TW201821075A - Pharmaceutical composition of Minocycline and manufacturing method thereof - Google Patents

Abstract

The present disclosure relates to a pharmaceutical composition comprising Minocycline for treating Acinetobacter bacteria infection. The present disclosure also relates to a pharmaceutical composition comprising Minocycline and other compound(s) for treating Acinetobacter baumannii infection.

Description

 Merino tetracycline pharmaceutical composition and preparation method thereof  

The present disclosure relates to a pharmaceutical composition for treating Gram-negative bacilli or Acinetobacter infection, using Minocycline alone or in combination with other compounds.

Gram-negative bacilli are one of the important causes of nosocomial infections. Acinetobacter is a type of Gram-negative bacilli that does not ferment sugars. Its size is 2.0μm×1.2μm, but its shape is mostly spherical. It can exist in a single shape, but it is often arranged in pairs, sometimes forming a chain, in solid medium. It is mainly caused by diplococcus, and the liquid medium is mostly short rod-shaped and even filamentous. Gram staining is often difficult to decolorize, so it is easy to cause false positive bacteria. Acinetobacter is widely found in nature, mainly in water and soil, and can also be isolated from healthy human skin, saliva, pharynx, eyes, ears, respiratory tract, genitourinary tract and other parts. The bacteria can also be detected in milk, dairy products, poultry and frozen foods. The virulence of the bacterium is not strong, and Acinetobacter baumannii has strong pathogenicity. Under normal circumstances, it does not cause infection, and when the host's resistance is lowered, it can cause disease.

Acinetobacter is an opportunistic pathogen that does not cause disease in general and can cause infection only when the host's resistance is reduced. The main pathogenic factors are bacteriocin, capsule, and pili. Severe primary disease, such as chronic lung disease, malignant tumors, burns and low immune function can often lead to the incidence of this infection. In hospitals, due to the large or long-term application of steroids, immunosuppressive agents and antibiotics, the human immune function is low and the normal flora imbalance in the body is the main cause of sepsis in hospital infections. It is still not easy to control, and there are resistant strains. There are problems such as one after another.

The objectives and advantages of the disclosure are described in part or in the description.

It is an object of the present invention to provide a pharmaceutical composition or solid preparation for treating Acinetobacter infection comprising Minocycline and a pharmaceutically acceptable carrier, excipient or diluent. Among them, the Acinetobacter is selected from Acinetobacter baumannii. Further, the pharmaceutical composition or solid preparation comprises menocycline and at least one anti-living agent or an antibiotic selected from the group consisting of antibiotics, wherein the pharmaceutical composition or the solid preparation is obtained by: forming the beauty And a tetracycline and the enhancer, the antibiotic or an aqueous solution of the mixture of the enhancer and the antibiotic; and converting the aqueous solution into the pharmaceutical composition or the solid preparation.

Another object of the present invention is to provide a combination pharmaceutical composition for treating Acinetobacter baumannii infection comprising Minocycline and at least one additional compound, and a pharmaceutically acceptable carrier, excipient or diluent . Among them, the additional compound is selected from the group consisting of sulbactam, colistin, imipenem, meropenem and one of the anti-life-promoting agents for promoting antibiotics. Wherein the enhancer is selected from the group consisting of:

And mixing of at least two of the above.

Minocycline is an antibiotic and has the function of inhibiting the production of bacterial proteins and can treat many different parts of the body and various bacterial infections such as bronchitis, keratitis, gastrointestinal infections, pharyngitis, pneumonia, sinusitis, urinary tract infections, and Skin infections. In recent years, studies have indicated that menocycline has anti-microbial effects including inhibition of matrix metalloproteinases (Golub, LM et al., 1991), inhibition of tumor-induced vascular proliferation (Maragoudakis, ME et al., 1994), inhibition of malignancy. Cell growth (Masumori, N., et al 1994) and inhibition of bone resorption (Rifkin, BR et al., 1994), inhibition of oxygen free radical release from polymorphonuclear neutrophils (Gabler, W. & Creamer, H , 1991; Gabler, W., Smith, J. & Tsukuda, N. 1992), Inducible nitric oxide synthase (iNOS) [a regulator of inflammatory response (Amin, ARet) Al., 1996)] inhibits nitrification of tyrosine protein by scavenging peroxynitrite (Whiteman, M. & Halliwell, B. 1997). Experimental and clinical studies have shown that menocycline can effectively inhibit rheumatoid arthritis and other inflammatory diseases (Furst, DE 1998; Nordstrom, D. et al., 1998; Greenwald, RA et al., 1992) In 1998, Yrjanheikki, et al. proposed that menocycline has neuroprotective effects in cerebral ischemia experiments, and in 2001, Rene O, et al. pointed out that after the brain was injured by external forces, Caspase-1 and Capase-3 is locally activated in neurons, and the patient can be given tetracycline to reduce damage to tissues, thus confirming that Traumatic brain injury promotes neuronal cell loss and neurological dysfunction and cell death. The path of Apoptotic is activated (Chen M. et al., 2000; Contic AC. et al., 1998; Fink KB. et al., 1999; O'Dell DM. et al., 2000; Sinson G .et al., 1997; Yakovlev AG. et al., 1997). In addition, menocycline inhibits the expression of Caspase-1 and Capase-3 and delays cell or animal death in Huntington's gene transfer mouse model (Chen M. et al., 2000) ).

