CN117137918A - Pharmaceutical composition and application thereof - Google Patents
Pharmaceutical composition and application thereof Download PDFInfo
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- CN117137918A CN117137918A CN202311291440.2A CN202311291440A CN117137918A CN 117137918 A CN117137918 A CN 117137918A CN 202311291440 A CN202311291440 A CN 202311291440A CN 117137918 A CN117137918 A CN 117137918A
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- China
- Prior art keywords
- pharmaceutical composition
- bedaquiline
- pyrazinamide
- sitafloxacin
- linezolid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 69
- 239000003814 drug Substances 0.000 claims abstract description 51
- QUIJNHUBAXPXFS-XLJNKUFUSA-N bedaquiline Chemical compound C1([C@H](C2=CC3=CC(Br)=CC=C3N=C2OC)[C@@](O)(CCN(C)C)C=2C3=CC=CC=C3C=CC=2)=CC=CC=C1 QUIJNHUBAXPXFS-XLJNKUFUSA-N 0.000 claims abstract description 39
- 229960000508 bedaquiline Drugs 0.000 claims abstract description 39
- 229960005206 pyrazinamide Drugs 0.000 claims abstract description 37
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 claims abstract description 37
- MPORYQCGWFQFLA-ONPDANIMSA-N 7-[(7s)-7-amino-5-azaspiro[2.4]heptan-5-yl]-8-chloro-6-fluoro-1-[(1r,2s)-2-fluorocyclopropyl]-4-oxoquinoline-3-carboxylic acid;trihydrate Chemical compound O.O.O.C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1.C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 MPORYQCGWFQFLA-ONPDANIMSA-N 0.000 claims abstract description 33
- 229960003177 sitafloxacin Drugs 0.000 claims abstract description 33
- 201000008827 tuberculosis Diseases 0.000 claims abstract description 22
- 238000011282 treatment Methods 0.000 claims abstract description 17
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 claims description 26
- 229960003907 linezolid Drugs 0.000 claims description 26
- 229960003350 isoniazid Drugs 0.000 claims description 21
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 claims description 21
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 claims description 18
- 230000002401 inhibitory effect Effects 0.000 claims description 17
- 241000187479 Mycobacterium tuberculosis Species 0.000 claims description 15
- 229960001225 rifampicin Drugs 0.000 claims description 12
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 claims description 11
- 229960000285 ethambutol Drugs 0.000 claims description 9
- 229960002599 rifapentine Drugs 0.000 claims description 9
- WDZCUPBHRAEYDL-GZAUEHORSA-N rifapentine Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C(O)=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N(CC1)CCN1C1CCCC1 WDZCUPBHRAEYDL-GZAUEHORSA-N 0.000 claims description 9
- 229960003702 moxifloxacin Drugs 0.000 claims description 8
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- -1 cotinamide Chemical compound 0.000 claims description 3
- 229940079593 drug Drugs 0.000 abstract description 32
- 230000002147 killing effect Effects 0.000 abstract description 16
- 241001302239 Mycobacterium tuberculosis complex Species 0.000 abstract description 15
- 230000001954 sterilising effect Effects 0.000 abstract description 15
- 238000004659 sterilization and disinfection Methods 0.000 abstract description 15
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- 210000000952 spleen Anatomy 0.000 description 5
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- 230000002365 anti-tubercular Effects 0.000 description 4
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- 108010077805 Bacterial Proteins Proteins 0.000 description 3
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- 239000007923 nasal drop Substances 0.000 description 2
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- NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
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- 210000001835 viscera Anatomy 0.000 description 2
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- 230000002407 ATP formation Effects 0.000 description 1
- 108700023418 Amidases Proteins 0.000 description 1
- 108020004513 Bacterial RNA Proteins 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 241000186359 Mycobacterium Species 0.000 description 1
- 125000003001 N-formyl-L-methionyl group Chemical group O=C([H])N([H])[C@]([H])(C(=O)[*])C([H])([H])C([H])([H])SC([H])([H])[H] 0.000 description 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
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- 241000191940 Staphylococcus Species 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 102000005922 amidase Human genes 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
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- 238000010241 blood sampling Methods 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
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- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- 229940124307 fluoroquinolone Drugs 0.000 description 1
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- 210000002865 immune cell Anatomy 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229960003376 levofloxacin Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
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- 108020004999 messenger RNA Proteins 0.000 description 1
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- 238000010172 mouse model Methods 0.000 description 1
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- 239000012466 permeate Substances 0.000 description 1
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- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
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- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a pharmaceutical composition and application thereof. The pharmaceutical composition comprises bedaquiline, pyrazinamide and sitafloxacin. The pharmaceutical composition provided by the invention can greatly shorten the time for killing the mycobacterium tuberculosis complex, and solves the problems of long sterilization time and poor patient compliance of the existing medicines; the tuberculosis treatment is failed and the acquired drug resistance is caused.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a pharmaceutical composition and application thereof.
