CN102441171A - Local temperature-sensitive antibacterial drug sustained-release agent and preparation method thereof - Google Patents

Abstract

The present invention relates to the technical field of medical biomaterials. In recent years, local antibacterial slow-release dosage forms have attracted great attention, but these preparation materials do not have temperature-sensitive properties, and there are problems such as biocompatibility and biodegradability. And this kind of slow-release preparation method is complicated. The invention provides a temperature-sensitive sustained-release dosage form of antibacterial drugs for local use and a preparation method thereof. Temperature-sensitive properties, embedding antibacterial drugs, and preparing a local injectable or implantable temperature-sensitive drug sustained-release preparation. The sustained-release agent of the present invention is injected or implanted into a lesion or an operation site to realize local sustained-release medication for preventing or treating bacterial infection. The invention has the advantages of injectable temperature sensitivity, maintaining local effective drug concentration, good biocompatibility, biodegradability, not affecting wound healing and the like.

Description

A kind of topical temperature-sensitive antibacterial slow-release agent and preparation method thereof

technical field

The invention relates to the technical field of medical biomaterials, in particular to a locally applied temperature-sensitive antimicrobial slow-release agent and a preparation method thereof.

Background technique

The treatment of bacterial infection is mainly through oral, intravenous, intramuscular injection of antibacterial drugs and other systemic administration methods, and the drugs are absorbed into the blood circulation to play a therapeutic role. However, its disadvantage is that for many chronic lesions, especially local lesions, due to poor blood circulation and low blood drug concentration, it is impossible to obtain a sustained and effective drug concentration at the lesion site, which is not enough to kill bacteria completely, and increasing the drug dose is also necessary. Will be limited by drug side effects. At the same time, the frequency of administration is frequent, which also brings pain and inconvenience to patients.

Therefore, in recent years, sustained-release formulations of topical antimicrobials have attracted great attention. Such as Chinese patent application CN200810301576.6, title of invention: a slow-release injection containing antibiotics, publication number: CN101283981; Chinese patent application CN200810301569.6, title of invention: a slow-release injection containing antibiotics and its application, publication number: CN101301270; Chinese patent application CN200610200474.6, title of invention: a locally applied antibiotic sustained-release agent, publication number: CN1883706, etc., by preparing an injectable locally-used antibacterial drug sustained-release preparation, maintaining local effective drug concentration, and treating role. However, these preparation materials do not have temperature-sensitive properties, and there are problems such as biocompatibility and biodegradability, and the preparation methods for such sustained release are complicated.

Thermosensitive hydroxybutyl chitosan is chemically modified by natural polymer polysaccharide chitosan, and the hydroxybutyl group is grafted onto the molecular backbone of chitosan. The introduction of hydrophilic groups changes the Hydrogen bonding within the aqueous system balances the system, resulting in temperature sensitivity. Hydroxybutyl chitosan has good water solubility and temperature sensitivity, its phase transition temperature is low, and its gelation speed is fast. It can form a gel with a certain strength within 60 seconds at 37 ° C, and its temperature sensitivity It is reversible (refer to the Chinese patent CN200910052695.7 filed by the applicant on June 9, 2009, title of the invention: temperature-sensitive chitosan preparation and its preparation and application, publication number: CN101579353).

The preparation and biological function research of temperature-sensitive hydroxybutyl chitosan has just started in the world, and the application research in the slow-release drug delivery system has not been reported yet.

Contents of the invention

The object of the present invention is to provide a temperature-sensitive antibacterial slow-release agent for local application. Another object of the present invention is to provide a preparation method of the temperature-sensitive antibacterial slow-release agent.

The present invention specifically uses the temperature-sensitive degradable biomaterial hydroxybutyl chitosan as a slow-release carrier, uniformly embeds antibacterial drugs under low temperature conditions, and prepares antibacterial drug slow-release gel preparations, which are injected or implanted locally Infected foci, or surgical sites, for the treatment or prevention of localized infections. It is in a solution state at low temperature and in a gel state at human physiological temperature. Taking advantage of this temperature-sensitive property, the hydrogel can dissolve water-soluble antibacterial drugs when it is in a low-temperature solution state; and when injected into human tissues such as subcutaneous and muscle, the solution containing antibacterial drugs can be quickly transformed into a gel in situ. When the antimicrobial drug has been evenly distributed in the gel, it will be released from the gel smoothly under the dual promotion of diffusion and gel self-degradation in the body, so as to achieve the purpose of sustained release of the drug.