The structural formula of Miele tetracycline is as follows:

Its chemical structure consists of four rings, which are also called "tetracyclic" antibiotics. Miminotetracycline is highly soluble, has a half-life of 11-26 hours, and has a high penetration of the Blood Brain Barrier. For a method for synthesizing Mieletetracycline, reference may be made to the method for synthesizing Mirin tetracycline disclosed in U.S. Patent Nos. 3,418,182, 3,226,436, and 4,948,136. Most of the current preparations such as injections, sustained release agents and the like are menocycline hydrochloride. Therefore, the use of minocycline hydrochloride which is stable and easy to produce, transport and store is beneficial to the use of minocycline hydrochloride.

The chemical name of Compound A in Chinese is (4 R , 4a S , 5a R , 12a S )-4,7-bis(dimethylamine)-3,10,12,12a-tetrahydroxy-1,11-dioxo- 1,4,4a,5,5a,6,11,12a-octahydrotetraphenyl-2-carboacetamide (hereinafter referred to as tetracycline A), the structural formula of tetracycline A is as follows:

For the synthesis and correlation analysis of tetracycline A, reference can be made to the paper J. Chromato. Sci., 16, 93-101 (1978).

The chemical name of Compound B in Chinese is (4 S , 4a S , 5a R , 12a S )-4-(dimethylamine)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4 , 4a, 5, 5a, 6, 11, 12a-octahydrotetraphenyl-2-carboacetamide (hereinafter referred to as tetracycline B), the structural formula of tetracycline B is as follows:

For information on the synthesis and correlation analysis of tetracycline B, refer to the paper Conover et al. J. Am. Chem. Soc. 84: 3222-24, 1962.

The chemical name of compound C in Chinese is (4 S , 4a S , 5a R , 12a S )-7-amino-4-(dimethylamine)-3,10,12,12a-tetrahydroxy-1,11-di Oxygen-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboacetamide (hereinafter referred to as tetracycline C), the structural formula of tetracycline C is as follows:

For information on the synthesis and correlation analysis of tetracycline C, reference is made to U.S. Patent No. 8,492,365.

The Chinese chemical name of Compound D is (4 S , 4a S , 5a R , 12a S )-4-(dimethylamine)-3,10,12,12a-tetrahydroxy-7-(methylamine)-1,11 -Dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboacetamide (hereinafter referred to as tetracycline D), the structural formula of tetracycline D is as follows:

For the synthesis and correlation analysis of tetracycline D, reference is made to US Pat. No. 7,214,669.

The present disclosure provides a solid preparation or a pharmaceutical composition having improved anti-life, comprising Minocycline and an anti-living agent for promoting antibiotics as described above (for example, tetracycline A, tetracycline B, Tetracycline C and tetracycline D) or another antibiotic. Wherein the solid preparation or the pharmaceutical composition is obtained by forming the menocycline and the enhancer, the antibiotic or an aqueous solution of the enhancer mixed with the antibiotic; and converting the aqueous solution into the solid preparation or medicine Composition.

