KR20160046138A - Composition for Prevention or Treatment of Infectious Disease Comprising Non-steroidal Anti-inflammatory Drug - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating infectious diseases, containing a non-steroidal anti-inflammatory drug (NSAID). The pharmaceutical composition of the present invention exhibits antibiotic activity and also has little or no antibiotic resistance, thereby being able to be helpfully used in preventing or treating various infectious diseases caused by pathogenic microorganisms, especially pathogenic bacteria.

Description

TECHNICAL FIELD The present invention relates to a composition for preventing or treating an infectious disease containing a non-steroidal anti-inflammatory drug,

The present invention relates to a composition for preventing or treating an infectious disease containing a non-steroidal anti-inflammatory drug (NSAID), and more particularly, to a composition for preventing or treating an infectious disease comprising a non-steroidal anti- (ABR), and can be used for the prevention or treatment of pathogenic microorganisms, particularly infectious diseases caused by pathogenic bacteria.

After penicillin was discovered by Alexander Fleming in 1928, antibiotics have been widely used to treat bacterial infections in medical and home settings. Since then, antibiotics have greatly improved general health and have significantly reduced mortality from microbial infections, which has led to a dramatic increase in the use of antibiotics over the last few decades. However, recent resistance to antibiotics caused by the widespread use of antibiotics has received attention.

Antibiotic resistance is a major threat to human health and is increasing worldwide. According to the World Health Organization, more than 50% of strains of Escherichia coli, Klebsiella pneumoniae and Staphylococcus aureus bacteria are resistant to commonly used antibiotics Respectively. Antibiotic resistance is not limited to a specific area or country, but has the potential to occur on a global scale. According to a report by the World Health Organization, about 450,000 multidrug-resistant tuberculosis have been reported in 2012.

Antibiotic-resistant bacteria have to deal with more powerful antibiotics, which not only has to pay for more expensive healthcare costs, but it can cause even more damage to the human body. Increasing global antibiotic resistance increases antibiotic resistance even against the most potent antibiotics, increasing the likelihood of developing super-bacteria, which is a serious threat. Antibiotic resistance is a serious health problem worldwide, and it is necessary to develop effective antibiotics continuously, or to develop antibiotics that show little or no resistance to bacteria. Antibiotic resistance can affect anyone and requires a change in awareness of antibiotics.

On the other hand, non-steroidal anti-inflammatory drugs have received much attention in the pharmaceutical field. Most non-steroidal anti-inflammatory drugs are commonly used for the treatment of inflammation and mild pain (Patent Document 1), and cyclooxygenase (COX) enzyme is a substance that is involved in inflammation, pain and heat generation, (Non-Patent Document 1). However, it is not yet known whether non-steroidal anti-inflammatory drugs can function as antibiotics against pathogenic microorganisms.

Thus, the present inventors have confirmed that various non-steroidal anti-inflammatory agents exhibit antibiotic activity against pathogenic microorganisms, particularly pathogenic bacteria, and cause no or less antibiotic resistance, which is one of the side effects of conventional antibiotics, Non-steroidal anti-inflammatory drugs can be used for the prevention or treatment of various infectious diseases.

Korean Patent Publication No. 10-2007-0084152

 Lee, Choong-Ki, Yeongnam Medical Science Journal, Vol. 17, No. 1, 1-11, 2000

It is an object of the present invention to provide a composition for preventing or treating an infectious disease caused by a pathogenic microorganism containing a non-steroidal anti-inflammatory drug.

In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating an infectious disease caused by a pathogenic microorganism containing a non-steroidal anti-inflammatory drug.