The invention provides a temperature-sensitive antimicrobial slow-release agent for topical use. The slow-release agent is prepared by the following method: firstly, homogeneous oxybutane is prepared at low temperature or normal temperature (greater than 0°C and less than 20°C). base chitosan solution, and then evenly disperse and embed the antibacterial drug in it, and stir evenly, that is, the antibacterial drug sustained-release agent with hydroxybutyl chitosan as the sustained-release carrier.

The above-mentioned temperature-sensitive antimicrobial sustained-release preparation may be a sustained-release injection or a sustained-release implant.

The present invention also provides a method for preparing a local temperature-sensitive antimicrobial slow-release agent. The method specifically comprises: preparing 1-10% (W/V) hydroxybutyl chitosan solution, stirred in a container at a speed of 50-200 rpm for 2-6 hours to make the solution homogeneous; then add a certain amount of 0.1%-50 % (W/V) antibacterial drug solution, the final drug concentration is 0.1%-20% (W/V); 50-200 rpm stirring for 1-3 hours to make the solution in a homogeneous state.

The solvent may be double distilled water, physiological saline, water for injection, pH6.8-pH7.5 buffer solution and the like.

The antibacterial drugs should be water-soluble antibacterial drugs, these drugs are, but not limited to: β-lactam antibacterial drugs, especially cephalosporin antibacterial drugs, such as cefazolin, cephalothin, cefacetonitrile, cefapirin , cefathiamidine, cefoxime, cephradine, cefuroxime, cefotiam, cefamandole, cefanixime, cefereide, cefotaxime, ceftriaxone, ceftazidime, cefoperazone, ceftizoxime, cefoperazone Dizim, cefpiramide, cefmenoxime, cefsulodin, cefpirome, cefepime, etc; Minol, etc.; or lincomycin, clindamycin, lincomycin, etc.; or polypeptide antibacterial drugs, such as vancomycin, norvancomycin, teicoplanin, etc.; or quinolone antibacterial drugs , such as norfloxacin, ciprofloxacin, ofloxacin, enoxacin, pefloxacin, lomefloxacin, fleroxacin, ciloxacin, pazufloxacin, clinfloxacin, grafloxacin , Amfloxacin, Tosufloxacin, Prefloxacin, Orbimycin, Olafloxacin, Katrafloxacin, Levofloxacin, Gatifloxacin, Nortifloxacin, Gemifloxacin, etc.; and the above Salts or esters of drugs.

The antibacterial drug can be any one or a combination of two or more drugs mentioned above.

The temperature-sensitive antimicrobial slow-release agent for topical application of the present invention can form a gel with a certain strength within 60 seconds at a physiological temperature of 37°C.

The present invention creatively utilizes hydroxybutyl chitosan as a slow-release carrier. The temperature-sensitive characteristic of this slow-release carrier can uniformly embed antibacterial drugs under low temperature or normal temperature conditions, and inject or implant it into the lesion in the body. Fast curing at physiological temperature, sustained drug release. The dosage form can be used at the lesion site of bacterial infection or the operation site to maintain local effective drug concentration and achieve the purpose of treating or preventing bacterial infection.

The technical effect of the present invention is as follows: the temperature-sensitive biopolymer material hydroxybutyl chitosan is used as the slow-release carrier, which realizes the injectability of the drug carrier, facilitates the operation, and reduces the pain of the patient; the preparation condition is mild , does not require the participation of cross-linking agents, initiators and other substances, and there is no heat release during the process, ensuring that the activity of the sustained-release drug is not affected; the antibacterial thermosensitive gel is injected into the infected lesion or surgical site, Slowly release the drug, maintain the local effective drug concentration, and reduce the toxic and side effects of the systemic application of the drug; it can be prepared according to clinical needs, and release one or more antibiotic drugs; in addition, most of the injectable thermosensitive hydrogel systems It has no definite shape, can fully fill the tissue gap after injection, and then undergoes a phase transition in situ in the body, and is especially suitable for local implantation in the body. Due to the good biocompatibility and biodegradability of the slow-release carrier hydroxybutyl chitosan, the biosafety is increased, and secondary surgery is avoided. Since this dosage form is a one-time topical application of antibacterial slow-release agent, it brings convenience to clinical use, and also greatly reduces the amount of antibacterial drugs used after surgery, which meets the clinical requirements of strictly regulating the use of antibacterial drugs.

