CN115350194A - Medicine composition and application thereof - Google Patents

Medicine composition and application thereof Download PDF

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Publication number
CN115350194A
CN115350194A CN202210834772.XA CN202210834772A CN115350194A CN 115350194 A CN115350194 A CN 115350194A CN 202210834772 A CN202210834772 A CN 202210834772A CN 115350194 A CN115350194 A CN 115350194A
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otb
pharmaceutical
pharmaceutical composition
drug
treatment
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陆宇
朱慧
付雷
张炜焱
王彬
郭少晨
陈曦
刘海婷
丁杨明
王宁
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Beijing Chest Hospital
Beijing Tuberculosis and Thoracic Tumor Research Institute
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Beijing Tuberculosis and Thoracic Tumor Research Institute
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    • 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
    • A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines 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
    • A61K31/435—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
    • A61K31/495—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
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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

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Abstract

The invention provides a pharmaceutical composition for treating tuberculosis, which comprises the following active components: pyrifazimine (TBI-166) or a pharmaceutically acceptable salt thereof, bedaquiline (BDQ) or a pharmaceutically acceptable salt thereof, and OTB-658 or a pharmaceutically acceptable salt thereof. The drug combination or the drug combination of the invention is used for treating drug-resistant tuberculosis, improving the curative effect of the drug-resistant tuberculosis and reducing the risk of relapse.

Description

Medicine composition and application thereof
The technical field is as follows:
the invention relates to a new drug combination for treating drug-resistant tuberculosis, in particular to a new scheme which is composed of a new drug for resisting drug-resistant tuberculosis in China, namely, pirafolimine (TBI-166), OTB-658 and Bedaquiline (BDQ), and is taken orally for a short period of time.
Background art:
tuberculosis (TB) is a chronic infectious disease caused by infection with Mycobacterium Tuberculosis (MTB). At present, tuberculosis treatment cycle is long, and even TB caused by sensitive bacteria needs 4 first-line medicines for 6 months. For drug-resistant tuberculosis patients, the WHO recommends a long-term treatment regimen that takes 18 to 24 months and consists of at least 4 effective anti-TB drugs. The main reasons of low cure rate of multi-drug resistant tuberculosis are the shortage of anti-tuberculosis drugs, large adverse reaction, long treatment period, poor patient compliance and the like, and the clinical dilemma that an effective scheme cannot be formed by enough drugs is often caused. Tuberculosis, in particular to drug-resistant tuberculosis treatment, a drug with a new structure and a new mechanism is urgently needed.
Due to the existence of different flora in tuberculosis focus and the rapid development of drug resistance of MTB to single drug, drug combination is a key weapon for treating tuberculosis, i.e. tuberculosis treatment must be carried out in a drug combination mode. In addition, the clearance of MTB, which remains dormant in the host, is a key factor in determining the length of a tuberculosis chemotherapy course. Therefore, the development of new effective combination treatment regimens is crucial to shortening the course of treatment for tuberculosis. The development of a novel anti-tuberculosis combined scheme can improve the curative effect, shorten the treatment time, improve the compliance of patients, reduce the side effect, reduce the cost and improve the cure rate.
The pyrifazimine (TBI-166) is a novel imine phenazine antituberculosis drug obtained by the cooperation of the subject group and the pharmaceutical research institute of the Chinese medical academy of sciences on the basis of the Clofazimine (CFZ) structure, has stronger antituberculosis activity and reduces adverse reactions such as skin staining. Clinical drug lots (lot number: 2016L10025/2016L 09987) from the food and drug administration (CFDA) were obtained in 2016, and currently, pirfenim is undergoing phase IIa clinical trials (CTR 20202345). OTB-658 is a novel oxazolidinone drug obtained by the cooperation of the subject group and the pharmaceutical research institute of Chinese academy of medical sciences and improved on the basis of Linezolid (LZD) structure, and has stronger antitubercular activity and greatly improved safety. Currently, OTB-658 is undergoing phase I clinical trials.
Figure BDA0003749463940000021
So far, no report about the combined application of the open edge of the pyridine and the OTB-658 and Bedaquin at home and abroad is available.