According to the present disclosure, the other antibiotic may be selected from the group consisting of: amikacin, apramycin, arbekacin, bambermycins, butinosin. ), dibekacin, dihydrostreptomycin, fortimicin, gentamicin, isepamicin, kanamycin , micronomicin, neomycin, netilmicin, paromomycin, ribostamycin, sisomicin, spectinomycin (spectinomycin), streptomycin, tobramycin, trospectomycin; chloramphenicol antibiotics (amphenicols), such as azidofenicol, chloramphenicol ( Chloramphenicol), florfenicol, thiamphenicol; ansamycins, such as rifamide, rifampin, rifampic Sifamycin sv, rifapentine, rifaximin, beta-lactam (beta-lac) Tam), comprising: carbacephem, such as loracarbef; carbapenems, biapenem, imipenem, meropenem ( Meropenem), panipenem; cephalosporins, such as cefaclor, cefadoxil, cefmandole, ceficizine ), cefezedone, cefazolin, cefcapene pivoxil, cefclidin, cefdinir, cefditoren, cefepime (cefepime), cefetamet, cefixime, cefodizime, cefonicid, cefoperazone, ceforanide, ceflin (cefotaxime), cefotiam, cefozopran, cefpimizole, cefpiramide, cefpifome, cefpodoxime proxetil, cefprozil Cefprozil), cefroxadine, Cefsulodin, ceftazidime, cefteram, ceftezole, ceftibuten, ceftizoxime, ceftrixone , cefuroxime, cefuzonam, cephacetrile sodium, cephalexin, cephaloglycin, cephaloridine, cephalosporin (cephalosporin), cephalothin, cephapirin sodium, cephradine, cephamycins, cefbuperazone, cefotetan ), cefoxitin, monobactams, aztreonam, carumonam, tigemonam, oxygen cephem antibiotics (oxacephems), flomoxef, moxalactam, penicillins, amdinocillin, amoxicillin, ampicillin, apalcillin Apalcillin), apocylin (aspoxic) Illin), azidocillin, azlocillin, bacampicillin, benzylpenicillin sodium, carbenicillin, carindacillin, clindacillin Crometocillin), cloxacillin, cyclacillin, dicloxacillin, epicillin, fenbenicillin, floxacillin, hetacillin ), lenampicillin, metampicillin, methicillin sodium, mezlocillin, nafcillin sodium, oxacillin, culture Peasecillin, penicillin G, penicillin N, penicillin O, penicillin V, penimepicycline, phenethicillin potassium , piperacillin, pivampicillin, propicillin, quinacillin, sulbenicillin, sultamicin Illin), talampicillin, temocillin, ticarcillin, ritipenem, lincosamides, clindamycin, forest Lincomycin, macrolides, azithromycin, carbomycin, clarithromycin, dihithromycin, erythromycin , josamycin, leucomycin, midecamycin, miokamycin, oleandomycin, primycin, rosin Rokitamycin, rosaramicin, roxithromycin, spiramycin, treleandomycin, polypeptides, amphomycin , bacitracin, capreomycin, colistin, enramycin, enviomycin, fusafungine, Brevibacterium Peptidin S, mikamycin, polymyxin B (polymyxin B), pristinamycin, ristocetin, teicoplanin, thiostrepton, tuberactinomycin, bacillus Tyrocidine, tyrothricin, vancomycin, viomycin, virginiamycin, tetracyclines, apicycline, gold mold Chlortetracycline, clomocycline, demeclocycline, doxycycline, guamecycline, lymecycline, and clocycline Meclocycline), methacycline, oxytetracycline, penimepicycline, pipacycline, rolitetracycline, sancycline, tetracycline (tetracycline), cycloserine, mupirocin, synthetic antibacterials, 2,4-siaminopyrimidines, bromop Lin (brodimoprim), tetraoxyn (tetroxopri m), trimethoprim, nitrofurans, furaltadone, furazolium chloride, nifuradene, nifuratel ), nifurfoline, nifurpirinol, nifurprazine, nifurtoinol, quinolones and analogs, west Cinoxacin, ciprofloxacin, clinafloxacin, difloxacin, enoxacin, fleroxacin, flumequine ), grepafloxacin, lomefloxacin, miloxacin, nadifloxacin, nalidixic acid, norfloxacin, Ofloxacin, oxolinic acid, pazufloxacin, pefloxacin, pipemidic acid, piromidic acid, lo Rosaoxacin, rufloxacin, sparfloxacin, temafloxa Cin), tosufloxacin, trovafloxacin, sulfonamides, benzylsulfamide, chloramine-B, chloramine-T, Dichloramine T, mafenide, noprylsulfamide, phthalylsulfacetamide, phthalylsulfathiazole, salazosulfadimidine, amber sulfathiazole Succinylsulfathiazole), sulfabenzamide, sulfacetamide, sulfachlorpyridazine, sulfachrysoidine, sulfacytine, sulfadiazine, sulfadicramide ), sulfadimethoxine, sulfadoxine, sulbactam, sulfaethidole, sulfaguanidine, sulfaguanol, sulfonamide Sulfalene, sulfaloxic acid, sulfamerazine, sulfameter, sulfamethazine, sulfonamide Sulfamethizole, sulfamethoxazole, sulfamethoxypyridazine, sulfametrole, sulfamidochrysoidine, sulfamoxole, sulfanilamide , sulfanilylurea, sulfanitran, sulfaphenazole, sulfaproxyline, sulfapyrazine, sulfapyridine, sulfasomizole, sulfonamide Sulfasymazine, sulfathiazole, sulfathiourea, sulfatolamide, sulfisomidine, sulfisoxazole; sulfones, vinegar Acedapsone, acediasulfone, acetosulfone sodium, dapsone, diathymosulfone, glucosulfone sodium, styrene-acrylic acid Solasulfone, succisulfone, sulfanilic acid, sulfoxone sodium, chlorfluoxol (cl Ofoctol), hexedine, methenamine, nitroxoline, taurolidine, and combinations of at least two of the foregoing.