In the present invention, the term "nonsteroidal antiinflammatory agent " is used to include without limitation pharmaceutical agents that are structurally and non-steroidally used for fever, pain, inflammation and the like. The non-steroidal anti-inflammatory agents include aspirin, naproxen, ibuprofen, aceclofenac, meloxicam, dexibuprofen, cetaminophen, The compounds of the present invention may be used in combination with other active ingredients such as, for example, diflunisal, salsalate, sodium salicylate, cinnoxicam, piroxicam, tenoxicam, diclofenac, etodolac), ketorolac, sulindac, fenbufen, flurbiprofen, ketoprofen, tiaprofenic acid, fenoprofen ( fenoprofen, oxaprozin, flufenamic acid, mefenamic acid, meclofenamate, tolfenamic acid, etofenamate, indomethacin, (indomethacin), and the like, but are not limited thereto.

In the present invention, the term "infectious disease" is used in a sense to include, without limitation, infectious diseases resulting from substantially all kinds of pathogenic microorganisms. Such pathogenic microorganisms include, but are not limited to, bacteria, viruses, and fungi.

According to one embodiment of the present invention, the bacteria include Escherichia coli, Bacillus cereus, Staphylococcus aureus, Clostridium perfringens, But are not limited to, Staphylococcus gallinarum, Salmonella pullorum, Salmonella enteritidis, Campylobacter jejuni, and the like. According to another embodiment of the present invention, the virus includes viruses such as influenza virus, adenovirus, parainfluenza virus, linovirus, respiratory syncytial virus, herpes virus, cytomegalovirus, hepatitis virus (for example, hepatitis B virus or hepatitis C virus ), But the present invention is not limited thereto. According to another embodiment of the present invention, the fungi include, but are not limited to, Aspergillus, Candida albicans, Cryptococcus neoformans, and the like .

In the present invention, the infectious diseases caused by the pathogenic microorganisms include diarrhea, vomiting, food poisoning, abscess, dermatitis, osteoarthritis, bacteremia, pneumonia, toxic shock syndrome, hyperthermia, sepsis, edema, mastitis, intestinal colicosis But is not limited thereto.

The pharmaceutical composition of the present invention may further contain, in addition to the above non-steroidal anti-inflammatory agent, other components that can increase the antibiotic activity of the non-steroidal anti-inflammatory drug within a range that does not impair the antibiotic effect . For example, conventional adjuvants such as antioxidants, stabilizers, solubilizers, vitamins, pigments and flavoring agents, or carriers may be further included.

In addition, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier. The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention include those conventionally used in the formulation and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, , Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not. The pharmaceutical composition may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components.

The administration route of the pharmaceutical composition includes oral, intravenous, intramuscular, intraarterial, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal administration, preferably parenteral administration, A topical application method is more preferable. The parenterally includes subcutaneous, intravenous, intramuscular, intralesional injection or infusion techniques without limitation.

In addition, the pharmaceutical composition of the present invention may contain at least one active ingredient which exhibits the same or similar functions, for example, conventional antibiotics, antimicrobial agents, antifungal agents, etc., in addition to the nonsteroidal antiinflammatory agent. The pharmaceutical compositions may be formulated in the form of powders, granules, tablets, capsules, oral preparations such as suspensions, emulsions and syrups, external preparations, suppositories and sterilized injection solutions according to conventional methods.

Solid form preparations for oral administration include powders, granules, tablets, capsules, soft capsules, and the like. Liquid preparations for oral administration include suspensions, solutions, emulsions, syrups and the like. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin, which are simple diluents commonly used. have. As the agent for parenteral administration, the external preparation such as powders, granules, tablets, capsules, sterilized aqueous solutions, liquid preparations, non-aqueous solutions, suspensions, emulsions, syrups, suppositories and aerosols, The composition may be formulated in the form of a cream, a gel, a patch, a spray, an ointment, a warning agent, a lotion, a liniment, a pasta or a cataplasma, But is not limited thereto. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like. The pharmaceutical compositions may additionally contain preservatives, stabilizers, wettable or emulsifying accelerators, adjuvants such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, Or can be formulated according to the coating method.