The invention provides a novel, simple and convenient novel combined drug regimen which is orally taken and consists of pyrifazimine, bedaquiline and OTB-658, and is used for treating drug-resistant tuberculosis, improving the curative effect of the drug-resistant tuberculosis and reducing the risk of relapse.
Disclosure of Invention
The invention provides a pharmaceutical composition for treating tuberculosis, which consists of piracetam (TBI-166), bedaquiline (BDQ) and OTB-658. Through comparison, analysis and evaluation of the drug combination in the mouse tuberculosis model, the drug combination has the advantages and potential of drug-resistant tuberculosis treatment.
The pharmaceutical composition of the invention comprises the following active pharmaceutical ingredients in parts by weight:
100-300mg of pyrifluazinam
Bedaquiline 100-300mg
OTB-658 300-600mg。
Preferably, the pharmaceutical composition of the present invention comprises the following pharmaceutical active ingredients in the following amounts:
100-200mg of pyrifluazinam
Bedaquin 100-200mg
OTB-658 300-600mg。
Further preferably, the pharmaceutical composition of the present invention comprises the following pharmaceutical active ingredients in amounts:
100-200mg of pyrifluazinam
Bedaquiline 200mg
OTB-658 300-600mg。
It is another object of the present invention to provide a process for the preparation of the pharmaceutical composition of the present invention.
The invention combines the 3 active ingredients according to the weight ratio, and is prepared according to the conventional method of pharmacy.
The pharmaceutical composition of the invention can be in any form of medicine which can be taken: such as: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, buccal agents, granules, pills, powders, ointments, pellets, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, patches.
Preferably, the pharmaceutical composition of the present invention is prepared into an oral preparation.
The pharmaceutical preparation composition of the present invention is preferably in the form of a unit dose pharmaceutical preparation, for example, when the pharmaceutical preparation composition is prepared into a medicament, the unit dose medicament can contain the pharmaceutical composition of the present invention, and the rest is pharmaceutically acceptable auxiliary materials. The pharmaceutically acceptable adjuvant may be 0.01-99.99% by weight of the total weight of the preparation.
The pharmaceutical preparation composition of the present invention is used in an amount determined according to the recommended or patient condition of the present invention, for example, 1 to 3 times a day. 1-20 tablets at a time, and the like.
Preferably, the pharmaceutical preparation composition of the present invention is an oral preparation. The oral preparation is selected from one of capsule, tablet, dripping pill, granule, concentrated pill and oral liquid.
The pharmaceutical preparation composition of the present invention, which is a preparation for oral administration, may contain auxiliary materials such as binders, fillers, diluents, tabletting agents, lubricants, disintegrants, coloring agents, flavoring agents and wetting agents, and the tablet may be coated if necessary.
Suitable fillers include cellulose, mannitol, lactose and other similar fillers. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
The pharmaceutical preparation of the present invention can be prepared into solid oral compositions by conventional methods such as mixing, filling, tabletting and the like. Repeated mixing can distribute the active throughout those compositions that use large amounts of filler.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate or acacia; non-aqueous carriers (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerol, propylene glycol or ethyl alcohol; preservatives, for example p-hydroxybenzyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
The pharmaceutical compositions of the present invention may be formulated as solid pharmaceutical preparations in the form of powders, tablets, dispersible powders, capsules, cachets, and solid carriers. The solid carrier which may be used is preferably one or more substances selected from diluents, flavouring agents, solubilising agents, lubricants, suspending agents, binders, bulking agents and the like, or may be an encapsulating substance. Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, cocoa butter, and the like. Because of their ease of administration, tablets, powders, cachets, capsules and the like represent the most advantageous oral solid dosage forms.
The invention also provides the dosage of the pharmaceutical composition.
The recommended dosage for treating the drug-resistant tuberculosis is TBI-166 and 100-200mg respectively; BDQ,200mg; OTB-658, 300-600mg; all are orally administered once a day.
The treatment course for the drug-resistant tuberculosis treatment is at least 6 months.
Another object of the present invention is to provide the use of the pharmaceutical composition in the preparation of a medicament for the treatment of tuberculosis.
In particular to the application in the medicine for treating drug-resistant tuberculosis.