Description of drawings

Figure 1 shows 1#, 2#, 3#, 4# hydroxybutyl chitosan gel and blank control gel embedded with cefotiam hydrochloride, and the temperature change affects the storage modulus G' and loss modulus G" Impact.

Figure 2 shows the curing time of 1#, 2#, 3#, 4# hydroxybutyl chitosan gel embedded with cefotiam hydrochloride and the blank control gel at 37°C, expressed as the storage modulus of the sample G' and loss modulus G" with time.

Figure 3 is a scanning electron micrograph of a blank hydroxybutyl chitosan gel.

Fig. 4 is a scanning electron micrograph of a hydroxybutyl chitosan gel embedded with cefotiam hydrochloride, and the drug concentration is 2.5% (W/V).

Figure 5 is the drug sustained release curve of 1#, 2#, 3# embedded cefotiam hydrochloride hydroxybutyl chitosan gel in pH7.2 phosphate buffer solution, 1#, 2#, 3# The drug contents in the glue are respectively 2.5%, 1.25%, and 0.5% (W/V).

Figure 6 shows the inhibitory effect of 1#, 2#, 3#, 4# hydroxybutyl chitosan gel embedded with cefotiam hydrochloride on Staphylococcus aureus, showing the diameter of the inhibition zone, 1#, 2# , The drug content in 3# gel is respectively 2.5%, 1.25%, 0.5% (W/V).

Fig. 7 is the detection result of the local drug concentration of the sample applied in vivo.

Fig. 8 is the detection result of the drug concentration in the blood of the sample applied in vivo.

Detailed ways

The implementation of the present invention will be described in detail below in conjunction with the embodiments of the present invention and the accompanying drawings. The following embodiments are implemented on the premise of the technical solution of the present invention, and detailed implementation methods and specific operating procedures are provided. However, the present invention The scope of protection is not limited to the following examples.

Example 1

Use double-distilled water to prepare 100 milliliters of 2.5% (W/V) hydroxybutyl chitosan solution at 4° C., stir in a beaker at a speed of 100 rpm for 5 hours, so that the solution is in a homogeneous state. Then add 12.5% (W/V) antimicrobial drug cefotiam hydrochloride solution prepared by 25 milliliters of double distilled water, and the drug concentration is finally 2.5% (W/V). Stir at 100 rpm for 2 hours to make the drug evenly dispersed in the hydroxybutyl chitosan solution. That is, 125 milliliters of hydroxybutyl chitosan solution embedding cefotiam hydrochloride was prepared, wherein the final concentration of the sustained-release carrier was 2%, and the concentration of the sustained-release drug was 2.5% (W/V).

Example 2

Use double-distilled water to prepare 100 milliliters of 2.5% (W/V) hydroxybutyl chitosan solution at 4° C., stir in a beaker at a speed of 100 rpm for 5 hours, so that the solution is in a homogeneous state. Then add 6.25% (W/V) antimicrobial drug cefotiam hydrochloride solution prepared by 25 milliliters of double distilled water, and the drug concentration is finally 1.25% (W/V). Stir at 100 rpm for 2 hours to make the drug evenly dispersed in the hydroxybutyl chitosan solution. That is, 125 milliliters of hydroxybutyl chitosan solution embedding cefotiam hydrochloride was prepared, wherein the final concentration of the slow-release carrier was 2%, and the drug concentration was 1.25% (W/V).

Example 3

Use double-distilled water to prepare 100 milliliters of 2.5% (W/V) hydroxybutyl chitosan solution at 4° C., stir in a beaker at a speed of 100 rpm for 5 hours, so that the solution is in a homogeneous state. Then add 2.5% (W/V) antibacterial drug cefotiam hydrochloride solution prepared by 25 milliliters of double distilled water, and the drug concentration is finally 0.5% (W/V). Stir at 100 rpm for 2 hours to make the drug evenly dispersed in the hydroxybutyl chitosan solution. That is, 125 milliliters of hydroxybutyl chitosan solution embedding cefotiam hydrochloride was prepared, wherein the final concentration of the slow-release carrier was 2%, and the drug concentration was 0.5% (W/V).

