阅读说明：本技术 灵菌红素和苯唑西林或其衍生物的组合物、其应用以及包含其的药物 (Composition of prodigiosin and oxacillin or derivatives thereof, application thereof and medicine containing composition ) 是由 徐畅 陈婉玲 高飞 谢桦函 李志鹏 姜长安 于 2020-12-03 设计创作，主要内容包括：本发明涉及一种灵菌红素和苯唑西林或其衍生物的组合物,其中灵菌红素和苯唑西林或其衍生物的质量比为1～2.55：1,本发明还提供了上述组合物在制备治疗耐甲氧西林金黄色葡萄球菌感染性疾病中的应用,并提供了一种用于治疗耐甲氧西林金黄色葡萄球菌感染性疾病的药物。本发明的组合物以及含有该组合物的药物具有明显高于两者单一成分的抑菌效果。(The invention relates to a composition of prodigiosin and oxacillin or derivatives thereof, wherein the mass ratio of prodigiosin to oxacillin or derivatives thereof is (1-2.55): the invention also provides application of the composition in preparation of medicines for treating methicillin-resistant staphylococcus aureus infectious diseases, and provides a medicine for treating methicillin-resistant staphylococcus aureus infectious diseases. The composition and the medicine containing the composition have the bacteriostatic effect obviously higher than that of a single component of the composition and the medicine.)

1. The composition of prodigiosin and oxacillin or derivatives thereof is characterized in that the mass ratio of the prodigiosin to the oxacillin or derivatives thereof is 1-2.55: 1.

2. the composition of prodigiosin and oxacillin or derivatives thereof according to claim 1, wherein the mass ratio of prodigiosin to oxacillin or derivatives thereof is 1.33-1.75: 1.

3. the composition of prodigiosin and oxacillin or derivatives thereof according to any one of claims 1 or 2, wherein the oxacillin derivative is oxacillin sodium.

4. Use of a combination of prodigiosin and oxacillin or a derivative thereof according to any one of claims 1 to 3 for the preparation of a medicament for the treatment of methicillin-resistant staphylococcus aureus infectious diseases.

5. A medicament for the treatment of methicillin-resistant staphylococcus aureus infectious diseases, comprising a combination of prodigiosin and oxacillin or a derivative thereof according to any one of claims 1 to 3.

6. The medicament of claim 5, further comprising a combination of one or more of pharmaceutically acceptable carriers, excipients, diluents, adjuvants.

7. The medicament of claim 6, wherein the medicament is any one of a compound tablet, a compound capsule or a compound powder.

8. The drug according to claim 7, which is a composite tablet, wherein each 300g of the composite tablet comprises the following raw material components by mass: 9g of a composition of prodigiosin and oxacillin or derivatives thereof, 0-200 g of starch, 0-200 g of pregelatinized starch, 3g of talcum powder, 0-58 g of hydroxypropyl cellulose, 0-58 g of sodium carboxymethyl cellulose, 0-30 g of sodium carboxymethyl starch and 0-30 g of cross-linked polyvinylpyrrolidone, wherein the mass ratio of the prodigiosin to the oxacillin or derivatives thereof is 1.25-2: 1.

9. the medicine as claimed in claim 7, wherein the medicine is a compound capsule, and each 250g of the compound capsule comprises the following raw material components by mass: 7g of a composition of prodigiosin and oxacillin or derivatives thereof, 0-210 g of pregelatinized starch, 0-210 g of starch, 15g of mannitol, 0-3 g of magnesium stearate, 0-3 g of talcum powder and 15g of sodium carboxymethyl starch, wherein the mass ratio of the prodigiosin to the oxacillin or derivatives thereof is (1-1.8): 1.

10. the medicine according to claim 7, wherein the medicine is a compound powder, and each 3000g of the compound powder comprises the following raw material components in parts by mass: 110g of a composition of prodigiosin and oxacillin or derivatives thereof, 2430g of starch, 60000-80 g of polyethylene glycol, 0-80 g of superfine silica gel powder, 0-80 g of talcum powder, 0-150 g of carbomer, 0-150 g of hydroxypropyl methyl cellulose and 0-150 g of sodium carboxymethyl cellulose, wherein the mass ratio of the prodigiosin to the oxacillin or derivatives thereof is 1.44-2.14: 1.