The invention also provides the treatment course and the related experimental effect of the pharmaceutical composition.
By comparison with the BDQ + PMD + LZD (BPaL) combination in the mouse tuberculosis model, the course of treatment to be recommended for clinical application was the same as the BPaL combination, i.e. a course of treatment of 6 months. The present invention provides a recent efficacy assessment of a combination of fluazinam, bedaquiline and OTB-658. Based on comparison with BPaL in a mouse tuberculosis model, the 6-month treatment course of the pharmaceutical composition (TBI-166 + BDQ + OTB-658) is not inferior to the curative effect of the BPaL composition.
The invention also provides for the evaluation of recurrence following treatment of tuberculosis with a combination of pirfazimine, bedaquiline and OTB-658: based on the comparison with the BPaL combination in the mouse tuberculosis model, the treatment course of TBI-166+ BDQ + OTB-658 for 6 months is not inferior to the long-term curative effect of the BPaL combination.
The invention also provides a pharmaceutical combination package, which comprises a pyrifazimine tablet (the dosage of the active ingredients is 100-200 mg), a biddaloquinoline tablet (the dosage of the active ingredients is 200 mg) and an OTB-658 tablet (the dosage of the active ingredients is 300-600 mg).
Wherein, the tablet can be replaced by other oral preparations, such as capsule, granule, pill, powder, etc.
Wherein, the oral preparation is prepared according to a conventional method.
The main technical scheme of the invention comprises the following aspects:
1) The novel scheme of TBI-166 Bi+ BDQ BitB-658 combination is found to have equivalent or slightly superior curative effect on BPaL combination in C3HeB/FeJ mouse tuberculosis model.
2) The curative effect and the recurrence rate of the new scheme of the combination of TBI-166, BDQ, and BiSB-658 in a BALB/c mouse tuberculosis model are equivalent to those of the combination of BPaL.
Compared with the existing medicine scheme, the invention has the following advantages:
(1) the method is novel: no relevant report is found at home and abroad;
(2) the combined medicine is few, is orally taken and is convenient and easy to obtain;
(3) the treatment course is short: drug-resistant tuberculosis treatment for 6 months;
(4) the curative effect is good: comparable efficacy compared to BPaL regimen;
(5) the recurrence rate is low: the recurrence rate was similar compared to the BPaL regimen.
Drawings
FIG. 1, CFU counts of M.tuberculosis in lung tissue (left) and spleen (right) of C3HeB/FeJ mice on day 0 of treatment and 8 weeks after dosing in the C3HeB/FeJ mouse tuberculosis model.
CFU counts of M.tuberculosis in lung tissue (left) and spleen (right) of C3HeB/FeJ mice on day 0and 8 weeks after administration. All groups of combination groups in the figure significantly reduced colony counts compared to untreated groups. In C3HeB/FeJ, the bactericidal activity of all the drug combinations is obviously higher than that of the BPaL combination.
FIG. 2, comparison of efficacy of combination drug administration in BALB/c mouse tuberculosis model.
BALB/c mice tuberculosis model treatment mice lung and spleen colony Counts (CFU) after 2 weeks, 4 weeks, 8 weeks.
Detailed Description
The invention is described in detail below with reference to the drawings and examples, which are intended to be illustrative of the invention and not limiting.
Experimental example 1
According to the aerosol infection apparatus (099C A4224 infection Exposure System)) The standard protocol of (3) infection of SPF-grade female C3HeB/FeJ mice (6 weeks old, 20. + -.2 g body weight) with Mycobacterium tuberculosis Standard Strain H 37 R V (ATCC 27294), infection dose 3X 10 7 CFU/ml. After infection, mice were randomly picked and divided into 5 per cage. 3 mice were sacrificed 2 weeks and 3 weeks after infection and viable cell counts of lung and spleen tissues were performed. The drug treatment is started on day 21 of infection, the drugs are all made into suspension with 0.5 percent of CMC, the drug is once prepared with 5 times of drug amount per week, the drug is preserved at 4 ℃, the drug is orally administrated by stomach irrigation through warm water bath before administration, the administration volume is 0.3ml, and the drug is administrated 5 times per week. The mice in each group were sacrificed individually after a total of 8 weeks, all 3 days after drug withdrawal (to prevent residual effects of the drug). Dissecting under aseptic operation, treating group containing TBI-166 and BDQ, and applying 7H10 culture medium containing 0.4% activated carbon for viable count. The drug treatment groups were discontinued after 8 weeks of treatment, except for the CFU count for the dissection, 5 mice in each group were observed for 3 months, i.e. the dissection was performed 3 months after discontinuation, and the viable lung and spleen were counted to observe the recurrence.