The dosage of the pharmaceutical composition of the present invention may be variously changed depending on various factors including the age, body weight, general health, sex, administration time, route of administration, rate of excretion, drug combination and severity of a specific disease. In addition, the pharmaceutical composition of the present invention can be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers. The pharmaceutical composition may be administered at a dose within the range of 0.1 to 100 mg / kg on an adult basis, and when the pharmaceutical composition is an external preparation, it may be administered once to 5 times a day It is preferable to continue the application for 1 month or longer, but the dose does not limit the scope of the present invention.

When the pharmaceutical composition is formulated in unit dose form, it is preferable that the non-steroidal anti-inflammatory agent is contained in an effective dose of about 1 to 1,000 mg, and the dosage required for adult treatment is The range of about 10 to 5,000 mg per day is usually, but not limited to, a higher daily dose in some patients may be preferred. The pharmaceutical composition may be used alone or in combination with methods using surgery, radiation therapy, hormone therapy, chemotherapy, and biological response modifiers.

According to the present invention, for six different bacterial strains (Escherichia coli, Bacillus cereus, Staphylococcus aureus, Clostridium perfringens, Staphylococcus galina room and Salmonella pool room), nonsteroidal anti-inflammatory drugs , Such as penicillin, ampicillin, methicillin, kanamycin, lincomycin, chloramphenicol and cephadoxin, and to confirm whether the non-steroidal anti-inflammatory agent causes antibiotic resistance. According to a preferred embodiment of the present invention, the aspirin eradicates 95% or more of Escherichia coli, 100% of Staphylococcus aureus and 25% or more of Clostridium perfringens. In addition, meloxicam reduces Clostridium perfringens to about 25%, and dexibupropene decreases Staphylococcus aureus and Clostridium perfringens to about 85% and 15%, respectively (See Table 5 and Fig. 4). According to another preferred embodiment of the present invention, the bacterium does not show any change in antibiotic sensitivity even when exposed to aspirin, naproxen, ibuprofen, aceclofenac, meloxicam and dexibuprofen for a long time, (See Table 6 and Figures 7 to 10). ≪ tb > < TABLE > This is distinct from the results obtained from exposure to antibiotics in which the bacteria obtained substantial antibiotic resistance after only two agar diffusion tests (see Figures 5 and 6).

As noted above, antibiotic resistance is an important issue in the public health of humankind worldwide in terms of both prevention and response to bacterial infections, and as the use of antibiotics increases, the number of bacteria resistant to the antibiotic increases. This accelerates research to develop more powerful and effective antibiotics for bacteria that are resistant to antibiotics. However, according to the present invention, the non-steroidal anti-inflammatory agent does not affect the antibiotic sensitivity of the bacteria, and in some cases may increase antibiotic sensitivity. These non-steroidal anti-inflammatory agents may have certain limitations in completely replacing conventional antibiotics because their antibiotic properties are relatively weak, but they may be used to alleviate mild bacterial infections and may also include antibiotics that do not exhibit resistance to bacteria It can also act as an important material for development. In addition, the non-steroidal anti-inflammatory agent is very likely to be used as an antibiotic for solving the antibiotic resistance problem.

The composition for preventing or treating an infectious disease containing a non-steroidal anti-inflammatory drug of the present invention not only exhibits antibiotic activity but also has little or no resistance to antibiotic resistance. Therefore, the composition for preventing or treating infectious diseases caused by pathogenic microorganisms, It can be useful for prevention and treatment.

FIG. 1 is a photograph showing the kind of non-steroidal anti-inflammatory agent used in the present invention. FIG.
Figure 2 is a photograph showing whether the bacteria exhibiting antibiotic resistance or antibiotic sensitivity in the Aga diffusion test form a clear zone.
FIG. 3 is a photograph showing an experimental procedure of the child diffusion test.
4 is a graph showing the growth rate of bacteria cultured in a medium containing a non-steroidal anti-inflammatory agent.
Figure 5 is a photograph showing the change of the transparent zone in bacteria exposed to kanamycin.
Figure 6 is a graph showing the change of the clear zone in bacteria exposed to kanamycin.
Figure 7 is a graph showing the size of the transparent zone in E. coli after exposure to the non-steroidal anti-inflammatory agent.
Figure 8 is a graph showing the size of the clear zone in Bacillus cereus after exposure to non-steroidal anti-inflammatory agents.
Figure 9 is a graph showing the size of the transparent zone in Staphylococcus aureus after exposure to non-steroidal anti-inflammatory agents.
Figure 10 is a graph showing the size of the clear zone in Clostridium perfringens after exposure to non-steroidal anti-inflammatory agents.