Example 4

Use double-distilled water to prepare 125 milliliters of 2% (W/V) hydroxybutyl chitosan solution at 4° C., stir in a beaker at a speed of 100 rpm for 5 hours, so that the solution is in a homogeneous state. That is, 125 milliliters of hydroxybutyl chitosan solution was prepared, which was a blank control without medicine, and wherein the final concentration of the slow-release carrier was 2% (W/V).

Example 5

Use physiological saline to prepare 100 milliliters of 1.5% (W/V) hydroxybutyl chitosan solution at 15° C., and stir for 3 hours at a speed of 50 rpm in a beaker to make the solution homogeneous. Then add 1.5% (W/V) antibacterial drug clindamycin solution prepared by 50 milliliters of normal saline, and the drug concentration is finally 0.5% (W/V). Stir at 50 rpm for 1 hour to disperse the drug evenly in the hydroxybutyl chitosan solution. That is, 150 milliliters of hydroxybutyl chitosan solutions embedding clindamycin were prepared, wherein the final concentration of the slow-release carrier was 1%, and the drug concentration was 0.5% (W/V).

Example 6

Use water for injection to prepare 100 milliliters of 6% (W/V) hydroxybutyl chitosan solution at 10° C., stir in a beaker at a speed of 200 rpm for 6 hours, so that the solution is in a homogeneous state. Then add 15% (W/V) antimicrobial drug ofloxacin solution prepared by 50 mL of normal saline, and the drug concentration is finally 0.5% (W/V). Stir at 200 rpm for 3 hours to make the drug evenly dispersed in the hydroxybutyl chitosan solution. That is, 150 milliliters of hydroxybutyl chitosan solutions embedding ofloxacin were prepared, wherein the final concentration of the slow-release carrier was 4%, and the drug concentration was 5% (W/V).

Example 7: In vitro rheological property detection

The first step, according to embodiment 1, embodiment 2, embodiment 3, embodiment 4, prepare the hydroxybutyl chitosan solution and blank control solution of embedding antimicrobial drug cefotiam hydrochloride respectively, drug concentration 1# is 2.5 %, 2# is 1.25%, 3# is 0.5% (W/V), and 4# is a blank control without medicine.

In the second step, 1#, 2#, 3#, 4# contain cefotiam hydrochloride hydroxybutyl chitosan solution and blank control solution, use a rheometer to detect its temperature-sensitive rheology, which shows that the temperature change affects the sample Effect of storage modulus G' and loss modulus G" (temperature range 5-50°C), and curing time of samples under isothermal conditions at 37°C.

The results are shown in Figure 1. The critical curing temperatures of the four samples are all 20°C. When it is lower than 20°C, G' is lower than G", and the sample behaves as a viscous liquid solution in this state; when it is higher than 20°C, G' is greater than G", and the sample behaves as an elastic solid solution in this state. Gel, the higher the temperature, the stronger the gel. Figure 2 shows that under isothermal conditions at 37°C, all four samples solidified from solution state to stable elastic gel within 60 seconds. The results also showed that the curing temperature and curing time of the drug-loaded gel and the blank gel were not significantly different.

Example 8: Morphological Analysis

The first step, according to embodiment 1, embodiment 4, prepare the hydroxybutyl chitosan solution and the blank control solution of embedding antimicrobial drug cefotiam hydrochloride respectively, 1# drug concentration is 2.5%, 4# is not containing drug blank control.

In the second step, 1# and 4# hydroxybutyl chitosan solutions containing cefotiam hydrochloride and the blank control solution took 5 milliliters each, placed in a mold, and solidified into a gel within 10 minutes at 37° C. The samples were then freeze-dried using a freeze dryer.

In the third step, the dried samples of 1# and 4# were cut and sprayed with gold, and the microscopic internal structure of the samples was observed with a scanning electron microscope.

The results are shown in Figure 3 and Figure 4, the dried drug-loaded and blank hydroxybutyl chitosan gels are both porous network structures. It can also be seen from the micrographs that there is a thin layer of granular substances on the pore wall of the drug-loaded hydroxybutyl chitosan sample, while the pore wall of the blank sample without drug loading is smooth. It shows that the drug is uniformly dispersed in the hydroxybutyl chitosan gel.