Technical Field

The invention relates to the technical field of medicines, in particular to a composition of prodigiosin and oxacillin or derivatives thereof, application thereof and a medicine containing the same.

Background

Prodigiosin (PG), a natural red pigment with a polypyrrole ring, is a secondary metabolite produced by some actinomycetes, Serratia and other bacteria, and was first isolated from Serratia marcescens (Serratia marcocens) by Amok, Harashima et al in 1929. In recent years, many researchers have found that prodigiosin is a very potential antibacterial drug. In-vitro antibacterial tests show that prodigiosin has good antibacterial effect on bacillus subtilis, escherichia coli, pseudomonas aeruginosa and the like, and has certain medication potential.

Methicillin-resistant staphylococcus aureus (MRSA) is one of the major pathogenic bacteria of hospital and community infections, often causing acute suppurative pneumonia in adults and children. Methicillin-resistant staphylococcus aureus is resistant to both beta-lactam and cephalosporin antibiotics, has different degrees of drug resistance to aminoglycoside, macrolide and tetracycline drugs, and is mainly treated by combining oxacillin with other antibiotics in clinic. However, under the selection pressure of antibiotics, the sensitivity of methicillin-resistant staphylococcus aureus to the antibiotics is continuously reduced, so that the disease is repeatedly attacked, and the treatment effect of patients is influenced. Therefore, the search for effective new drugs is a problem to be solved urgently.

Disclosure of Invention

The invention provides a composition of prodigiosin and oxacillin or derivatives thereof, application thereof and a medicament containing the composition, which aims to solve the problem of drug resistance of methicillin-resistant staphylococcus aureus to the continuous decline of the sensitivity of the existing antibiotics.

The invention provides a composition of prodigiosin and oxacillin or derivatives thereof, wherein the mass ratio of prodigiosin to oxacillin or derivatives thereof is (1-2.55): 1.

further, the mass ratio of the prodigiosin to the oxacillin or the derivative thereof is 1.33-1.75: 1.

further, the derivative of oxacillin is oxacillin sodium.

On the other hand, the invention provides the application of the composition of the prodigiosin and the oxacillin or the derivative thereof in preparing medicines for treating methicillin-resistant staphylococcus aureus infectious diseases.

In another aspect, the invention provides a medicament for treating methicillin-resistant staphylococcus aureus infectious diseases, comprising a composition of the prodigiosin and oxacillin or derivatives thereof.

Further, the medicine contains a combination comprising one or more of pharmaceutically acceptable carriers, excipients, diluents and adjuvants.

Further, the medicine is any one of compound tablets, compound capsules or compound powder.

Further, the medicine is a compound tablet, and each 300g of the compound tablet comprises the following raw material components in mass: 9g of a composition of prodigiosin and oxacillin or derivatives thereof, 0-200 g of starch, 0-200 g of pregelatinized starch, 3g of talcum powder, 0-58 g of hydroxypropyl cellulose, 0-58 g of sodium carboxymethyl cellulose, 0-30 g of sodium carboxymethyl starch and 0-30 g of cross-linked polyvinylpyrrolidone, wherein the mass ratio of the prodigiosin to the oxacillin or derivatives thereof is 1.25-2: 1.

further, the medicine is a compound capsule, and each 250g of the compound capsule comprises the following raw material components in parts by mass: 7g of a composition of prodigiosin and oxacillin or derivatives thereof, 0-210 g of pregelatinized starch, 0-210 g of starch, 15g of mannitol, 0-3 g of magnesium stearate, 0-3 g of talcum powder and 15g of sodium carboxymethyl starch, wherein the mass ratio of the prodigiosin to the oxacillin or derivatives thereof is (1-1.8): 1.