Hereinafter, the present invention will be described in detail by way of examples.

However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example 1. Confirmation of antibiotic sensitivity of pathogenic bacteria

1.1. Preparation of non-steroidal anti-inflammatory drugs

A total of six different types of nonsteroidal anti-inflammatory drugs (aspirin (USP) (PT Bayer, Korea), naproxen (RPcorp, Korea), ibuprofen (KP) (PHARVIS KOREA, Korea), aceclofenac Mirae Pharm Korea, Korea, and dexibupropene (KOLMAR KOREA, Korea)). As shown in Table 1, the indicated weight of the tablet and the weight of the actual active ingredient were compared for each non-steroidal anti-inflammatory agent. Along with the amount of ingredients contained in each tablet, the information was used to calculate the amount of solvent needed to dissolve each non-steroidal anti-inflammatory agent to produce a non-steroidal anti-inflammatory agent medium with the same concentration. Aspirin, ibuprofen, and dexibuprofen were dissolved in 6.7 ml nutrient broth (NB), respectively, of the purified eggs. Similarly, naproxen and aceclofenac have respectively dissolved purified eggs in 10 ml nutrient broth, in the case of meloxicam the capsules are removed and the powder inside is dissolved in 10 ml nutrient broth.

Anti-inflammatory agent ingredient Tablet weight
(Of the active ingredient
Weight) (mg) Active ingredient
Weight (mg) manufacturer Seller Byer Aspirin Aspirin (USP) 600 (600) 500 PT Byer
Indonesia BAYER KOREA TAK-SEN Naproxen (1200) 250 RPcorp GREEN CROSS PHARVIS
IBUPROFEN Ibuprofen
(KP) 400 (560) 400 PHARVIS KOREA Aceclofen Tab. Aceclofenac 100 (200) 100 Dong-A ST Melcam Cap. Meloxicam 7.5 (320) 7.5 Mirae Pharm Korea DEXIPIN TAB. Dexibupropene 400 (640) 400 KOLMAR KOREA

1.2. Preparation of antibiotics

Prior to testing antibiotic activity of nonsteroidal anti-inflammatory drugs, the characteristics of the test samples of seven widely used antibiotics (penicillin, ampicillin, methicillin, cephadoxine, kanamycin, lincomycin and chloramphenicol) were determined. Of these, penicillin, ampicillin and methicillin are included in the beta-lactam-based penicillin. The family of antibiotics acts on the peptidoglycan cell wall. Also, the first-generation cephalosporin, cephadodon, reacts with the peptidoglycan cell wall. In contrast, aminoglycoside-based kanamycin acts on a specific protein in bacteria, and lincomycin, a member of the lincomaside family, and chloramphenicol, which is not classified as any family, respond to 50S subunit rRNA. The above information is summarized in Table 2.

penicillin Ampicillin Methicillin Sepazardon line penicillin
(? -lactam) penicillin
(? -lactam) penicillin
(? -lactam) Cephalosporin
(First generation) Gram stain type positivity positivity positivity positivity Functional region Peptidoglycan
Cell wall Peptidoglycan
Cell wall Peptidoglycan
Cell wall Peptidoglycan
Cell wall Kanamycin Lincomycin Chloramphenicol line Aminoglycoside Rinkosamid Other Gram stain type voice voice Positive, negative Functional region protein 50S subunit rRNA 50S subunit rRNA