Embodiment 9: In vitro simulated sustained release test

The first step, according to embodiment 1, embodiment 2, embodiment 3, embodiment 4, prepare the hydroxybutyl chitosan solution and blank control solution of embedding antimicrobial drug cefotiam hydrochloride respectively, drug concentration 1# is 2.5 %, 2# is 1.25%, 3# is 0.5% (W/V), and 4# is a blank control without medicine.

The second step, 1#, 2#, 3#, 4# containing cefotiam hydrochloride hydroxybutyl chitosan solution and blank control solution, take 1 ml each, put them in the sample tube, and form a gel at 37 ° C State, and then add 5 ml of pH 7.2 phosphate buffer. Place at 37°C and shake at 80 rpm for 1 to 7 days. Collect 5 ml of slow-release solution at a specific time to detect the drug content, and replace with 5 ml of fresh pH7.2 phosphate buffer.

The third step is to use an ultraviolet spectrophotometer to detect the content of cefotiam hydrochloride at a wavelength of 256nm.

The results are shown in Figure 5, about 80% of the CFH was released within 12 hours, followed by a sustained slow release of the drug. The extract of the 4# blank control gel has no ultraviolet absorption peak at a wavelength of 256nm, indicating that the slow-release carrier hydroxybutyl chitosan has no effect on the detection of drug content.

Embodiment 10: in vitro antibacterial test

The first step, according to embodiment 1, embodiment 2, embodiment 3, embodiment 4, prepare the hydroxybutyl chitosan solution containing antimicrobial drug cefotiam hydrochloride respectively, drug concentration 1# is 2.5%, 2# is 1.25%, 3# is 0.5% (W/V), and 4# is a blank control without medicine.

In the second step, prepare a suspension of Staphylococcus aureus with a concentration of 1.5× ¹⁰⁸ /ml, spread it evenly on the MH plate, place the Oxford cup on it, and load 1#, 2#, and 3# with the drug Solution, add to Oxford cup, 0.2ml/tube. After culturing, the diameter of the inhibition zone was observed. After culturing for 72 hours, the gel was replaced on a new bacteria-coated MH plate to continue culturing, and the diameter of the inhibition zone was observed.

The results are shown in Figure 6. 1#, 2#, and 3# drug-loaded gels all had obvious inhibition zones in 1-9 days, and all of them could effectively inhibit the growth of Staphylococcus aureus. And with the increase of drug concentration in the gel, the diameter of the inhibition zone also increased significantly. 4# Blank hydroxybutyl chitosan only has a certain contact inhibitory effect on Staphylococcus aureus within 1-3 days, and the effect is obviously weaker than that of antibacterial drugs.

Example 11: In vivo application sample blood and local drug concentration detection

In the first step, according to Example 1, a hydroxybutyl chitosan solution embedding the antibacterial drug cefotiam hydrochloride was prepared, wherein the drug concentration 1# was 2.5%. In addition, double distilled water was used to prepare an aqueous solution with a concentration of 2.5% cefotiam hydrochloride as a control.

In the second step, taking rats as experimental objects, they are divided into two groups: group 1, the hydroxybutyl chitosan solution embedded with cefotiam hydrochloride with a drug concentration of 2.5%, is injected into the legs of rats In the muscle, each rat was injected with 0.4ml; in group 2, the control group was injected with 2.5% cefotiam hydrochloride aqueous solution into the leg muscles of the rats, and each rat was injected with 0.4ml.

In the third step, 1, 2, 6, 24, and 48 hours after injection, samples were taken respectively to detect the drug concentration at the local administration site and the blood drug concentration of the rat.

The results are shown in Figure 7 and Figure 8. Compared with the aqueous solution of local injection of antibacterial drugs, the temperature-sensitive gel embedded with drugs can release the drugs in a short-term and sustained manner at the injection site, and maintain the local effective drug concentration within 48 hours . And can prolong the drug concentration in the blood to 48 hours.