further, the medicine is compound powder, and each 3000g of the compound powder comprises the following raw material components in parts by mass: 110g of a composition of prodigiosin and oxacillin or derivatives thereof, 2430g of starch, 60000-80 g of polyethylene glycol, 0-80 g of superfine silica gel powder, 0-80 g of talcum powder, 0-150 g of carbomer, 0-150 g of hydroxypropyl methyl cellulose and 0-150 g of sodium carboxymethyl cellulose, wherein the mass ratio of the prodigiosin to the oxacillin or derivatives thereof is 1.44-2.14: 1.

the invention has the beneficial effects that: the prodigiosin and oxacillin or derivatives thereof are combined, the composition has a bacteriostatic effect which is obviously higher than that of a single component of the prodigiosin and oxacillin or derivatives thereof, and the bacteriostatic effect of the composition is not a simple addition of the bacteriostatic effects of the single components of the prodigiosin and oxacillin or derivatives thereof, so that the drug resistance problem caused by single antibiotic medication is avoided in the application of the drug with the composition. The invention also provides a medicine containing the composition, and provides a composite tablet, a composite capsule and a composite powder of the composition.

Detailed Description

The principles and features of this invention are described below in conjunction with specific embodiments, which are set forth merely to illustrate the invention and are not intended to limit the scope of the invention.

The inventor unexpectedly finds that the combination of the prodigiosin and the oxacillin or the derivatives thereof has a bacteriostatic effect obviously higher than that of the combination of the two single components, and prepares the combination of the prodigiosin and the oxacillin or the derivatives thereof and a medicament containing the same.

In the following examples, a oxacillin derivative, specifically oxacillin sodium, was used.

In the examples of the present invention, methicillin-resistant Staphylococcus aureus (MRSA) standard strain (ATCC33591) was purchased from American Tissue Culture Collection (USA); the oxacillin sodium used was purchased from sigma aldrich trade ltd; the prodigiosin used was purchased from Shanghai-derived leaf Biotech Co.

EXAMPLE 1 combination of prodigiosin and oxacillin or its derivatives Minimum Inhibitory Concentration (MIC) against methicillin-resistant Staphylococcus aureus (MRSA)

Inoculating MRSA bacterial suspension into LB culture medium, culturing at 37 deg.C overnight, correcting bacterial liquid to make it equal to 0.5 McLeod turbidimetric standard, and adding LB culture medium according to the ratio of 1: 200 of the diluted solution is ready for use.

Preparing 11 test tubes, preparing 2ml of prodigiosin LB culture medium solution with the working concentration of 50 mu g/ml from one test tube, adding 1ml into the test tube containing 1ml of LB culture medium, uniformly mixing, sucking 1ml out, adding into a third tube, repeating the process until the 11 th tube is reached, sucking 1ml out and discarding, wherein the final content of prodigiosin in each test tube is 50, 25, 12.5, 6.25, 3.125, 1.562, 0.781, 0.391, 0.195, 0.098 and 0.049 mu g/ml in sequence.

Preparing a oxacillin sodium LB culture medium solution with the working concentration of 50 mu g/ml according to the method, and performing gradient dilution in the same way.

The following solutions were prepared according to the above method, and the gradient dilution was performed in the same manner.

Composition a of prodigiosin and oxacillin or derivatives thereof: LB culture medium solution containing 50 mug/ml prodigiosin and 15 mug/ml oxacillin sodium;

composition B of prodigiosin and oxacillin or derivatives thereof: LB culture medium solution containing 50 mug/ml prodigiosin and 20 mug/ml oxacillin sodium;

composition C of prodigiosin and oxacillin or derivatives thereof: LB culture medium solution containing 50 mug/ml prodigiosin and 25 mug/ml oxacillin sodium;

composition D of prodigiosin and oxacillin or derivatives thereof: LB culture medium solution containing 50 mug/ml prodigiosin and 30 mug/ml oxacillin sodium;

composition E of prodigiosin and oxacillin or derivatives thereof: LB culture medium solution containing 50 mug/ml prodigiosin and 37.5 mug/ml oxacillin sodium.

Finally, the volume of each tube in each test tube is 1 ml. Blank LB medium control was also included for control.