The pharmaceutical compositions of the present disclosure can be formulated into a suitable dosage form for parenteral or oral administration using techniques well known in the art, including, but not limited to, injections, such as, for example, injections, Sterile aqueous solutions or dispersions, lyophilized dosage forms, sterile powder dosage forms, lozenges, tablets, pills, capsules, and the like. In the manufacture of the pharmaceutical composition of the present disclosure, the menocycline may be mixed with the enhancer or other antibiotics or separately into a drug component suitable for administration and then packaged into a dosage form suitable for administration.

Preferably, the pharmaceutical composition according to the present disclosure may be manufactured into a dosage form suitable for injection, which may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion. A liquid, as well as a sterile lyophilized powder for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and non-aqueous carriers, diluents, solvents, including water, ethanol, propylene glycol, polyethylene glycol, glycerin, olive oil, and the like, and such as ethyl oil An organic ester for the injection of an acid salt.

As used herein, the term "therapeutically effective amount" means that when a pharmaceutical composition or solid preparation according to the present disclosure is administered to an individual in need of treatment with the pharmaceutical composition, it is sufficient to provide the desired therapeutic effect. Do not cause serious harm to the individual's body organs or tissues. The therapeutically effective amount will vary depending on various factors including, for example, the type of disorder, the weight, age, physical condition and response of the individual to be treated, the route of administration of the drug, and the like. This therapeutically effective amount can be determined by those skilled in the art.

The pharmaceutical composition or the solid preparation according to the present disclosure may be administered in a single dose or divided into several doses via parenteral or oral administration, and the antibiotic and the enhancer or another antibiotic are two drugs. Or the three drug components can be administered simultaneously or separately. The dosage and the number of administrations of the pharmaceutical composition or the solid preparation according to the present disclosure may vary depending on the severity of the disease to be treated, the route of administration, and the weight, age, physical condition and reaction of the individual to be treated. .

The disclosure will be further illustrated by the following examples, but it should be understood that these examples are for illustrative purposes only and are not to be construed as limiting.

