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CN110314232A - The composition being made of lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor - Google Patents

  • ️Fri Oct 11 2019
The composition being made of lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor Download PDF

Info

Publication number
CN110314232A
CN110314232A CN201910714006.8A CN201910714006A CN110314232A CN 110314232 A CN110314232 A CN 110314232A CN 201910714006 A CN201910714006 A CN 201910714006A CN 110314232 A CN110314232 A CN 110314232A Authority
CN
China
Prior art keywords
hydroxy
inhibitor
coa reductase
composition
methylglutaryl coa
Prior art date
2019-08-03
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201910714006.8A
Other languages
Chinese (zh)
Inventor
向飞
孙伟光
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Huang Yong Hua
Original Assignee
Huang Yong Hua
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
2019-08-03
Filing date
2019-08-03
Publication date
2019-10-11
2019-08-03 Application filed by Huang Yong Hua filed Critical Huang Yong Hua
2019-08-03 Priority to CN201910714006.8A priority Critical patent/CN110314232A/en
2019-10-11 Publication of CN110314232A publication Critical patent/CN110314232A/en
Status Pending legal-status Critical Current

Links

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  • 229940123934 Reductase inhibitor Drugs 0.000 title claims abstract description 35
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  • 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 11
  • AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 claims abstract description 9
  • 229960001243 orlistat Drugs 0.000 claims abstract description 9
  • ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 claims abstract description 7
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  • 229960002855 simvastatin Drugs 0.000 claims abstract description 7
  • RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims abstract description 7
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  • XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims abstract description 6
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Classifications

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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract

The present invention provides a kind of composition being made of lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor and containing the pharmaceutical preparation of the composition.Preferably, lipase inhibitor of the present invention is selected from orlistat and west for one of Li Sita；And the hydroxy-3-methylglutaryl CoA reductase inhibitor is selected from one of Atorvastatin, Rosuvastatin, Simvastatin, Fluvastatin, Pravastatin, Lovastatin and Pitavastatin or its pharmaceutically acceptable salt.The antibacterial action that composition of the present invention can generate collaboration simultaneously is acted on the inhibition histamine release cooperateed with, so as to improve the effect and economic feature that bacterium infection causes anaphylactia patient treatment.

Description

The group being made of lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor Close object

Technical field

The invention belongs to pharmaceutical technology fields, and in particular to it is a kind of by lipase inhibitor and hydroxyl first glutaryl coenzyme A also The composition that reductase inhibitor is constituted and the pharmaceutical preparation containing the composition.

Background technique

Allergy is also referred to as allergic reaction.It is body by antigenicity substance (such as bacterium, virus, helminth, pollen Deng) stimulation after caused tissue damage or physiological dysfunction.Belong to abnormal or Focal immune response.Usually said Allergic reaction refers to I type allergic reaction, i.e. type Ⅰ hypersensitivity reaction.Its mechanism is to generate spy after anaphylactogen enters in allergy sufferers body Anisotropic antibody, the latter are incorporated in the surface of mast cell, make body in sensitization, loose thin when secondary contact allergy original Born of the same parents' degranulation, and a variety of chemical mediators are discharged, such as serotonin, slow reacting substance, histamine, leukotriene.These media cause Pathological change or symptom be referred to as type Ⅰ hypersensitivity reaction speed hair phase.

The release of inhibition histamine is one of the main mechanism of a variety of Claritins.

As previously mentioned, bacterium stimulation is one of the reason of leading to allergy, at the same have inhibit histamine release effect and The drug of antibacterial action will bring beneficial effect for improving the therapeutic effect of the patient of bacterium cause allergy, especially can Improve the economic feature of its treatment.

It is clinical using Atorvastatin as hydroxyl first glutaryl coenzyme A (HMG-CoA) reductase inhibitor class drug of representative Upper common regulating plasma lipid medicine, the antibacterial activity of such drug appears in the newspapers announcement repeatly in recent years.Jerwood S et al. researches show that (J Antimicrob Chemother.2008 Feb；61 (2): 362-4), Simvastatin and Fluvastatin all have certain antibacterial Effect, wherein the former is respectively 29.2 and 74.9mg/L to the average MIC of MSSA and MRSA, and in contrast, Fluvastatin Antibacterial action is substantially less than Simvastatin.Welsh AM et al. reports (Pathology.2009；41 (7): 689-91) claim atropic Cutting down statin and Rosuvastatin also has antibacterial action, but is all remarkably higher than it to the MIC value of MRSA and MSSA and is used to adjust blood Typical blood concentration when rouge.Masadeh M(Ann Clin Microbiol Antimicrob.2012 May 7；11:13) Et al. also report the antibacterial action of Atorvastatin, Simvastatin and Rosuvastatin, but its MIC value it is equal > 100mg/L, and And antibacterial action mechanism is unrelated with hydroxyl first glutaryl coenzyme A.

The research of Krauth MT et al. confirms (Allergy.2006Mar；61 (3): 281-8.), Atorvastatin with Cerivastatin can inhibit the histamine release of people's mast cell of anti-IgE induction.