1.3. Preparation of bacteria

Seven different bacterial strains (Korean Collection for Type Cultures 1682), Bacillus cereus (Korean Culture Center of Microorganisms 40138), Staphylococcus aureus (KCTC 1928), Clostridium perfringens (KCTC 3269), Hankyong National University and Hankyong National University) was used in the present invention. Escherichia coli and Staphylococcus galina room are Gram stain positive. Clostridium perfringens grows in anaerobic environments unlike other bacterial strains used in this experiment. In addition, Bacillus cereus and Clostridium perfringens are bacteria that form spores.

bacteria Gram stain growth shape Spore formation Escherichia coli voice Aerobic Bar none Bacillus cereus positivity Conditional aerobic Bar Endogenous spores Staphylococcus aureus positivity Conditional aerobic rectangle none Clostridium perfringens positivity Anaerobic Bar Endogenous spores Stil Phillokokus Galina Room positivity Conditional aerobic rectangle none Salmonella Pool Room voice Conditional aerobic Bar none

1.4. Preparation of badge

Nutrient broth, nutrient agar (NA), MRS agar and MRS broth were prepared using powder purchased from the manufacturer (BD difco, France). 8 g of nutritional broth, 23 g of nutritional agar, 70 g of MRS agar and 55 g of MRS broth were each dissolved in 1 l of distilled water and subjected to autoclaving at 121 ° C and 1.2 atm pressure for 15 minutes And sterilized. The vessel was removed from the autoclave and allowed to cool to room temperature. When the temperature reached 50 ° C, the nutrient agar and the MRS agar medium were transferred aseptically, and 25 ml aliquots were poured into each Petri dish to solidify. 40 ml nutrient broth and MRS broth medium were each poured into test tubes and kept in a 4 ° C refrigerator for later use.

1.5. Culture of bacteria

The bacterial strains used in this example were cultured from a bacterial stock solution refrigerated at 4 占 폚. Escherichia coli was cultured by dropping 5 μl of a bacterial stock solution with a micropipette in a test tube having 5 ml of nutrient broth medium containing a non-steroidal anti-inflammatory agent or antibiotic. Then, the medium was placed in an incubator and cultured at 37 DEG C for 24 hours. The test tube was then removed from the incubator and the optical density (OD) was measured using a UV optical spectrometer at a UV wavelength of 630 nm. The same procedure was performed on Bacillus cereus and Staphylococcus aureus. Clostridium perfringens were cultured using the same method, but MRS broth medium was used instead of nutrient broth medium.

1.6. Baby spread test

The stock solution of room bacteria in 5 μl of Escherichia coli, Bacillus cereus, Staphylococcus aureus, Clostridium perfringens, Staphylococcus galina room and Salmonella pool was suspended in 5 ml nutrient broth or MRS broth And cultured at 37 ° C for 24 hours. 10 [mu] l of the medium was applied evenly to the nutrient agar or MRS agar phase, and a hole was made in the center of the agar plate. Ten microliters of penicillin, ampicillin, methicillin, kanamycin, lingocomycin, chloramphenicol or sepafadone were dropped into the wells and allowed to stand for 2 minutes in the aseptic phase and dry. The prepared agar plates were incubated at 37 ° C for 24 hours, and then the diameter of the transparent zone was specified and recorded. Absence of a clear zone indicates that the antibiotic resistance of the bacteria to the antibiotic is present, and the presence of a transparent zone indicates that the bacteria are susceptible to antibiotics (see FIG. 2).

10 [mu] L of Escherichia coli, Bacillus cereus, Staphylococcus aureus and Clostridium perfringens, which had been cultured in a medium containing a non-steroidal anti-inflammatory agent, were dropped on agar plates and evenly sprayed. Three holes were drilled into the plate in the form of an equilateral triangle, and 10 [mu] l of kanamycin, lincomycin and cephaladone were dropped. This was allowed to stand for 2 minutes on a sterile condition, followed by drying, followed by incubation at 37 ° C for 24 hours. The diameter of the transparent zone was then measured for each agar plate.