And sequentially adding the MRSA suspension with the corrected concentration into each test tube, wherein the addition amount of each test tube is 0.05ml, and uniformly mixing after the addition. Each test tube was incubated at 37 ℃ for 18 hours and then observed for the presence or absence of visible turbidity, which is indicated by "√" when visible turbidity is observed in the test tube and "\" when invisible turbidity is observed in the test tube, the results are shown in tables 1-1 and 1-2.

TABLE 1-1 minimum inhibitory concentrations MIC (μ g/ml) of prodigiosin and oxacillin sodium, respectively, for MRSA

TABLE 1-2 minimum inhibitory concentrations MIC (μ g/ml) for compositions of prodigiosin and oxacillin or derivatives thereof for MRSA

According to the test results in the table 1-1, the minimum inhibitory concentration of prodigiosin to MRSA is 3.125-6.25. mu.g/ml, the minimum inhibitory concentration of oxacillin sodium to MRSA is 1.562-3.125. mu.g/ml, and the two antibiotics have good antibacterial activity to MRSA.

According to the test results in tables 1-2, the bacteriostatic effect of the composition of prodigiosin and oxacillin or derivatives thereof on MRSA is obviously stronger than that of the composition of prodigiosin and oxacillin or derivatives thereof when the two are used alone, and the minimum bacteriostatic concentration of the composition of prodigiosin and oxacillin sodium is minimum when the concentration ratio of the prodigiosin to oxacillin sodium is 2:1, and the minimum bacteriostatic concentration range is between 0.195 and 0.391 mu g/ml, which indicates that the bacteriostatic effect of the composition of prodigiosin and oxacillin or derivatives thereof on MRSA is obviously stronger than that of the composition of prodigiosin and oxacillin or derivatives thereof when the two are used alone.

EXAMPLE 2 preparation of a medicament for the treatment of methicillin-resistant Staphylococcus aureus infectious diseases

The medicament for treating methicillin-resistant staphylococcus aureus infectious diseases comprises the composition of prodigiosin and oxacillin or derivatives thereof in example 1.

Preferably, the composition also comprises one or more of pharmaceutically acceptable carriers, excipients, diluents and adjuvants.

Preferably, the medicament is any one of compound tablets, compound capsules or compound powder.

Preferably, the medicine is a compound tablet, and each 300g of the compound tablet comprises the following raw material components in mass: 9g of a composition of prodigiosin and oxacillin or derivatives thereof, 0-200 g of starch, 0-200 g of pregelatinized starch, 3g of talcum powder, 0-58 g of hydroxypropyl cellulose, 0-58 g of sodium carboxymethyl cellulose, 0-30 g of sodium carboxymethyl starch and 0-30 g of cross-linked polyvinylpyrrolidone, wherein the mass ratio of the prodigiosin to the oxacillin or derivatives thereof is 1.25-2: 1.

preferably, the compound tablet consists of the following raw material components in mass: 5.5g of prodigiosin, 3.5g of oxacillin sodium, 200g of starch, 300g of talcum powder, 58g of hydroxypropyl cellulose and 30g of cross-linked polyvinylpyrrolidone.

The preparation method of the composite tablet comprises the following steps:

s1, respectively weighing starch and hydroxypropyl cellulose, placing the starch and the hydroxypropyl cellulose in a mixing tank, stirring and mixing for 30 minutes, and sieving by using a 80-mesh sieve;

s2, adding the prodigiosin, the oxacillin sodium, the talcum powder and the cross-linked polyvinylpyrrolidone into the material obtained in the step S1, and mixing for 30 minutes to fully and uniformly mix the material;

s3, directly tabletting the mixed materials in the step S2 to prepare the composite tablet containing the composition of prodigiosin and oxacillin or derivatives thereof.

