetic joint infection can be an acute hematogenous PJI occurring within about 4 weeks after the surgery.

In some embodiments, the therapeutic agent further comprises other components selected from other drugs, pharmaceutically acceptable carriers, solvents and buffers. For example, in the therapeutic agent, the compound of formula (I) and the other components do not mix with each other. For example, the compound of formula (I) and the other components do not mix with each other may refer to that the compound of formula (I) and the other components are placed in different containers and/or devices, respectively. For example, the compound of formula (I) and the other components do not mix with each other may refer to that the container or device for placing the compound of formula (I) in the therapeutic agent and the container or device for placing the other components are placed in different storage spaces and/or under different storage conditions, respectively. For example, the compound of formula (I) and the other components do not mix with each other may refer to The compound of formula (I) and other components in the therapeutic agent are separately packaged and stored in specific measurement units in containers and/or devices respectively placed therein. For example, the compound of formula (I) and the other components are not mixed with each other, which may mean that the compound of formula (I) and the other components are mixed only before using the therapeutic agent, and the mixing process may include using a mixing device included or not included in the therapeutic agent, transferring the compound of formula (I) or other components to a container or device where another component is placed for mixing, and/or transferring both the compound of formula (I) and the other components to another container or device for mixing.

In some embodiments, the therapeutic agent comprises other components selected from other drugs, pharmaceutically acceptable carriers, solvents and buffers, and the compound of formula (I) is mixed with one or more of the other components. For example, the compound of formula (I) is mixed with one or more of the other components, which may refer to the compound of formula (I) and one or more of the other components being mixed and placed in the same container or device. For example, the compound of formula (I) is mixed with one or more of the other components, which may refer to the compound of formula (I) and one or more of the other components being mixed and then stored in the same or different containers or devices in specific measurement units. For example, the compound of formula (I) is mixed with one or more of the other components, which may refer to the compound of formula (I) and one or more of the other components being mixed, and then further mixing is required before the therapeutic agent is used (for example, it is necessary to shake vigorously to fully mix them).

In some embodiments, the therapeutic agent is formulated to be suitable for co-administration with an effective amount of other therapeutic agents to the subject in need. For example, the therapeutic agent can be formulated to be suitable for co-administration with an effective amount of other therapeutic agents to the subject in need, wherein the other therapeutic agent can be administered by injection (mainly non-intravenous route, for example, intramuscular injection and/or subcutaneous injection), oral administration, intracavitary administration, enteral administration and/or transdermal absorption to the subject. For example, the other therapeutic agent can be selected from antibacterial agents, anesthetics, analgesics, sedatives, hormone drugs, anti-inflammatory drugs, anticoagulants, platelet aggregation inhibitors, antipyretics, cell membrane permeabilization agents and muscle relaxants.

Without intending to be bound by any theory, the following embodiments are merely intended to illustrate the methods and uses of the present application and are not intended to limit the scope of the invention of the present application.

Example

Example 1

Study on the effectiveness and safety of this preventive program

1. Tissue distribution, plasma pharmacokinetic (PK) analysis, safety and tolerability of the compound of formula (I) after intravenous (IV) infusion before artificial joint prosthesis replacement surgery

In this example, 9 THA (total hip arthroplasty) subjects and 4 TKA (total knee arthroplasty) subjects were selected. They received a single intravenous injection of the compound of formula (I) (TNP-2092) 2 hours (±20 minutes) before anesthesia induction. Infusion (300 mg, infusion time is 60 minutes ± 10 minutes). Subsequently, all subjects underwent the artificial joint prosthesis replacement surgery in the orthopedic surgery field for conventional THA and TKA, and during the operation, bone tissue samples and synovial fluid samples of the subjects were collected for measuring the concentration of the compound of formula (I) in bone tissue and synovial fluid. The results are summarized in Table 1.

Table 1 Concentration of the compound of formula (I) in bone and synovial fluid after single-dose intravenous infusion before surgery

The results show that the concentration of the compound of formula (I) (TNP-2092) in joint tissue and synovial fluid is significantly higher than its MIC ₉₀ value (15 ng/mL) against Staphylococcus aureus and Staphylococcus epidermidis. At the same time, the concentration of the compound of formula (I) distributed in bone tissue after about 2 hours of intravenous infusion is higher in the hip than in the knee. And according to the long terminal half-life and accumulation of the compound of formula (I), its concentration in joint tissue is expected to increase after multiple administrations every 12 hours during the treatment period.

Note: (1) MIC ₉₀ value: minimum inhibitory concentration required to inhibit 90% growth of target strain; (2) MIC ₉₀ data referenced from: Fisher CR, Schmidt-Malan SM, Ma Z, Yuan Y, He S, Patel R, In vitro activity of TNP-2092 against periprosthetic joint infection-associated staphylococci, Diagn Microbiol Infect Dis. 2020 Jul; 97(3): 115040 (doi: 10.1016/j.diagmicrobio.2020.115040).

2. Evaluation of venous injury with different single intravenous infusion times

In this example, three groups of experiments were conducted simultaneously with a single infusion time increased from 20 minutes to 60 minutes to study how to reduce the risk of extravasation and venous injury and improve the comfort of the subjects. The experimental scheme settings for each group are shown in the following table.