In addition, kanamycin was used as a test antibiotic to evaluate antibiotic susceptibility after bacterial exposure to antibiotics. The experiment was carried out by dropping 10 μl of 1 ×, 0.1 ×, and 0.01 × concentrations of kanamycin into the wells of the agar plate.

As a result, all of the six bacterial strains described in Table 3 exhibited resistance to penicillin family antibiotics including the most widely used antibiotics today. Notably, all bacteria have acquired antibiotic resistance to chloramphenicol. In addition, Clostridium perfringens gained resistance to kanamycin, Staphylococcus galina room and Salmonella fulloom have obtained resistance to sepafadone. However, all bacteria were still sensitive to lincomycin. Thus, all six bacteria were found to have multiple resistance to at least four, and most often less than five, antibiotics among the seven selected antibiotics (Table 4).

bacteria penicillin Ampicillin Methicillin Kanamycin Lincomycin Chloramphenicol Sepazardon Escherichia coli R R R S S R S B. Sereus R R R S S R S S. Aureus R R R S S R S C. Puffin Gens R R R R S R S S. Galina Room R R R S S R R S. pool room R R R S S R R Sensitivity 0 0 0 5 6 0 4 Resistance 6 6 6 One 0 6 2

In the above, "R" indicates resistance and "S" indicates sensitivity.

Example 2. Antibiotic effect of non-steroidal anti-inflammatory agent

The antibiotic effect of the seven non-steroidal anti-inflammatory agents disclosed in Table 2 was confirmed according to the method described in Example 1.5. For this, Escherichia coli, Bacillus cereus, Staphylococcus aureus and Clostridium perfringens were cultured in 10% non-steroidal anti-inflammatory media and OD values were recorded in Table 6.

As a result, when E. coli was cultured in aspirin (USP) medium, the OD value was 0.008 lower than that of the control solution, 0.246. Similarly, Staphylococcus aureus showed 0.036 when cultured in dexibuprofen medium compared to 0.258 in the control, and -0.016 when cultured in aspirin (USP) It indicates that Cocus aureus did not grow at all. Clostridium perfringens showed a control OD value of 1.257, which decreased to 0.924 when cultured in meloxicam medium and decreased to 0.919 when cultured in aspirin (USP) medium (Table 5).

bacteria Control group Naproxen Meloxicam Dexibupropene Ibuprofen
(KP) Aceclofenac aspirin
(USP) Escherichia coli 0.246 0.317 0.233 0.301 0.276 0.247 0.008 B. Sereus 0.16 0.169 0.169 0.231 0.191 0.169 0.179 S. Aureus 0.258 0.278 0.294 0.036 0.283 0.231 -0.016 C. Puffin Gens 1.257 1.355 0.924 1.06 1.335 1.306 0.919

Further, further investigation of the effect of non-steroidal anti-inflammatory agents on bacterial elimination by calculating the percentage of bacteria reduced compared to the control group revealed that meloxicam, dexibupropene, acetalophenac and aspirin Showed clear antibiotic properties. Specifically, non-steroidal anti-inflammatory drug media containing meloxicam showed a 26.5% reduction in the number of Clostridium perfringens bacteria compared to the control medium. The medium containing dexibupropene showed a remarkable effect of 86% reduction on Staphylococcus aureus and a reduction of 15.7% on Clostridium perfringens. Aceclofenac also exhibited antibiotic properties that reduced the number of Staphylococcus aureus bacteria by 10.5%. Of the non-steroidal anti-inflammatory drugs, aspirin reduced the number of E. coli by 96.7%, decreased Staphylococcus aureus by 100%, and Clostridium perfringens by 26.9% showed the most remarkable antibiotic properties (Fig. 4).

Example  3. Antibiotics and Nonsteroidal  Changes in antibiotic susceptibility of bacteria after exposure to anti-inflammatory agents

3.1. Changes in antibiotic sensitivity after exposure to antibiotics

First, in Example 1.5. E. coli, Bacillus cereus, and Staphylococcus aureus bacteria were used to determine the rate at which bacteria acquire antibiotic resistance according to the methods described in US Pat.