The results show that: after 8 weeks of treatment, the mean CFU count in the lung was 8.22log10 CFU, in the spleen was 4.47log10 CFU, and each drug combination treatment had significant bactericidal effect (p < 0.001). Based on the combination of TBI-166+ BDQ + LZD, we compare the antitubercular activity of a new combination of OTB-658 replacing LZD by 50mg/kg or 100mg/kg (see the results in Table 1), and in this experiment we find that the antitubercular activity of other drug combinations including TBI-166+ BDQ + OTB-658 (100) is slightly better than that of BPaL combination (as shown in figure 1) except TBI-166+ BDQ + OTB-658 (50).
We also initially assessed the recurrence rate, with 5 mice per dose group, and withheld for 12 weeks after 8 weeks of treatment, with results shown in table 1. 1 of 5 mice (20%) recur after the TBI-166+ BDQ + LZD regimen is treated for 8 weeks and the drug is stopped for 12 weeks, while 5 of the group TBI-166+ BDQ + OTB-658 (50) recur with statistically significant differences (p < 0.05), and 3 of 5 of the group TBI-166+ BDQ + OTB-658 (100) recur, however, with no statistical significance.
TABLE 1 CFU counts in lungs and spleens at each treatment time point in the C3HeB/FeJ mouse model and relapse rates in mice after drug withdrawal
Figure BDA0003749463940000071
a D0 and W8 represent the number of days of treatment. D0: treatment was started 19 days after infection. W8: the treatment is carried out for 8 weeks. D: day(s); w: and (4) week. Values are mean ± standard deviation, n =5.
b Drug (abbreviation) and dose administered: bedaquiline (BDQ), 25mg/kg; pretomanid (PMD), 100mg/kg; linezolid (LZD), 100mg/kg; pyrifazimine (TBI-166), 20mg/kg; OTB-658 (50), 50mg/kg; OTB-658, 100mg/kg; BPaL, BDQ + PMD + LZD.
c Treatment 8 weeks drug withdrawal 12 weeks (W8 + W12), mice lung and spleen homogenates were cultured on 7H10 plates containing activated charcoal. * P<0.05 (compare to TBI-166+ BDQ + LZD group). n =5
Experimental example 2
Female BALB/c mice, 6 weeks old, weigh 18-20g and are acclimated for 1 week prior to the experiment. Mice were infected by aerosol inhalation using an aerosol infection device (099C A4224, glas-Col) to infect M.tuberculosis standard strain H37Rv. 3 mice were sacrificed at day 3 and week 4 post-infection to determine bacterial counts at the onset of infection and treatment, respectively. Treatment regimens were given with BPaL and TBI-166+ BDQ + OTB-658, respectively; blank negative control and 2 treatment regimen groups of mice were sacrificed 5 mice each after 2 weeks of treatment to assess EBA, and 5 mice per group were sacrificed 4 or 8 weeks of treatment to assess bactericidal activity of each regimen.
Table 2, figure 2 results show: in the tuberculosis infection model, after 2 weeks of treatment, the mean CFU count in the lungs of mice in the BPaL treated group is 3.99 + -0.47log10 CFU, and the mean CFU count in the lungs of mice in the TBI-166+, BDQ + OTB-658 treated group is 3.89 + -0.20log10 CFU. Both treatment regimen groups were significantly reduced compared to the blank control group and there was no statistical difference between the two groups, indicating that both treatment regimens showed clear early bactericidal activity, and that both treatment regimen groups treated for 8 weeks mice achieved lung and spleen tissue sterility, and that both treatment regimens had comparable bactericidal activity.