Checkerboard assay

The checkerboard bactericidal test is an in vitro test to test the combined effect of antibiotics (see Jorgensenm, JH and Turnidge, JD, 2003, Manual of Clinical Microbiology). Step (1) The two compounds or compound combinations to be tested α, β are successively diluted to a concentration gradient by a multiple of Mueller Hinton Broth (BD, Cat. No. 296164), for example, 1 time, 1/2 times, 1/4 times, 1/8 times, 1/16 times, 1/32 times, 1/64 times, and a concentration range of 0 (Broth only), so a total of 8x8=64 holes are used, leaving the rest of the plate 32 holes; step (2) in the 96-well plate, according to the same concentration gradient, uniformly mix 100μL of each compound α, β, to reach a volume of 200μL; step (3) add bacteria liquid to make each hole the final bacterial liquid The concentration was approximately 10 ⁵ CFU/mL, in which subsequent strains were inoculated on Muller's Hilton blood agar plate (see, National Committee for Clinical Laboratory Standards, 2002) and placed in a 37 ° C incubator overnight. The colonies were scraped with a cotton swab and inoculated into a 5 ml tube containing 2 mL of 0.85% NaCl and adjusted to a turbidity of McFarland 0.5. 1 ml of the bacterial solution was added to 4 ml of Mueller Hinton Broth. 5 μL of the bacterial solution was added to the compound α, β solution which had been prepared as described above to reach a final bacterial concentration of about 10 ⁵ CFU/mL; and step (4) was placed in a 35 ± 2 ° C incubator overnight, and then visually removed from the naked eye. The turbidity was observed at the bottom of the 96-well plate, and the lowest antibiotic concentration without bacteria growth was recorded, which is the MIC and the range of the combined inhibitory concentration was also read. The combined inhibition range can be used to determine the fractional inhibitory concentration index (FICI): FICI = MIC [α] combination / MIC [α] alone + MIC [β] combination / MIC [β] alone

Synergyism, 0.5: addition (synergism)

Indifference,>0.5-4: no difference (indifference)

Antagonism,>4: Antagonism

Since the resistance of each strain is different, the initial concentration setting of the compound will be different. The detailed initial concentration is shown in the following groups.

The Acinetobacter baumannii tested in the present disclosure was obtained from various medical institutions. In the Sequencing type database of the medical institution, there were 83 strains of Acinetobacter baumannii. Among them, sequence type 208 accounted for 10 strains, sequence type 218 accounted for 12 strains, sequence type 455 accounted for 15 strains, sequence type 555 accounted for 5 strains, sequence type 556 accounted for 4 strains and sequence type 685 accounted for 2 strains.

As shown in Table 1, the sequence of the selected 10 strains of Acinetobacter baumannii can cover most of the sequence types in the Acinetobacter baumannii database in medical institutions, and is not specifically selected for Acinetobacter baumannii.

The disclosure discloses that the minimum inhibitory concentration (MIC) of menocycline for the above 10 strains of Acinetobacter baumannii is as follows:  

This disclosure will be based on the minimum inhibitory concentration (MIC) pre-measured in Table 2 to design the MIC and FICI of Mieletetracycline (referred to as Mino in Table 3) and other enhancer combinations or antibiotics to facilitate the determination of Mieletetracycline and other enhancers. Whether the combination of the combination or the antibiotic has a synergy effect on the above 10 strains of Acinetobacter baumannii, the results are summarized in Table 3 below.

As shown in Table 3, the enhancer with improved resistance to life did reduce the value of the Inhibitory Concentration Index (FICI), thus confirming that the enhancer does have the effect of synergy. If the MIC concentration (μg/mL) of the MIC[α] combination of Mino in Table 3 is divided by the MIC concentration (μg/mL) of tetracycline A or tetracycline B (the MIC concentration of tetracycline B is the same as tetracycline C and tetracycline B) The range of the weight ratio of menocycline to tetracycline A or tetracycline B can be obtained.

For example, in the strain of strain No. 2010JRL180, in the group of menocycline and mixed tetracycline A to tetracycline C, it can be seen from Table 3 that the concentration of MIC of menocycline alone is 4 μg/mL, and tetracycline A, tetracycline The individual MIC concentrations of B and tetracycline C were 6 μg/mL, 2 μg/mL, and 2 μg/mL, respectively. When the combination of menocycline and tetracycline A, tetracycline B and tetracycline C was combined, the MIC[α] combination concentration of menocycline was 1.6 μg/mL, and the MIC [β] combination concentration of tetracycline A was observed. 0.0176 μg/mL, and the combined concentration of tetracycline B and C in MIC [β] was 0.0059 μg/mL. Dividing 0.0176 by 1.6 is 0.011. If 0.0059 is divided by 1.6 to 0.0037, the weight ratio of tetracycline A to menocycline is 0.011, and the weight ratio of tetracycline B to menocycline is 0.0037. After finishing Table 3, it is found that the weight ratio of tetracycline A to menocycline ranges from 0.005 to 0.059, and the weight ratio of tetracyclines B, C, and D to menocycline is in the range of 0.00167 to 0.0167. In other words, the weight percentage ratio of tetracycline A to menocycline ranges from 0.5% to 5.9%, and the weight percentage of tetracycline B, C, D and menocycline ranges from 0.167% to 1.967%. Similarly, after finishing Table 3, it can be seen that the weight ratio of imipenem to menocycline ranges from 0.018186 to 0.586625, so the weight percentage of imipenem and metotetracycline ranges from 1.8667% to 58.6625%. The weight ratio of meropenem to menocycline ranges from 0.0133 to 0.490625, so the weight percentage of meropenem and menocycline ranges from 1.33% to 49.0625%. The weight ratio of sabberta to menocycline ranges from 0.0453 to 0.33, so the weight percentage of sabetta and minocycline ranges from 4.53% to 33%. The weight ratio of colistatin to menocycline ranges from 0.003167 to 0.038, so the weight percentage of colistin and metotetracycline ranges from 0.3167% to 3.8%.