Background
Tuberculosis is an infectious disease caused by a single infectious source, and medicines recommended by new-diagnosis Drug-sensitive tuberculosis (DS-TB) patients are consolidated by isoniazid (H), rifampicin (R), pyrazinamide (Z), ethambutol (E) in a strengthening period added with isoniazid (H) and rifampicin (R) of 4 months. The success rate of the standardized antituberculous treatment for the drug-sensitive tuberculosis patients is about 80.1 percent. Drawbacks of conventional anti-tuberculosis treatment regimens include: the treatment course of drug-sensitive tuberculosis is long, and patient compliance is poor; the treatment failure and acquired drug resistance caused by the method lead tuberculosis to be widely spread in communities, and the tuberculosis control difficulty is increased.
Disclosure of Invention
The invention mainly aims to provide a pharmaceutical composition and application thereof, and aims to solve the problems of poor effect and long service life of preparing a medicine for treating tuberculosis in the prior art.
To achieve the above object, the present invention proposes, in one aspect, a pharmaceutical composition comprising bedaquiline, pyrazinamide and sitafloxacin.
Therefore, the pharmaceutical composition provided by the invention can greatly shorten the time for killing the mycobacterium tuberculosis complex, and solves the problems of long sterilization time and poor patient compliance of the existing medicines; the resulting failure of treatment and acquired drug resistance.
Optionally, the mass ratio between the bedaquiline, the pyrazinamide and the sitafloxacin is (1-4): (10-20): (2-4).
In the proper proportion range, the time for killing the mycobacterium tuberculosis complex can be effectively shortened under the condition of better sterilization effect.
Optionally, the pharmaceutical composition further comprises at least one of linezolid, cotinamide, isoniazid, moxifloxacin, rifampin, rifapentine, ethambutol.
The medicine composition can be added with other kinds of medicines which are conventionally used for preventing and treating tuberculosis, and has better effect.
Optionally, the pharmaceutical composition comprises bedaquiline, pyrazinamide, sitafloxacin, and linezolid.
Under the combination mode, the pharmaceutical composition can effectively shorten the time for killing the mycobacterium tuberculosis complex under the condition of better sterilization effect.
Optionally, the mass ratio between the bedaquiline and the linezolid is (1-4): (6-12).
In the proper proportion range, the time for killing the mycobacterium tuberculosis complex can be effectively shortened under the condition of better sterilization effect.
Optionally, the pharmaceutical composition comprises bedaquiline, pyrazinamide, sitafloxacin, linezolid, and isoniazid.
Under the combination mode, the pharmaceutical composition can effectively shorten the time for killing the mycobacterium tuberculosis complex under the condition of better sterilization effect.
Optionally, the mass ratio between the bedaquiline, linezolid and isoniazid is (1-4): (6-12): (3-9).
In the proper proportion range, the time for killing the mycobacterium tuberculosis complex can be effectively shortened under the condition of better sterilization effect.
In another aspect, the invention provides the use of the above pharmaceutical composition in the manufacture of a medicament for the treatment of tuberculosis.
In a further aspect, the invention provides the use of the above pharmaceutical composition in the preparation of a medicament for inhibiting mycobacterium tuberculosis.
According to the technical scheme, the provided pharmaceutical composition can greatly shorten the time for killing the mycobacterium tuberculosis complex, and solves the problems of long sterilization time and poor patient compliance of the existing medicines; the resulting failure of treatment and acquired drug resistance.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and other drawings may be obtained according to the structures shown in these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a graph showing changes in pulmonary CFU after mice are infected with a susceptible strain of Mycobacterium tuberculosis by nasal drops and treated with different pharmaceutical compositions;
FIG. 2 is a graph showing changes in spleen CFU after mice are infected with a Mycobacterium tuberculosis susceptible strain by nasal drops and treated with different pharmaceutical compositions.