Table 2: CFU counting condition of lungs and spleens of mice in BPaL and TBI-166+BDQ+OTB-658 treatment group
Figure BDA0003749463940000091
D0, W2, W4, W8 represent each treatment time point. (D0): treatment was started 4 weeks after infection. Drug (abbreviation) and dose administered: bedaquiline (BDQ), 25mg/kg; pretomanid (PMD), 100mg/kg; linezolid (LZD), 100mg/kg; pyrifazimine (TBI-166), 20mg/kg; OTB-658, 100mg/kg; BPaL, BDQ + PMD + LZD. Experimental example 3
The bactericidal activity and bactericidal activity of the TBI-166+ BDQ + OTB-658 new protocol was further evaluated on a BALB/c mouse model: female BALB/c mice of 6 weeks old are divided into 6 cages, and are raised in a constant-temperature constant-humidity negative-pressure infected animal room for 1 week before the experiment to adapt to the environment. Atomizing to infect mice in two batches by aerosol infection device, wherein the infection dose is 5 multiplied by 10 5 CFU/ml. At 10 days and 4 weeks post-infection, 3 mice were sacrificed to determine the baseline number of tubercle bacillus in the lungs at the initiation of infection and at the beginning of treatment. Treatment with BPaL, TBI-166+ BDQ + LZD, TBI-166+ BDQ + OTB-658 begins 4 weeks after infection of BALB/c mice. The negative control group was given CMC. 6 mice per group were sacrificed 4 or 8 weeks after the administration of the treatment to evaluate the bactericidal activity of each protocol.
All drugs were dissolved or suspended in an aqueous solution containing 0.5% sodium carboxymethyl cellulose (CMC) in the form of single or multiple drugs at the respective drug concentrations: OTB-658 (100 mg/kg), TBI-166 (20 mg/kg), BDQ (25 mg/kg), PMD (100 mg/kg), LZD (100 mg/kg). Mice were dosed 5 days a week (monday to friday), 0.2ml each time. After 4 and 8 weeks of treatment, 6 mice per group were dissected. Taking out spleen and lung tissues, respectively soaking in 3.0ml of sterile normal saline, homogenizing, diluting the homogenized tissue suspension by 10,100and 1000 times, and uniformly coating 0.1ml of the homogenized stock solution and 3 graded diluents on a 7H10 solid culture plate. To reduce the effect of the migration effect of TBI-166 and BDQ on the results of the experiment, tissue homogenates of TBI-166 or BDQ treated mice were inoculated onto 7H10 solid culture plates supplemented with 0.4% charcoal (wt/vol) to eliminate the effect of residual TBI-166 on the results. All solid plates were incubated in a 5% carbon dioxide incubator at 37 ℃ for at least 4 weeks. The lung and spleen CFU counts were dissected for evaluation of relapse status for observation 3 months after 4 and 8 weeks of treatment, respectively, and 15 mice were given drug withdrawal.
Mice in each treatment group showed no growth, i.e., achieved sterility, of viable counts in lung and spleen tissue at 4 and 8 weeks of treatment, respectively. The recurrence rate for 3 months after 4 weeks of treatment is 69.23% (9/13) for the BPaL group and 33.33% (5/15) for the TBI-166+ BDQ + LZD group; the recurrence rate of TBI-166 Bib+OTB-658 group 60% (9/15) after 8 weeks of treatment is 0% (0/15) respectively for 3 months; 14.29% (2/14); 6.67% (1/15); three groups were equally effective in preventing relapse (table 3). The safety of each group of mice is good.
Table 3 relapse rates in mice treated with BPaL, TBI-166, BDQ, LZD and TBI-166, BDQ, OTB-658
Figure BDA0003749463940000101
Figure BDA0003749463940000111
a D0, W4, W8 represent each treatment time point. (D0): treatment was started 2 weeks after infection. (W4 + W12)/(W8 + W12): treatment was stopped for 12 weeks after the 4-week or 8-week dosing regimen. Mouse lung and spleen homogenates were cultured on 7H10 plates containing activated charcoal. ns, not significant (compared to BPaL). n =15.TBI-166 Bu BDQ+PZA group 1 mouse and BPaL group 2 mice die due to the accident of gavage.
b Drug (abbreviation) and dose: bedaquiline (BDQ), 25mg/kg; potomanib (PMD), 100mg/kg; linezolid (LZD), 100mg/kg; pyrifazimine (TBI-166), 20mg/kg; OTB-658 (100), 100mg/kg; BPaL, BDQ + PMD + LZD.