As a result, although all three bacteria showed sensitivity to 1 x kanamycin, all of these bacteria were sensitive to 0.1 x and 0.01 x kanamycin, except that Staphylococcus aureus was sensitive to 0.1 x kanamycin I did not show sensitivity. However, when the second infant strain was incubated with bacteria located closest to the central transparent zone, the bacteria soon began to show signs of antibiotic resistance. In particular, Bacillus cereus was completely resistant and the clear zone decreased from a diameter of 0.7 cm to none at all. In addition, the transparent zone of E. coli decreased from a diameter of 1.5 cm to a diameter of 0.7 cm, which is smaller than the original 50%, and that of Staphylococcus aureus decreased from a diameter of 1.6 cm to a diameter of 1.3 cm. From the above results, when using conventional antibiotics, Bacillus cereus obtained complete antibiotic resistance against kanamycin after only two Aga diffusion tests and Escherichia coli and Staphylococcus aureus obtained antibiotic resistance (FIGS. 5 and 6).

3.2. Changes in antibiotic susceptibility after exposure to non-steroidal anti-inflammatory agents

Next, four bacterial strains (E. coli, Bacillus cereus, Staphylococcus aureus and Clostridium perfringens) were cultured in a medium containing 10% non-steroidal anti-inflammatory agent. After a few days of exposure, an agar diffusion test on the bacteria was carried out according to the method described in Example 1.6. Above to determine whether there was a change in the antibiotic sensitivity. Clear zone measurements revealed that all bacterial strains were susceptible to kanamycin, lincomycin and cephadone antibiotics, except that the Bacillus cereus bacteria cultivated in dexibuprofen medium were resistant to kanamycin (Table 6). From the above results, it was confirmed that even when the bacteria were exposed to the nonsteroidal anti-inflammatory agent, no type of antibiotic resistance occurred.

Escherichia coli B. Sereus NSAID Kanamycin Lincomycin Sepazardon Kanamycin Lincomycin Sepazardon Control group S S S S S S Aspirin (USP) S S S S S S Naproxen S S S S S S Ibuprofen (KP) S S S S S S Aceclofenac S S S S S S Meloxicam S S S S S S Dexibupropene S S S R S S S. Aureus C. Puffin Gens NSAID Kanamycin Lincomycin Sepazardon Lincomycin Sepazardon Control group S S S S S Aspirin (USP) S S S S S Naproxen S S S S S Ibuprofen (KP) S S S S S Aceclofenac S S S S S Meloxicam S S S S S Dexibupropene - - - S S

Specifically, if E. coli is resistant to a particular antibiotic, there will be no clear zone, and if sensitive, there will be a clear zone. However, in determining whether the bacteria are resistant to antibiotics, microscopic deviations in the diameter of the transparent zone are negligible. Escherichia coli did not show such a bias in antibiotic sensitivity even when exposed to nonsteroidal anti-inflammatory drug medium. Especially, in the case of kanamycin, E. coli cultured on ibuprofen (KP) medium had the largest transparent zone area, and when cultured on naproxene, the transparent zone was the smallest. However, this subtle change in the transparent zone was not significant. In the case of lingocomycin and cephazodone, E. coli remained sensitive even after exposure to non-steroidal anti-inflammatory agents (Fig. 7).

Bacillus cereus retained antibiotic susceptibility to kanamycin and cephazone. However, in the case of lincomycin, Bacillus cereus cultured in naproxen, aceclofenac, and deckibuprofen media all showed symptoms of increased antibiotic resistance to lincomycin (Fig. 8).

Staphylococcus aureus had a change in antibiotic sensitivity to kanamycin and lincomycin when exposed to non-steroidal anti-inflammatory media. Staphylococcus aureus cultured in aspirin (USP), ibuprofen (KP), aceclofenac and meloxicam decreased the size of the clear zone, which means that the antibiotic sensitivity to kanamycin was reduced. In addition, the bacteria consistently showed reduced antibiotic susceptibility to lincomycin when exposed to non-steroidal anti-inflammatory agents (Fig. 9).