The achievement of the objects, functional features and advantages of the present invention will be further described with reference to the accompanying drawings, in conjunction with the embodiments.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention. In addition, the meaning of "and/or" as it appears throughout includes three parallel schemes, for example "A and/or B", including the A scheme, or the B scheme, or the scheme where A and B are satisfied simultaneously. In addition, the technical solutions of the embodiments may be combined with each other, but it is necessary to base that the technical solutions can be realized by those skilled in the art, and when the technical solutions are contradictory or cannot be realized, the combination of the technical solutions should be regarded as not exist and not within the protection scope of the present invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Tuberculosis is an infectious disease caused by a single infectious source, and medicines recommended by new-diagnosis Drug-sensitive tuberculosis (DS-TB) patients are consolidated by isoniazid (H), rifampicin (R), pyrazinamide (Z), ethambutol (E) in a strengthening period added with isoniazid (H) and rifampicin (R) of 4 months. The success rate of the standardized antituberculous treatment for the drug-sensitive tuberculosis patients is about 80.1 percent. Drawbacks of conventional anti-tuberculosis treatment regimens include: the treatment course of drug-sensitive tuberculosis is long, and patient compliance is poor; the treatment failure and acquired drug resistance caused by the method lead tuberculosis to be widely spread in communities, and the tuberculosis control difficulty is increased. Four drug combinations consisting of isoniazid + rifapentine + pyrazinamide + moxifloxacin appear later, requiring 4 months. The existing treatment scheme can not break through the bottleneck of 2-month short-range chemotherapy, and the main reason is the lack of medicines for efficiently killing the remaining bacteria.
The stay bacteria are a small number of strains in the mycobacterium tuberculosis complex, can effectively evade the immune response of a host, and resist the influence of conventional medicines. In general, the remaining bacteria are in a dormant state in the patient, but cannot be killed by immune cells or drugs sufficiently, and can be recovered to an active state under specific conditions, so that the remaining bacteria are an important pathogen source for patient recurrence after treatment.
In view of this, the present invention proposes a pharmaceutical composition comprising bedaquiline, pyrazinamide and sitafloxacin.
Among them, bedaquiline (BDQ) acts on the respiratory chain system to inhibit energy synthesis of tubercle bacillus, and BDQ inhibits ATP synthase by binding to the c subunit, resulting in reduced ATP synthesis and death of tubercle bacillus.
The action mechanism of pyrazinamide is possibly related to pyrazinic acid, the pyrazinamide enters tubercle bacillus bodies, amidase in the bacillus bodies removes amide groups, and the pyrazinamide is converted into pyrazinic acid to play an antibacterial role.
Sitafloxacin is a novel fluoroquinolone antibacterial drug, and has good antibacterial effect on clinically common drug-resistant strains such as staphylococcus, streptococcus pneumoniae, enterobacter and the like. Sitafloxacin has good antibacterial effect on persistent and recurrent infections. MIC values of sitafloxacin in treating clinical common pathogenic microorganisms are generally superior to those of levofloxacin, and the minimum inhibitory concentration of sitafloxacin in treating various drug-resistant infections is lower than that of moxifloxacin.
Therefore, the pharmaceutical composition provided by the invention comprises the three medicines, has a synergistic effect, can greatly shorten the time for killing the mycobacterium tuberculosis complex, and solves the problems of long sterilization time and poor patient compliance of the existing medicines; the resulting failure of treatment and acquired drug resistance.
In some embodiments, the mass ratio between the bedaquiline, pyrazinamide, and sitafloxacin is (1-4): (10-20): (2-4). In the proper proportion range, the time for killing the mycobacterium tuberculosis complex can be effectively shortened under the condition of better sterilization effect. The mass ratio between the bedaquiline, pyrazinamide and sitafloxacin may be 1:10:2, 1:20:2, 1:10:4, 1:20:4, 4:10:2, 4:20:2, 4:10:4, 4:20:4, etc.
In some embodiments, the pharmaceutical composition further comprises at least one of linezolid, cotinamide, isoniazid, moxifloxacin, rifampin, rifapentine, ethambutol.
Among them, the mechanism of action of linezolid is mainly exerted by inhibiting bacterial protein synthesis. It is able to bind to the ribosomal 30S subunit of bacteria, blocking the protein synthesis process in bacteria.
The cotinamide achieves an antibacterial effect by inhibiting the synthesis of bacterial proteins. Bacterial protein synthesis involves three steps, initiation, extension and termination. In the initiation phase, ribosomal 50S subunit, 30S subunit, mRNA and initiation formyl methionyl tRNA (fMet-tRNA) bind and, after assembly into a 70S initiation complex, enter the extension phase. Oxazolidinone drugs can competitively bind to the P site of ribosomal 50S subunit, resulting in the inability of fMet-tRNA to bind to this site, thereby inhibiting 70S initiation complex formation and translocation of the peptide chain from a to P during peptide bond formation.