Preferably, the medicine is a compound capsule, and each 250g of the compound capsule comprises the following raw material components in parts by mass: 7g of a composition of prodigiosin and oxacillin or derivatives thereof, 0-210 g of pregelatinized starch, 0-210 g of starch, 15g of mannitol, 0-3 g of magnesium stearate, 0-3 g of talcum powder and 15g of sodium carboxymethyl starch, wherein the mass ratio of the prodigiosin to the oxacillin or derivatives thereof is (1-1.8): 1.

preferably, every 250g of the compound capsules contain 4g of prodigiosin and 3g of oxacillin sodium in the composition of the prodigiosin and oxacillin or the derivatives thereof; 210g of pregelatinized starch; 15g of mannitol; magnesium stearate is 3 g; the amount of sodium carboxymethyl starch was 15 g.

The preparation method of the compound capsule comprises the following steps:

d1, adding prodigiosin and oxacillin sodium powder into a dry press for granulation, granulating by a granulator, and screening by a rotary vibration screen to obtain prodigiosin and oxacillin sodium heavy powder particles;

d2, respectively crushing the pregelatinized starch, the mannitol, the magnesium stearate and the sodium carboxymethyl starch, and then sieving by using a rotary vibration sieve; weighing the prodigiosin and oxacillin sodium heavy powder particles and the screened pregelatinized starch, mannitol, magnesium stearate and sodium carboxymethyl starch, adding the mixture into a powder mixing machine, and uniformly mixing;

d3, filling the mixed medicinal powder into capsules by using a capsule filling machine to obtain the composite capsules containing the composition of the prodigiosin and the oxacillin or the derivatives thereof.

Preferably, the medicine is compound powder, and each 3000g of the compound powder comprises the following raw material components in parts by mass: 110g of a composition of prodigiosin and oxacillin or derivatives thereof, 2430g of starch, 60000-80 g of polyethylene glycol, 0-80 g of superfine silica gel powder, 0-80 g of talcum powder, 0-150 g of carbomer, 0-150 g of hydroxypropyl methyl cellulose and 0-150 g of sodium carboxymethyl cellulose, wherein the mass ratio of the prodigiosin to the oxacillin or derivatives thereof is 1.44-2.14: 1.

preferably, every 3000g of the composite powder contains 70g of prodigiosin and 40g of oxacillin sodium in the composition of prodigiosin and oxacillin or derivatives thereof; 80g of polyethylene glycol 6000; 2430g of starch; 80g of talcum powder; carbomer 150 g; the amount of sodium carboxymethylcellulose is 150 g.

The preparation method of the composite powder comprises the following steps:

m1, respectively sieving prodigiosin, oxacillin sodium, starch, sodium carboxymethylcellulose, polyethylene glycol 6000, talcum powder and carbomer raw material powder in the formula through a 120-mesh sieve for later use;

m2, placing the prepared prodigiosin and oxacillin sodium powder into a reaction pot for heating, and adding the prepared starch and sodium carboxymethylcellulose after the prodigiosin and oxacillin sodium are molten; mixing, cooling to room temperature, pulverizing, and sieving with 100 mesh sieve to obtain a first mixture;

m3, mixing the reserved polyethylene glycol 6000, talcum powder and carbomer with the first mixture for 10 minutes to obtain the composite powder containing the combination of the prodigiosin and the oxacillin or the derivative thereof.

The compound tablet, compound capsule and compound powder are respectively prepared according to the method.

TABLE 2A 1-A9 group composite tablet formulation containing prodigiosin and oxacillin or its derivative composition

TABLE 3 composite capsule formulation of groups B1-B9 containing prodigiosin and oxacillin or its derivatives

TABLE 4C 1-C9 composite powder formula of composition containing prodigiosin and oxacillin or derivatives thereof

Test example 1 bacteriostatic effect of prodigiosin and oxacillin or derivatives thereof and different formulations of drugs containing the same on MRSA

The bacteriostatic test method is that fresh MRSA is picked and inoculated in 4ml of LB culture medium in a clean bench. After inoculation, the culture tube is placed in a shaking table and cultured for 8h at 37 ℃ and 220 rpm. And uniformly coating 100 mu l of cultured MRSA bacterial suspension on the surface of an LB solid culture medium, respectively adding 0.5g of each compound tablet, capsule and powder of each experimental group into an Oxford cup, putting the LB solid culture medium into a 37 ℃ incubator, and taking out the Oxford cups of each group for 30min, 1h, 2h, 4h, 6h and 8h respectively to observe the diameter (cm) of a bacteriostatic circle.