In one embodiment of the present disclosure, the content of the pharmaceutical composition, wherein the weight percentage of the tetracycline A to the menocycline is between 0.5% and 5.9%, and the weight percentage of the tetracycline B and the menocycline It is between 0.167% and 1.967%, and the weight percentage of the tetracycline C to the menocycline is between 0.167% and 1.967%. In another embodiment, the content of the pharmaceutical composition, wherein the weight percentage of the tetracycline A to the menocycline is between 1.3% and 5.7%, and the weight percentage of the tetracycline B and the menocycline is The ratio by weight of the tetracycline C to the menocycline is from 0.433% to 1.9%, and the weight percentage of the tetracycline D to the menocycline is from 0.433% to 1.9%.

In still another embodiment, the content of the pharmaceutical composition, wherein the weight percentage of the tetracycline A to the menocycline is between 2.9% and 4.7%, and the weight percentage of the tetracycline B and the menocycline is Between 0.967% and 1.567%, and the weight percentage of the tetracycline C to the menocycline is between 0.967% and 1.567%, and the weight percentage of the tetracycline D to the menocycline is between 0.967% and 1.567%, and The percentage ratio of the sabetta to the menocycline is between 4.53% and 33%. In other embodiments, the contents of the pharmaceutical composition, wherein the weight percentage of the tetracycline A to the menocycline is between 3.5% and 5.1%, and the weight percentage of the tetracycline B to the menocycline is between 1.167% to 1.7%, and the weight percentage ratio of the tetracycline C to the menocycline is between 1.167% and 1.7%, and the weight percentage of the tetracycline D to the menocycline is between 1.167% and 1.7%, and the ratio is The weight percentage of colistin and the menocycline is between 0.3167% and 3.8%.

In an additional embodiment, the content of the pharmaceutical composition, wherein the weight percentage of the tetracycline A to the menocycline is between 0.9% and 2.5%, and the weight percentage of the tetracycline B to the menocycline is between 0.3% to 0.833%, and the weight percentage ratio of the tetracycline C to the menocycline is from 0.3% to 0.833%, and the weight percentage ratio of the tetracycline D to the menocycline is from 0.3% to 0.833%, and the ratio is The weight percentage of imipenem to the menocycline is between 1.8667% and 58.6625%. In still another embodiment, the content of the pharmaceutical composition, wherein the weight percentage of the tetracycline A to the menocycline is between 1.7% and 4.3%, and the weight percentage of the tetracycline B and the menocycline is Between 0.567% and 1.433%, and the weight percentage of the tetracycline C to the menocycline is from 0.567% to 1.433%, and the weight percentage of the tetracycline D to the menocycline is from 0.567% to 1.433%, and The weight percentage of the meropenem and the menocycline is between 1.33% and 49.0625%.

The present disclosure are computed by the test agent or compound dissolved in water, and are provided in weight percent, 88% to 94 a method of treating is selected from Acinetobacter baumannii (A.baumannii) infected for preparing a pharmaceutical composition, the method comprising %:1-6%:0.1-2%:0.1-2%:0.1-2%, after mixing Minocycline, tetracycline A, tetracycline B, tetracycline C and tetracycline D, dissolved in a hydrogen chloride aqueous solution as a solvent And adjusting to a pH between 2 and 2.5, and finally freeze drying the pharmaceutical composition. In other embodiments, the method comprises mixing Minocycline, tetracycline A at a weight percentage of 88%-94%: 1-6%: 0.1-2%: 0.1-2%: 0.1-2%, respectively. After tetracycline B, tetracycline C and tetracycline D, the solution is dissolved in an aqueous solution and adjusted to a pH of between 2 and 2.5 with hydrogen chloride, and finally the pharmaceutical composition is freeze-dried.