The isoniazid has the action mechanism that the aim of killing or inhibiting the growth of bacteria is achieved by inhibiting the synthesis of the cell wall of the mycobacterium tuberculosis.
The moxifloxacin antibacterial mechanism is mainly realized by blocking the activity of bacterial DNA gyrase. Bacterial DNA gyrase plays a vital role in the replication, recombination and repair of DNA. Bacterial DNA gyrase is capable of modulating the supercoiled structure of DNA, thereby assisting in the unwinding of DNA strands and the copying, splicing and repair of DNA. Moxifloxacin can bind to the a subunit in bacterial DNA gyrase and inhibit its catalysis, thereby disrupting the normal replication and repair process of the DNA strand. In addition, moxifloxacin can also be combined with bacterial DNA to prevent further expansion of DNA chains. These effects prevent the bacteria from undergoing efficient DNA replication and repair, resulting in bacterial death.
The principle of rifampicin is that rifampicin binds firmly to the β subunit of DNA-dependent RNA polymerase, inhibiting bacterial RNA synthesis.
Rifapentine is a cyclopentyl derivative of rifampicin, with lower minimum inhibitory concentration of mycobacterium tuberculosis than rifampicin, rifapentine Ding Duijie.
Ethambutol can permeate into mycobacterium to interfere with RNA synthesis, thereby inhibiting bacterial proliferation.
The medicine composition provided by the invention can be added with other kinds of medicines which are conventionally used for preventing and treating tuberculosis, and has better effect.
In some embodiments, the pharmaceutical composition comprises bedaquiline, pyrazinamide, sitafloxacin, and linezolid. By adopting the combination of the 4 medicines, on one hand, the medicine components are simple, and on the other hand, under the condition of better sterilization effect, the medicine composition can effectively shorten the time for killing the mycobacterium tuberculosis complex.
In some embodiments, the mass ratio between the bedaquiline and linezolid is (1-4): (6-12). In the proper proportion range, the time for killing the mycobacterium tuberculosis complex can be effectively shortened under the condition of better sterilization effect.
In some embodiments, the pharmaceutical composition comprises bedaquiline, pyrazinamide, sitafloxacin, linezolid, and isoniazid. By adopting the combination of the 5 medicines, on one hand, the medicine components are simple, and on the other hand, under the condition of better sterilization effect, the medicine composition can effectively shorten the time for killing the mycobacterium tuberculosis complex.
In some embodiments, the mass ratio between the bedaquiline, linezolid, and isoniazid is (1-4): (6-12): (3-9). In the proper proportion range, the time for killing the mycobacterium tuberculosis complex can be effectively shortened under the condition of better sterilization effect.
The mass ratio of each drug in the above pharmaceutical composition may refer to the mass ratio between the daily doses, and for example, the daily doses of each drug may be referred to in table 1 below.
Table 1 daily dosage of each drug in the pharmaceutical composition
In another aspect, the invention provides the use of the above pharmaceutical composition in the manufacture of a medicament for the treatment of tuberculosis.
In preparing a medicament for treating tuberculosis, the pharmaceutical composition can be prepared into any preparation based on the conventional method. The composition may be formulated into an oral dosage form (e.g., powder, tablet, capsule, syrup, pill, or granule) or a parenteral dosage form (e.g., injectable formulation). In addition, the composition can be prepared into systemic or topical dosage forms.
In a further aspect, the invention provides the use of the above pharmaceutical composition in the preparation of a medicament for inhibiting mycobacterium tuberculosis.
In preparing a drug for inhibiting mycobacterium tuberculosis, the pharmaceutical composition may be prepared into any formulation based on a conventional method. The composition may be formulated into an oral dosage form (e.g., powder, tablet, capsule, syrup, pill, or granule) or a parenteral dosage form (e.g., injectable formulation). In addition, the composition can be prepared into systemic or topical dosage forms.
The following technical solutions of the present invention will be described in further detail with reference to specific examples and drawings, and it should be understood that the following examples are only for explaining the present invention and are not intended to limit the present invention.
The mass of each drug in the following examples and comparative examples means the daily dose.
Example 1
The present example provides a pharmaceutical composition comprising 400mg of bedaquiline, 1000mg of pyrazinamide and 200mg of sitafloxacin.