It is two kinds of lipase inhibitor class loss of weight drugs that Li Sita (cetilistat) is replaced in orlistat and west, due to fat Enzyme has expression in various bacteria and regulates and controls the growth and function of bacterium, therefore orlistat may also have certain resist Bacterium effect, the present inventor also demonstrate this point in laboratory works.

The present inventor is in laboratory work it has also been found that orlistat and west for Li Sita also there is the histamine of moderate to inhibit Act on

Association is temporarily generated simultaneously without orlistat and hydroxy-3-methylglutaryl CoA reductase inhibitor drug combination in the prior art The technical teaching of same antibacterial action and the inhibition histamine release effect cooperateed with.

Summary of the invention

The purpose of the present invention is to provide one kind by lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor structure At composition and containing the pharmaceutical preparation of the composition, the composition can generate simultaneously the antibacterial action of collaboration with cooperate with Inhibition histamine release effect.

To achieve the goals above, present invention firstly provides one kind by lipase inhibitor and hydroxyl first glutaryl coenzyme A The composition that reductase inhibitor is constituted.

On the one hand preferred, lipase inhibitor of the present invention is selected from orlistat and west for one in Li Sita Kind；It is furthermore preferred that lipase inhibitor of the present invention is orlistat.

On the one hand preferred, hydroxy-3-methylglutaryl CoA reductase inhibitor of the present invention be selected from Atorvastatin, One of Rosuvastatin, Simvastatin, Fluvastatin, Pravastatin, Lovastatin and Pitavastatin or its pharmaceutically may be used The salt of receiving；It is further preferred that hydroxy-3-methylglutaryl CoA reductase inhibitor of the present invention be selected from Simvastatin, One of rosuvastain calcium, Atorvastatin calcium, Lovastatin, pravastatin sodium, Pitavastatin Calcium and fluvastatin sodium.

On the other hand preferred, lipase inhibitor and HMG-CoA reductase in composition of the present invention The ratio of the amount of the substance of inhibitor is between 0.008:1~158.489:1.

Another aspect of the present invention provides the pharmaceutical preparation containing composition as previously described.

Preferably, pharmaceutical preparation of the present invention is oral solid formulation.It is furthermore preferred that oral administration solid of the present invention Preparation is selected from one of capsule, tablet and granule.

Another aspect of the present invention provides foregoing composition and pharmaceutical preparation in preparation for treating bacterium sexuality Purposes in the drug of dye.

Another aspect of the present invention provides foregoing composition and pharmaceutical preparation in preparation for treating anaphylaxis disease Purposes in the drug of disease.

Another aspect of the present invention provides foregoing composition and pharmaceutical preparation in preparation simultaneously for treating bacterium Sexuality dye and the purposes in the drug of anaphylactia.

Preferably, bacterial infection of the present invention be by selected from actinomyces viscosus, bacteroides fragilis, brevibacterium epidermidis, Infection caused by one of clostridium difficile, clostridium tetani, paratyphosus A bacillus.

Composition of the present invention can generate antibacterial action and the antihistamine release action of collaboration simultaneously.

Specific embodiment

Below with reference to the embodiment of the present invention, clear, complete description is carried out to technical solution of the present invention, it is clear that retouched The embodiment stated is only a part of the embodiments of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, Every other embodiment obtained by those of ordinary skill in the art without making creative efforts, belongs to this hair The range of bright protection.

The ratio of the amount of substance of the present invention is lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor Substance amount ratio.

The present invention indicates the group of the two with "-" connection lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor Close object.

The preparation for the composition that embodiment 1 is made of lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor

The lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor of the ratio of the amount of predetermined substance are taken, it is sufficiently mixed Close to get.

The ratio of the amount of substance in test example of the present invention and embodiment include: 0.008:1,0.01:1,0.013:1, 0.016:1、0.02:1、0.025:1、0.032:1、0.04:1、0.05:1、0.063:1、0.079:1、0.1:1、0.126:1、 0.158:1、0.2:1、0.251:1、0.316:1、0.398:1、0.501:1、0.631:1、0.794:1、1:1、1.259:1、 1.585:1、1.995:1、2.512:1、3.162:1、3.981:1、5.012:1、6.31:1、7.943:1、10:1、12.589:1、 15.849:1、19.953:1、25.119:1、31.623:1、39.811:1、50.119:1、63.096:1、79.433:1、100: 1、125.893:1、158.489:1。

The antibacterial of the composition of 1 lipase inhibitor of test example, hydroxy-3-methylglutaryl CoA reductase inhibitor and the two Effect

Measure lipase inhibitor, hydroxy-3-methylglutaryl CoA reductase inhibitor and fat respectively using filter paper enzyme Bacteriostatic activity of the enzyme inhibitor-hydroxy-3-methylglutaryl CoA reductase inhibitor to various bacteria.Specifically, being drawn with liquid-transfering gun Prepared bacterial suspension (1 × 105Preparation method :/mL will live on slant tube culture medium for examination strain Change [37 ± 1 DEG C, 3 days], recycles oese to beat easily a small amount of lawn from inclined-plane, be respectively added to be contained with 50mL sterile physiological In the conical flask of salt water), it is uniformly applied to agar plate surface after cooling, plate containing bacterium is made.Sterilizing filter paper piece is taken, respectively It lets off in the tested material methanol solution of 6 kinds of concentration gradients and impregnates 1h, the 6mm circular filter paper piece impregnated is attached to above-mentioned make On plate containing bacterium, each culture dish (diameter 90mm) sticks the filter paper of 3 dipped same mass concentration tested material methanol solutions Piece (filter paper is spaced identical as far as possible), using 50% methanol solution as blank control.Processed plate containing bacterium is placed in 37 DEG C It is cultivated in insulating box for 24 hours, colony diameter is measured using crossing method, and calculate inhibiting rate (IR) according to following formula.