Composite tablets containing a composition of prodigiosin and oxacillin or derivatives thereof prepared in groups A1-A9 in example 2 were dissolved in one tablet for bacteriostatic test, and the following solutions were prepared as control groups for bacteriostatic test.

Control group a: LB solution containing 6mg prodigiosin and 3mg oxacillin sodium;

control group B: LB solution containing 5.5mg prodigiosin and 3.5mg oxacillin sodium;

control group C: LB solution containing 5mg prodigiosin and 4mg oxacillin sodium;

control group D: LB solution containing 9mg prodigiosin;

control group E: LB solution containing 9mg of oxacillin sodium.

The bacteriostatic diameters of each group of composite tablets and the control at different times are shown in table 5:

TABLE 5 results of MRSA inhibition test of prodigiosin and oxacillin or derivative composite tablets prepared according to different formulas

According to the table 5, the bacteriostatic effect of the prodigiosin and oxacillin or derivative composite tablets prepared by different formulas is obviously higher than that of a control group on MRSA, and the composite tablets containing the prodigiosin and oxacillin or derivative composite tablets prepared by the formulas of A3 group, A4 group, A6 group, A7 group and A8 group can have long-acting inhibitory effect on MRSA within 8 h; the composite tablet prepared by the formula of the group A6 has the largest diameter of the inhibition zone and the best inhibition effect on MRSA, and is used as the most preferable formula of the composite tablet of prodigiosin and oxacillin or derivatives thereof, wherein the formula contains 9g of the composition of the prodigiosin and oxacillin or derivatives thereof, 200g of starch, 3g of talcum powder, 58g of hydroxypropyl cellulose and 30g of cross-linked polyvinylpyrrolidone; wherein, the composition of the prodigiosin and the oxacillin or the derivative thereof contains 5.5g of prodigiosin and 3.5g of oxacillin sodium.

The composite capsules of the compositions containing prodigiosin and oxacillin or derivatives thereof prepared in the formula of the group B1-B9 in example 2 were dissolved in one capsule for bacteriostasis test, and the following solutions were prepared as control groups for bacteriostasis test.

Control group F: LB solution containing 4.5mg prodigiosin and 2.5mg oxacillin sodium;

control group G: LB solution containing 4mg prodigiosin and 3mg oxacillin sodium;

control group H: LB solution containing 3.5mg prodigiosin and 3.5mg oxacillin sodium;

control group I: LB solution containing 7mg prodigiosin;

control group J: LB solution containing 7mg of oxacillin sodium.

The bacteriostatic diameters of the compound capsules and the control at different times are shown in table 6.

TABLE 6 results of MRSA inhibition test of prodigiosin and oxacillin or their derivatives in composite capsules prepared according to different formulas

According to table 6, the bacteriostatic effect of the prodigiosin and oxacillin or derivative composite capsules prepared by different formulas is obviously higher than that of a control group on MRSA, and the composite capsules containing the prodigiosin and oxacillin or derivative composite capsules prepared by the formulas of groups B2, B3, B4, B6 and B7 can have long-acting inhibitory effect on MRSA within 8 hours; the prodigiosin and oxacillin or derivative compound capsule prepared by the formula B6 has the largest diameter of the inhibition zone and the best inhibition effect on MRSA, and the prodigiosin and oxacillin or derivative compound capsule prepared by the formula B6 is the most preferable formula.

In the formula of group B6, the raw materials and weight ratio are 7g of the composition of prodigiosin and oxacillin or derivatives thereof, 210g of pregelatinized starch, 15g of mannitol, 3g of magnesium stearate and 15g of sodium carboxymethyl starch; wherein, the composition of the prodigiosin and the oxacillin or the derivative thereof contains 4g of prodigiosin and 3g of oxacillin sodium.