The results showed that all subjects in Group 1 and Group 3, and 85% of subjects in Group 2 reported adverse events (AEs), while only 50% of subjects in the control group that received placebo (water for injection) reported AEs. The most common AE reports were adverse reactions at the injection site, which were 95.3% in Group 1, 96.7% in Group 2, 97.6% in Group 3, and 10.3% in the placebo group. 83%, 85%, 75%, and 33% of the subjects reported. Among the various injection site reactions reported, the most common was injection site thrombosis, which was reported by 67%, 8%, 0%, and 8% of the subjects in cohorts 1, 2, 3, and placebo, respectively. In order to alleviate the conditions at the injection site and improve the comfort of the subjects, the infusion duration and total amount of infusion varied between the groups. Overall, the injection site reactions of the three groups of subjects were slightly less than those of the other active treatment groups, and there were no reports of injection site thrombosis.

Claims (32)

A method for preventing periprosthetic joint infection (PJI), the method comprising intravenously infusing at least one therapeutic agent to a subject in need thereof, the therapeutic agent comprising about 100 mg to about 500 mg of a compound of formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product thereof, and the single intravenous infusion lasts about 20 minutes to about 3 hours,
The method according to claim 1, wherein the single intravenous infusion lasts for 60±10 minutes. According to the method of any one of claims 1-2, the therapeutic agent comprises about 200 mg to about 400 mg of the compound represented by formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance. According to the method of any one of claims 1 to 3, the therapeutic agent comprises about 300 mg of the compound represented by formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated product. The method according to any one of claims 1 to 4, comprising once daily or twice daily intravenous infusion. The method according to claim 5, wherein the interval between the two daily intravenous infusions is about 12 hours. The method according to any one of claims 1 to 6, comprising at least one intravenous infusion per day for 1 to 14 days. According to the method of claim 7, the first day of the period lasting from 1 day to 14 days is the day on which the subject undergoes artificial joint prosthesis replacement surgery. The method according to any one of claims 1-8, wherein the periprosthetic joint infection is caused by Gram-positive bacteria. The method according to any one of claims 1 to 9, wherein the periprosthetic joint infection is caused by Staphylococcus aureus and/or coagulase-negative Staphylococcus infection. According to the method of any one of claims 1-10, the periprosthetic joint infection (PJI) comprises early PJI, acute hematogenous PJI and chronic PJI. According to the method according to any one of claims 1-11, the periprosthetic joint infection is an early PJI occurring within about 3 months after the subject undergoes artificial joint prosthesis replacement surgery or an acute hematogenous PJI occurring within about 4 weeks after the surgery. According to the method of any one of claims 1-12, the therapeutic agent further comprises other components selected from other drugs, pharmaceutically acceptable carriers, solvents and buffers. According to the method of claim 13, the compound of formula (I) and the other components are not mixed with each other. According to the method of claim 13, the compound of formula (I) is mixed with one or more of the other components. The method according to any one of claims 1-15, further comprising administering to the subject in need thereof an effective amount of an additional therapeutic agent. Use of a compound of formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance thereof in the preparation of an intravenous infusion therapeutic agent, wherein the therapeutic agent is used to prevent periprosthetic joint infection; and a unit dose of the intravenous infusion therapeutic agent contains about 100 mg to about 500 mg of a compound of formula (I) and/or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance thereof, and is formulated to be suitable for administration to a subject in need thereof with a single infusion time of about 20 minutes to about 3 hours. The use according to claim 17, wherein the therapeutic agent is formulated to be administered to the subject in a single infusion time of 60±10 minutes. According to the use according to any one of claims 17-18, the unit dose of the therapeutic agent contains about 200 mg to about 400 mg of the compound represented by formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance. According to the use according to any one of claims 17 to 19, the unit dose of the therapeutic agent contains about 300 mg of the compound represented by formula (I) and/or its pharmaceutically acceptable salt, hydrate, solvate, prodrug, metabolite or deuterated substance. The use according to any one of claims 17 to 20, wherein the therapeutic agent comprises the unit dose suitable for providing once daily or twice daily intravenous infusion. The use according to any one of claims 17 to 21, wherein the therapeutic agent comprises the unit dose suitable for providing twice daily intravenous infusions, and the interval between the twice daily intravenous infusions is about 12 hours. The use according to any one of claims 17 to 22, wherein the therapeutic agent comprises a composition suitable for providing at least once a day and for a long time The unit dose is administered by intravenous infusion for 1 to 14 days. According to the use of claim 23, the first day of the duration of 1 to 14 days is the day on which the subject undergoes artificial joint prosthesis replacement surgery. The use according to any one of claims 17 to 24, wherein the peri-prosthetic joint infection is caused by Gram-positive bacteria. The use according to any one of claims 17 to 25, wherein the periprosthetic joint infection is caused by Staphylococcus aureus and/or coagulase-negative Staphylococcus. The use according to any one of claims 17 to 26, wherein the periprosthetic joint infection (PJI) comprises early PJI, acute hematogenous PJI and chronic PJI. The use according to any one of claims 17 to 27, wherein the periprosthetic joint infection is an early PJI occurring within about 3 months after the subject undergoes artificial joint prosthesis replacement surgery or an acute hematogenous PJI occurring within about 4 weeks after the surgery. The use according to any one of claims 17 to 28, wherein the therapeutic agent further comprises other components selected from other drugs, pharmaceutically acceptable carriers, solvents and buffers. According to the use according to claim 29, the compound of formula (I) and the other components are not mixed with each other. The use according to claim 29, wherein the compound of formula (I) is mixed with one or more of the other components. The use according to any one of claims 17-31, wherein the therapeutic agent is formulated to be suitable for co-administration with an effective amount of other therapeutic agents to the subject in need thereof.