Example 2
The present example provides a pharmaceutical composition comprising 200mg of bedaquiline, 2000mg of pyrazinamide and 400mg of sitafloxacin.
Example 3
The present example provides a pharmaceutical composition comprising 100mg of bedaquiline, 1200mg of pyrazinamide and 200mg of sitafloxacin.
Example 4
The present example provides a pharmaceutical composition comprising 400mg of bedaquiline, 1200mg of pyrazinamide, 200mg of sitafloxacin and 600mg of linezolid.
Example 5
The present example provides a pharmaceutical composition comprising 100mg of bedaquiline, 1000mg of pyrazinamide, 200mg of sitafloxacin and 600mg of linezolid.
Example 6
The present example provides a pharmaceutical composition comprising 100mg of bedaquiline, 1000mg of pyrazinamide, 200mg of sitafloxacin and 1200mg of linezolid.
Example 7
The present example provides a pharmaceutical composition comprising 400mg of bedaquiline, 2000mg of pyrazinamide, 400mg of sitafloxacin, 1200mg of linezolid.
Example 8
The present example provides a pharmaceutical composition comprising 100mg of bedaquiline, 1000mg of pyrazinamide, 200mg of sitafloxacin, 600mg of linezolid and 300mg of isoniazid.
Example 9
The present example provides a pharmaceutical composition comprising 100mg of bedaquiline, 1000mg of pyrazinamide, 200mg of sitafloxacin, 600mg of linezolid and 900mg of isoniazid.
Example 10
The present example provides a pharmaceutical composition comprising 400mg of bedaquiline, 2000mg of pyrazinamide, 400mg of sitafloxacin, 1200mg of linezolid and 900mg of isoniazid.
Example 11
The present example provides a pharmaceutical composition comprising 200mg of bedaquiline, 1200mg of pyrazinamide, 300mg of sitafloxacin, 1000mg of linezolid and 1000mg of isoniazid.
Example 12
This example provides a pharmaceutical composition comprising 400mg of bedaquiline, 2000mg of pyrazinamide, 400mg of sitafloxacin, and 1200mg of rifapentine.
Example 13
This example provides a pharmaceutical composition comprising 200mg of bedaquiline, 1200mg of pyrazinamide, 200mg of sitafloxacin, and 1200mg of rifapentine.
Example 14
The present example provides a pharmaceutical composition comprising 200mg of bedaquiline, 1200mg of pyrazinamide, 200mg of sitafloxacin and 1000mg of ethambutol.
Example 15
This example provides a pharmaceutical composition comprising 400mg of bedaquiline, 2000mg of pyrazinamide, 400mg of sitafloxacin, 1200mg of linezolid, and 1200mg of rifapentine.
Comparative example 1
This example provides a pharmaceutical composition comprising 1000mg isoniazid, 600mg rifampicin, 1000mg pyrazinamide and 1000mg ethambutol.
Comparative example 2
The present example provides a pharmaceutical composition comprising 100mg of bedaquiline, 1000mg of linezolid, 1000mg of isoniazid, 1000mg of ethambutol, 1000mg of pyrazinamide.
Application example 1
This example provides the use of the pharmaceutical composition of example 1 in the manufacture of a medicament for the treatment of tuberculosis.
Application example 2
This example provides the use of the pharmaceutical composition of example 4 in the manufacture of a medicament for inhibiting mycobacterium tuberculosis.
Application example 3
This example provides the use of the pharmaceutical composition of example 10 in the manufacture of a medicament for inhibiting mycobacterium tuberculosis.
Comparative example 1 was used
The present comparative example provides an application of the pharmaceutical composition of comparative example 1 in preparing a medicament for inhibiting mycobacterium tuberculosis.
Comparative example 2 was used
The present comparative example provides the use of the pharmaceutical composition of comparative example 2 in the preparation of a medicament for inhibiting mycobacterium tuberculosis.
Performance testing
The effectiveness of the existing tuberculosis treatment regimen was verified by a mouse model, and in different regimen models, the traditional treatment regimen HREZ (application comparative example 1), the existing published short-range treatment regimen BLHEZ (application comparative example 2), and the new and derivative regimens discovered by the applicant through research, including BZS (application example 1), and BZSL (application example 2), BZSHL (application example 3) were respectively verified. The time to bacterial negative transfer in lung tissue and spleen tissue in different protocol groups after drug intervention was compared.