The composite powders of the compositions containing prodigiosin and oxacillin or derivatives thereof prepared in the formula of the group C1-C9 in example 2 were dissolved in 0.2g of the composite powders respectively for bacteriostasis tests, and the following solutions were prepared respectively as control groups for bacteriostasis tests.

Control group K: LB solution containing 5mg prodigiosin and 2.4mg oxacillin sodium;

control group L: LB solution containing 4.7mg prodigiosin and 2.7mg oxacillin sodium;

control group M: LB solution containing 4.4mg prodigiosin and 3mg oxacillin sodium;

control group N: LB solution containing 7.4mg prodigiosin;

control group O: LB solution containing 7.4mg of oxacillin sodium.

The bacteriostatic diameters of the composite powder and the control at different times are shown in table 7.

TABLE 7 results of MRSA inhibition test of prodigiosin and oxacillin or their derivatives composite powder prepared by different formulations

Results are shown in table 7, the antibacterial effect of the prodigiosin and oxacillin or derivative composite powder prepared by different formulas is significantly higher than that of a control group on MRSA, and the prodigiosin and oxacillin or derivative composite powder prepared by the formulas of groups C1, C3, C5, C7 and C9 in example 6 can produce long-acting inhibition on MRSA within 8 hours; the prodigiosin and oxacillin or derivative composite powder prepared by the formula C5 has the largest diameter of the inhibition zone and the best inhibition effect on MRSA, and the prodigiosin and oxacillin or derivative composite powder is used as the most preferable formula.

In the formula of group C5, the raw materials and weight ratio are 110g of the composition of prodigiosin and oxacillin or derivatives thereof, 2430g of starch, 80g of polyethylene glycol 6000, 80g of talcum powder, 150g of carbomer and 150g of sodium carboxymethylcellulose; wherein, the composition of the prodigiosin and the oxacillin or the derivative thereof contains 70g of prodigiosin and 40g of oxacillin sodium.

Test example 2 stability test of composite tablet, composite capsule and composite powder containing a composition of prodigiosin and oxacillin or derivatives thereof

Stability tests were performed on the composite tablet of the formulation of group a6, the composite capsule of the formulation of group B6, and the composite powder of the formulation of group C5 prepared in example 2.

The test method comprises the following steps: the three groups of samples are packaged by an aluminum foil bag and a carton, and are kept stand for 0 month, 1 month, 2 months, 3 months and 6 months at the temperature of 30 +/-2 ℃ and the humidity of 65% +/-5% RH, the appearance, the weight difference, the drying weight loss, the dissolution rate and the contents of related substances of the samples are respectively examined and determined, and the results are shown in table 8:

table 8 stability test results for each set of samples

Note: PRO is prodigiosin and OXA is oxacillin.

According to the experimental results, after stability tests are carried out on the composite tablet prepared by the formula A6, the composite capsule prepared by the formula B6 and the composite powder prepared by the formula C5 in the example 2, the appearance and weight difference meet the regulations, the content of water and related substances is slightly changed, and the content of prodigiosin and oxacillin is basically unchanged. Therefore, the compound tablet of group A6, the compound capsule of group B6 and the compound powder of group C5 in the example of the present invention all have good stability.

Test example 3 therapeutic effect of composite tablet, composite capsule and composite powder containing a composition of prodigiosin and oxacillin or derivatives thereof on methicillin-resistant staphylococcus aureus infectious pneumonia

The composite tablet, composite capsule and composite powder of the composition containing the prodigiosin and the oxacillin or the derivatives thereof prepared in the example 2 are subjected to a comparison experiment of the treatment effect of the methicillin-resistant staphylococcus aureus infectious pneumonia and the commercially available drugs.

The samples selected in the test example were a composite tablet formulated with formulation a4, a composite capsule formulated with formulation B5, and a composite powder formulated with formulation C4.

The tested organisms in the test example are mice, specifically 90 SPF grade C57BL/6 mice, male, 6-8 weeks old, 10-25g, and purchased from Guangdong provincial medical laboratory animal center.