Claims (10)

1. A temperature-sensitive antimicrobial slow-release agent for topical use, characterized in that the slow-release agent is prepared by the following method: preparing homogeneous hydroxybutyl chitosan at a temperature greater than 0°C and less than 20°C Sugar solution, and then uniformly disperse and embed the antibacterial drug in it, and obtain the antibacterial drug sustained-release agent with hydroxybutyl chitosan as the sustained-release carrier. 2. A local temperature-sensitive antimicrobial sustained-release agent according to claim 1, characterized in that the specific preparation method of the sustained-release agent is as follows: use a solvent to prepare at a temperature greater than 0°C and less than 20°C 1-10% (W/V) hydroxybutyl chitosan solution, stirred in a container at a speed of 50-200 rpm for 2-6 hours to make the solution homogeneous; then add 0.1% of the same solvent -50% (W/V) antibacterial drug solution, so that the drug concentration is finally 0.1%-20% (W/V); 50-200 rpm stirring for 1-3 hours, making the solution in a homogeneous state, to obtain final product. 3. a kind of topical temperature-sensitive type antimicrobial slow-release agent according to claim 2, is characterized in that wherein said solvent is double distilled water, normal saline, water for injection or pH6.8-pH7.5 buffer liquid. 4. A locally used temperature-sensitive antimicrobial slow-release agent according to claim 1, 2 or 3, wherein said antibacterial drug is a water-soluble antibacterial drug. 5. a kind of topical temperature-sensitive type antimicrobial slow-release agent according to claim 4, is characterized in that wherein said antimicrobial is selected from following any one or more than two: cefazolin, cephalothin, Cefuroxime, Cefpirin, Cefathiamidine, Cefzidone, Cefradine, Cefuroxime, Cefotiam, Cefamandole, Cefinixime, Cefreide, Cefotaxime, Ceftriaxone, Ceftazidime, Cefoperazone , ceftizoxime, cefdizime, cefpiramide, cefmenoxime, cefsulodin, cefpirome, cefepime, cefoxitin, cefmetazole, cefotetan, cefbuperazone, cefminol, gram Lincomycin, Lincomycin, Vancomycin, Norvancomycin, Teicoplanin, Norfloxacin, Ciprofloxacin, Ofloxacin, Enoxacin, Pefloxacin, Luo Mefloxacin, Fleroxacin, Sirlofloxacin, Pazufloxacin, Clinfloxacin, Grefloxacin, Amfloxacin, Tosufloxacin, Prefloxacin, Orbimycin, Olafloxacin, Katra Floxacin, levofloxacin, gatifloxacin, notifloxacin, gemifloxacin. 6. A local temperature-sensitive antimicrobial sustained-release agent according to claim 1, 2 or 3, characterized in that the sustained-release agent is a sustained-release injection or a sustained-release implant. 7. a kind of preparation method of the thermosensitive type antimicrobial slow-release agent of topical use as claimed in claim 1, concrete steps are as follows: use solvent to prepare 1-10% (W /V) hydroxybutyl chitosan solution, stirred in a container for 2-6 hours at a speed of 50-200 rpm, making the solution homogeneous; then adding 0.1%-50% (W/ V) antibacterial drug solution, so that the drug concentration is finally 0.1%-20% (W/V); 50-200 rpm stirring for 1-3 hours, so that the solution is in a homogeneous state, to obtain final product. 8. The preparation method of the temperature-sensitive type antimicrobial slow-release agent for topical use according to claim 7, wherein said solvent is double distilled water, normal saline, water for injection or pH6.8-pH7.5 buffer. 9. The method for preparing the locally used temperature-sensitive antibacterial slow-release agent according to claim 7 or 8, wherein the antibacterial drug is a water-soluble antibacterial drug. 10. the preparation method of the temperature-sensitive antimicrobial slow-release agent of topical use according to claim 9, is characterized in that wherein said antibacterial drug is selected from following any one or more than two: cefazolin, cephalothin , cefotaxime, cefpirin, cefathiamidine, cefzidone, cefradine, cefuroxime, cefotiam, cefamandole, cefinixime, cefreide, cefotaxime, ceftriaxone, ceftazidime, cefoperazone Ketone, ceftizoxime, cefodizime, cefpiramide, cefmenoxime, cefsulodin, cefpirome, cefepime, cefoxitin, cefmetazole, cefotetan, cefirazone, cefminox, Clindamycin, Lincomycin, Vancomycin, Norvancomycin, Teicoplanin, Norfloxacin, Ciprofloxacin, Ofloxacin, Enoxacin, Pefloxacin, Lomefloxacin, Fleroxacin, Sirlofloxacin, Pazufloxacin, Klinfloxacin, Grefloxacin, Amfloxacin, Tosufloxacin, Prefloxacin, Orbimycin, Olafloxacin, Card Trofloxacin, levofloxacin, gatifloxacin, nortifloxacin, gemifloxacin.

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