The method comprises the following steps: mycobacterium tuberculosis standard strain H37Rv was cultured in Middlebrook7H9 liquid medium containing 10% OADC (containing 0.05% Tween 80) to logarithmic phase, and after filtration through an 8 μm filter membrane, it was kept at-80℃for use and subjected to colony count for dilution at a double ratio to determine the bacterial content. Mice were infected by nasal drip, and each mouse inhaled about 100CFU of bacteria in the lungs by adjusting the inhaled quantity. The actual dose of infection in mice was monitored periodically the next day after infection.
The test experiments were specifically divided into the following 6 groups: (1) 20 infected mice plus normal mouse diet; (2) 20 +hrez mice infected with mice; (3) 20 +BLHEZ mice infected with mice; (4) 20 +BZS mice infected with mice; (5) 20 +bzsl mice grains infected with mice; (6) 20 +BZSHL mice infected with mice. Periodic blood sampling and detection of murine lung and spleen bacterial load (CFU), detection of pathological lesion extent.
Tissue homogenate and colony count: periodically taking the viscera of a mouse after infection, aseptically separating the viscera, taking half of tissues in a 2mL spiral tube containing 0.5mL PBS-T80, adding a plurality of 1.5mm steel balls, three-dimensionally oscillating and crushing the tissues in a grinding bead homogenizer (BioSpec MiniBeadbeater-16), diluting the tissue homogenate by multiple ratios, respectively taking 0.1mL of the tissue homogenate, coating the tissue homogenate on a Middlebrook 7H11+10% OADC solid plate, and culturing for 3 weeks at 37 ℃ for colony counting.
Referring to fig. 1 and 2, fig. 1 is a graph showing changes in CFU in lung after mice were infected with a strain sensitive to mycobacterium tuberculosis and treated with different pharmaceutical compositions, and fig. 2 is a graph showing changes in CFU in spleen after mice were infected with a strain sensitive to mycobacterium tuberculosis and treated with different pharmaceutical compositions.
As can be seen from fig. 1, the use of the pharmaceutical composition (BZS, BZSL, BZSHL) provided by the invention for treating infected mice shows a rapid decrease in pulmonary bacterial load, and compared with the traditional scheme HREZ, the pharmaceutical composition provided by the invention shows a higher effective bactericidal effect compared with the BLHEZ scheme of the prior art, and can realize the transformation of pulmonary bacteria into negative within 42 days. The treatment scheme containing BZS has better negative transfer speed, and can show better effectiveness when being combined with other various medicines.
As can be seen from fig. 2, treatment of infected mice with the pharmaceutical composition (BZS, BZSL, BZSHL) provided by the present invention showed a rapid decrease in spleen bacterial load. Compared with the traditional HREZ scheme and the BLHEZ scheme in the prior art, the pharmaceutical composition provided by the invention has higher efficient sterilization effect, and can realize the transformation of lung bacteria into yin within 42 days. The treatment scheme containing BZS has better negative transfer speed, and can show better effectiveness when being combined with other various medicines.
The foregoing is merely a preferred embodiment of the present invention and is not intended to limit the scope of the present invention, but various modifications and variations will be apparent to those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (9)
1. A pharmaceutical composition comprising bedaquiline, pyrazinamide and sitafloxacin.
2. The pharmaceutical composition according to claim 1, wherein the mass ratio between the bedaquiline, pyrazinamide and sitafloxacin is (1-4): (10-20): (2-4).
3. The pharmaceutical composition of claim 1 or 2, further comprising at least one of linezolid, cotinamide, isoniazid, moxifloxacin, rifampin, rifapentine, ethambutol.
4. A pharmaceutical composition according to claim 3, wherein the pharmaceutical composition comprises bedaquiline, pyrazinamide, sitafloxacin and linezolid.
5. The pharmaceutical composition according to claim 4, wherein the mass ratio between the bedaquiline and linezolid is (1-4): (6-12).
6. A pharmaceutical composition according to claim 3, wherein the pharmaceutical composition comprises bedaquiline, pyrazinamide, sitafloxacin, linezolid, and isoniazid.
7. The pharmaceutical composition according to claim 6, wherein the mass ratio between bedaquiline, linezolid and isoniazid is (1-4): (6-12): (3-9).
8. Use of a pharmaceutical composition according to any one of claims 1-7 for the preparation of a medicament for the treatment of tuberculosis.
9. Use of the pharmaceutical composition of any one of claims 1-7 for the manufacture of a medicament for inhibiting mycobacterium tuberculosis.
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| CN202311291440.2A CN117137918A (en) | 2023-09-28 | 2023-09-28 | Pharmaceutical composition and application thereof |
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