Claims (13)

 A Minocycline pharmaceutical composition for Acinetobacter baumannii, comprising: menocycline and at least one anti-living agent selected from the group consisting of antibiotics and an antibiotic, wherein the pharmaceutical composition is obtained by the following means Obtaining: forming the menocycline and the enhancer, the antibiotic or an aqueous solution of the mixture of the enhancer and the antibiotic; and converting the aqueous solution into the pharmaceutical composition.   The pharmaceutical composition of claim 1, wherein the enhancer is selected from the group consisting of And mixing of at least two of the above.  The pharmaceutical composition of claim 2, wherein the antibiotic is selected from the group consisting of sulbactam, colistin, imipenem, and meropenem.    The pharmaceutical composition of claim 2, wherein the weight percentage of the formula (I) and the Mielecycline is between 0.5% and 5.9%, and the weight percentage of the formula (II) and the Mielecycline is The ratio is from 0.167% to 1.967%, and the weight percentage of the formula (III) and the menocycline is from 0.167% to 1.967%.    The pharmaceutical composition of claim 2, wherein the weight percentage of the formula (I) and the Mielecycline is between 1.3% and 5.7%, and the weight percentage of the formula (II) and the Mielecycline is Between 0.433% and 1.9%, and the weight percentage of the formula (III) and the Mielecycline is between 0.433% and 1.9%, and the weight percentage of the formula (4) and the Mielecycline is between 0.433% and 1.9%.    The pharmaceutical composition of claim 3, wherein the weight percentage of the formula (I) and the Mielecycline is between 2.9% and 4.7%, and the weight percentage of the formula (II) and the Mielecycline is Between 0.967% and 1.567%, and the weight percentage of the formula (III) and the Mielecycline is between 0.967% and 1.567%, and the weight percentage of the formula (4) and the Mielecycline is between 0.967% and 1.567%, and the weight percentage of the sabetta and the menocycline is between 4.53% and 33%.    The pharmaceutical composition according to Item 3, wherein the weight percentage of the formula (I) and the Mielecycline is between 3.5% and 5.1%, and the weight percentage of the formula (II) and the Mielecycline is Between 1.167% and 1.7%, and the weight percentage of the formula (III) and the menocycline is between 1.167% and 1.7%, and the weight percentage of the formula (4) and the menocycline is 1.167% to 1.7%, and the weight percentage ratio of the Cristin to the menocycline is between 0.3167% and 3.8%.    The pharmaceutical composition of claim 3, wherein the weight percentage of the formula (I) and the Mielecycline is between 0.9% and 2.5%, and the weight percentage of the formula (II) and the Mielecycline is Between 0.3% and 0.833%, and the weight percentage of the formula (III) and the Mielecycline is between 0.3% and 0.833%, and the weight percentage of the formula (4) and the Mielecycline is between 0.3% and 0.833%, and the weight percentage of the imipenem and the menocycline is between 1.8667% and 58.6625%.    The pharmaceutical composition of claim 3, wherein the weight percentage of the formula (I) and the Mielecycline is between 1.7% and 4.3%, and the weight percentage of the formula (II) and the Mielecycline is Between 0.567% and 1.433%, and the weight percentage of the formula (III) and the Mielecycline is between 0.567% and 1.433%, and the weight percentage ratio of the formula (4) to the Mielecycline is 0.567% to 1.433%, and the weight percentage ratio of the meropenem to the menocycline is between 1.33% and 49.0625%.    The pharmaceutical composition of claim 2, wherein the weight ratio of the menocycline to the antibiotic is in the range of 0.3167% to 58.6625%.    The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is for parenteral administration.    The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is for intravenous administration.   A method of treating is selected from Acinetobacter baumannii (A.baumannii) infected for preparing a pharmaceutical composition, comprising: a percentage by weight, respectively, of 88% -94%: 1-6%: 0.1%: 0.1 2%: 0.1-2%, mixed with Minocycline, tetracycline A, tetracycline B, tetracycline C and tetracycline D; dissolved in a hydrogen chloride aqueous solution as a solvent and adjusted to a pH between 2 and 2.5; and frozen The pharmaceutical composition is dried.