The experimental method comprises the following steps: the mice were randomly divided into 6 groups of 15 mice each, and the tested drugs in each group were:

group A: compound tablet prepared by formula of group A6 in example 2;

group B: a compound capsule prepared by the formula of group B6 in example 2;

group C: compound powder prepared by formula of group C5 in example 2;

group D: a marketed oxacillin sodium tablet (Ruiyang pharmacy);

group E: commercial prodigiosin powder;

and F group: blank control.

The experimental method comprises the following specific steps:

each group of mice was anesthetized by intraperitoneal injection of 5% chloral hydrate, and groups A-E were smallMice were inoculated with 50. mu.l (approximately 4.0X 10) by nasal drip⁹CFU) methicillin-resistant staphylococcus aureus bacterial liquid, inoculating 50 mu l of sterile normal saline into F group mice by nasal drip, standing the mice for 30 seconds after inoculation to ensure that the bacterial liquid is fully absorbed, and then placing the mice to lie flat until the mice naturally revive.

The administration of the mice is started 6 hours after the mice are infected with methicillin-resistant staphylococcus aureus, 0.24g of compound tablets prepared by the formula A6, 1 granule of compound capsules prepared by the formula B6 and 0.2g of compound powder prepared by the formula C5 are respectively taken for the groups A-C for oral administration at 1h, 12h, 24h and 36 h; group D, taking 1 tablet of commercially available oxacillin sodium tablet (Ruiyang pharmaceutical) for oral administration at 1h, 12h, 24h and 36h respectively, and group E, taking 7.5mg of commercially available prodigiosin powder at the same time point, dissolving in purified water, and infusing into mouse stomach; group F was gavaged with 1ml of saline at the same time point. Collecting blood samples after 36 hours of administration, taking 3 mice in each group, dislocating cervical vertebrae, killing, taking out left lungs of the mice under aseptic condition, analyzing the load of methicillin-resistant staphylococcus aureus in lung tissues and blood by using a plate dilution method, and calculating the average value of each group; and observing the rest mice for 3 days after the administration for 36h, inspecting the influence of the prodigiosin and oxacillin compound tablets, capsules and powder on the survival rate of mice with methicillin-resistant staphylococcus aureus infectious pneumonia, and calculating the average value of each group.

TABLE 9 determination of the methicillin-resistant Staphylococcus aureus load in the lung tissue and blood of mice

TABLE 10 determination of the protection Rate of combinations of prodigiosin and oxacillin or derivatives thereof against MRSA infectious pneumonia in mice

According to the experimental results shown in table 9, the MRSA loading capacity in lung tissues and blood of mice treated by prodigiosin and oxacillin or derivative composite tablets thereof, prodigiosin and oxacillin or derivative composite capsules thereof, prodigiosin and oxacillin or derivative composite powder thereof is obviously lower than that of mice treated by commercial oxacillin tablets and commercial oxacillin powder, which indicates that prodigiosin and oxacillin or derivative composite tablets, prodigiosin and oxacillin or derivative composite capsules thereof, and prodigiosin and oxacillin or derivative composite powder thereof prepared in the invention have stronger inhibition effect on MRSA.

The experimental results in table 10 show that the survival rate of the mice in the blank control group after three days of observation is 16.7%, the survival rates of the mice in the commercial oxacillin sodium tablet administration group and the commercial prodigiosin powder group are 75% and 50%, respectively, and the survival rates of the mice in the prodigiosin and oxacillin or derivative composite tablet group, the prodigiosin and oxacillin or derivative composite capsule group and the prodigiosin and oxacillin or derivative composite powder group are 100%, 91.7% and 91.7%, respectively, which are significantly higher than the survival rates of the mice in the commercial oxacillin sodium tablet administration group and the commercial prodigiosin powder group. The preparation method proves that the survival period of mice with methicillin-resistant staphylococcus aureus infectious pneumonia can be remarkably prolonged by the prodigiosin and oxacillin or derivative composite tablets thereof, the prodigiosin and oxacillin or derivative composite capsules thereof and the prodigiosin and oxacillin or derivative composite powder thereof, and the preparation method has great application value.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.