Example 1 pharmaceutical compositions of the invention
100mg of pyrifazimine
Bedaquiline 100mg
OTB-658 300mg。
Example 2 pharmaceutical compositions of the invention
Pifazimine 300mg
Bedaquiline 300mg
OTB-658 600mg。
Example 3 pharmaceutical compositions of the invention
100mg of pyrifazimine
Bedaquiline 100mg
OTB-658 300mg。
Example 4 pharmaceutical compositions of the invention
Pyrifazimine 200mg
Bedaquin 200mg
OTB-658 450mg。
Example 5 pharmaceutical compositions of the invention
100mg of pyrifazimine
Bedaquiline 100mg
OTB-658 600mg。
Example 6 pharmaceutical compositions of the invention
100mg of pyrifazimine
Bedaquiline 200mg
OTB-658 300mg。
Example 7 pharmaceutical compositions of the invention
Pyrifazimine 200mg
Bedaquin 200mg
OTB-658 600mg。
Example 8 pharmaceutical compositions of the invention
100mg of pyrifazimine
Bedaquiline 200mg
OTB-658 450mg。
Example 9 pharmaceutical compositions of the invention
Pifazimine 200mg
Bedaquiline 200mg
OTB-658 600mg。
Although specific embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these embodiments are merely illustrative and that various changes or modifications may be made without departing from the principles and spirit of the invention. The scope of the invention is therefore defined by the appended claims.

Claims (10)

1. The pharmaceutical composition for treating the drug-resistant tuberculosis is characterized in that the active component of the pharmaceutical composition comprises pyrifazimine (TBI-166) or pharmaceutically acceptable salt thereof; bedaquiline (BDQ) or a pharmaceutically acceptable salt thereof; OTB-658 or a pharmaceutically acceptable salt thereof.
2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical active ingredients are used in the following amounts:
100-300mg of pyrifluazinam
Bedaquiline 100-300mg
OTB-658 300-600mg。
3. The pharmaceutical composition according to claim 1, wherein the pharmaceutical active ingredients are used in the following amounts:
100-200mg of pyrifazimine
Bedaquin 100-200mg
OTB-658 300-600mg。
4. The pharmaceutical composition according to claim 1, wherein the pharmaceutical active ingredients are used in the following amounts:
100-200mg of pyrifazimine
Bedaquiline 200mg
OTB-658 300-600mg。
5. The pharmaceutical composition of claim 1, in any of the ingestible pharmaceutical forms: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, oral liquids, buccal agents, granules, electuary, pills, powders, ointments, pellets, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, patches.
6. A pharmaceutical preparation comprising the pharmaceutical composition of claim 5, further comprising pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients may be 0.01 to 99.99% by weight of the total weight of the preparation.
7. Use of a pharmaceutical composition according to claim 1 for the preparation of a medicament for the treatment of tuberculosis.
8. Use of a pharmaceutical composition according to claim 1 for the preparation of a medicament for the treatment of drug-resistant tuberculosis.
9. The pharmaceutical combination package is characterized by comprising the following components:
the dose of the active ingredients is 100-200mg of pyrifluzimine tablets, the dose of the active ingredients is 200mg of biddanoline tablets, and the dose of the active ingredients is 300-600mg of OTB-658 tablets.
10. Pharmaceutical combination package according to claim 9, wherein the tablets may be replaced by other oral preparations, such as capsules, granules, pills, powders, etc.
CN202210834772.XA 2022-07-16 2022-07-16 Medicine composition and application thereof Pending CN115350194A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
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CN108727406A (en) * 2017-03-28 2018-11-02 中国医学科学院药物研究所 The cyclosubstituted benzene of nitrogen-containing hetero and Evil piperazine oxazolidinone compounds and its preparation method and application
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Application publication date: 20221118