Since the stock samples of Clostridium perfringens were resistant to kanamycin from the beginning, the antibiotics were not used to determine antibiotic sensitivity changes. The bacterium showed symptoms of increased antibiotic susceptibility to lincomycin because of the increased size of all transparent areas when exposed to non-steroidal anti-inflammatory agents compared to the size of the control clear zone. However, Clostridium perfringens did not show any particular change in antibiotic sensitivity for sepafadone, and the size of all the transparent areas was similar, with only slight variations that were not seen as increased or decreased antibiotic susceptibility (Fig. 10 ).

Preparation Example 1. Preparation of a pharmaceutical composition containing a non-steroidal anti-inflammatory agent

<1-1> Preparation of tablets

Aspirin 500 mg

Corn starch 100 mg

100 mg of milk

2 mg of magnesium stearate

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

&Lt; 1-2 > Preparation of capsules

500 mg of naproxen

Corn starch 100 mg

100 mg of milk

2 mg of magnesium stearate

After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

&Lt; 1-3 > Preparation of pills

Ibuprofen 500 mg

800 mg of lactose

500 mg of glycerin

200 mg xylitol

After mixing the above components, they were prepared to be 2 g per one ring according to a conventional method.

<1-4> Preparation of Granules

Aceclofenac 150 mg

Soybean extract 50 mg

200 mg of glucose

600 mg of starch

After mixing the above components, 100 mg of 30% ethanol was added and the mixture was dried at 60 캜 to form granules, which were then filled in a capsule.

&Lt; 1-5 >

100 mg of dexibupropene

Lactose 1 g

The above components were mixed and packed in airtight bags to prepare powders.

Claims (10)

A pharmaceutical composition for preventing or treating an infectious disease caused by a pathogenic microorganism containing a non-steroidal anti-inflammatory drug. The method according to claim 1,
The nonsteroidal antiinflammatory agent may be selected from the group consisting of aspirin, naproxen, ibuprofen, aceclofenac, meloxicam, dexibupropene, cetaminophen, diflunisal, salsalate, sodium salicylate, , Diclofenac, etodolac, kenololac, sulindac, fenbufen, flurbiprofen, ketoprofen, triepropenic acid, fenoprofen, oxaprofen, flufenamic acid, mefenamic acid, Tolphenamic acid, etophenamate, and indomethacin. The method of claim 2,
Wherein said non-steroidal anti-inflammatory agent is selected from the group consisting of aspirin, naproxen, ibuprofen, aceclofenac, meloxicam and dexibuprofen. The method according to claim 1,
Wherein said pathogenic microorganism is selected from the group consisting of bacteria, viruses and fungi. The method of claim 4,
The bacteria are selected from the group consisting of Escherichia coli, Bacillus cereus, Staphylococcus aureus, Clostridium perfringens, Staphylococcus galina room and Salmonella pool room, Salmonella entereraitidis and Campylobacter jeju &Lt; / RTI &gt; The method of claim 4,
Wherein the virus is selected from the group consisting of influenza virus, adenovirus, parainfluenza virus, rhinovirus, respiratory syncytial virus, herpes virus, cytomegalovirus and hepatitis virus. The method of claim 4,
Wherein said fungus is selected from the group consisting of Aspergillus, Candida albicans and Cryptococcus neoformans. The method according to claim 1,
Wherein the infectious disease is selected from the group consisting of diarrhea, vomiting, food poisoning, abscess, dermatitis, osteoarthritis, bacteremia, pneumonia, toxic shock syndrome, hyperthermia, sepsis, edema disease, mastitis and intestinal colicosis. The method according to claim 1,
Wherein the active ingredient is selected from the group consisting of tablets, capsules, pills, granules and powders. The method according to claim 1,
Lt; RTI ID = 0.0 &gt; antibiotic resistance. &Lt; / RTI &gt;

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