It is mapped with logarithm of the inhibiting rate (IR) to drug concentration (μM), and carries out linear regression with Excel, according to recurrence Equation extrapolates the concentration for generating lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor when fa inhibits, respectively ICfa(A)With ICfa(B)Value.For drug combination, then with inhibiting rate (IR) to the concentration (μM) of lipase inhibitor in drug combination Logarithm (log (c)) mapping, and carries out linear regression with Excel, combined system when extrapolating fa inhibition according to regression equation The concentration of interior lipase inhibitor, i.e. ICfa(mixA), further according to the ratio of the amount of substance in combined system, when extrapolating fa inhibition The concentration of hydroxy-3-methylglutaryl CoA reductase inhibitor, i.e. IC in combined systemfa(mixB)。

The drug combination index (CI) generated when fa inhibits is calculated according to the following formula

It when CI < 1, as acts synergistically, CI value is smaller, acts synergistically stronger.

As a result as shown in table 1~6.

Collaboration bacteriostasis of 1 lipase inhibitor of the table-hydroxy-3-methylglutaryl CoA reductase inhibitor to actinomyces viscosus

2 lipase inhibitors of table-hydroxy-3-methylglutaryl CoA reductase inhibitor is to the antibacterial work of the collaboration of bacteroides fragilis With

3 lipase inhibitors of table-hydroxy-3-methylglutaryl CoA reductase inhibitor is to the antibacterial work of the collaboration of brevibacterium epidermidis With

Collaboration bacteriostasis of 4 lipase inhibitors of the table-hydroxy-3-methylglutaryl CoA reductase inhibitor to clostridium difficile

5 lipase inhibitors of table-hydroxy-3-methylglutaryl CoA reductase inhibitor is to the antibacterial work of the collaboration of clostridium tetani With

Collaboration of 6 lipase inhibitors of the table-hydroxy-3-methylglutaryl CoA reductase inhibitor to paratyphosus A bacillus Bacteriostasis

The composition of 2 lipase inhibitor of test example, hydroxy-3-methylglutaryl CoA reductase inhibitor and the two inhibits histamine The effect of release

Logarithmic growth phase, RBL-2H3 cell are collected, and its concentration is adjusted to 8 × 104/ mL is uniformly inoculated in 96 holes In plate, every 200 μ L cell suspension of hole, in 37 DEG C, 5%CO2, saturated humidity incubator in cultivate for 24 hours, discard culture medium, 200 (lipase inhibitor, hydroxy-3-methylglutaryl CoA reductase inhibitor, lipase inhibitor-hydroxyl first glutaryl are auxiliary for μ L tested material Enzyme A reductase inhibitor is scattered in PBS), while reagent controls group is set, 200 μ L PBS, 37 DEG C of incubations are added in every hole 30min.Be incubated for terminate after, take out 100 μ L of cell conditioned medium be placed in test fluorescent plate in (extra supernatant freezes in -20 DEG C of refrigerators It deposits, spare), after 50 μ L, 0.4mol/L NaOH is added in each hole of test board, 0.1% o-phthalaldehyde-methanol solution is added immediately 10 μ L are mixed, and are placed at room temperature for 10min, and 50 μ L, 0.5mol/L HCl is added and terminates reaction, (are entered with microplate reader detection A value immediately Ejected wave long 360nm, launch wavelength 450nm), all tested material groups are calculated as ASupernatant, solvent control group is calculated as ABackground。

Remaining cell is cracked with 0.5% Triton100-PBS solution in 96 orifice plates, after 37 DEG C of incubation 30min, is taken thin 100 μ L of cellular lysate liquid is placed in test fluorescent plate (extra lysate freezes in -20 DEG C of refrigerators, spare), each hole of test board After 50 μ L, 0.4mol/LNaOH is added, 0.1% o-phthalaldehyde-methanol solution, 10 μ L is added immediately, mixes, is placed at room temperature for 10min is added 50 μ L, 0.5mol/L HCl and terminates reaction, detects A value (incident wavelength with microplate reader immediately after mixing 360nm, launch wavelength 450nm), with A above-mentionedSupernatantThe sum of value is calculated as ASupernatant+cracking, the histamine of each tested material is calculated further according to following formula It discharges inhibiting rate (IR):

IR (%)=1- (ASupernatant-ABackground)/(ASupernatant+cracking-ABackground) × 100%

It is mapped with logarithm of the inhibiting rate (IR) to drug concentration (μM), and carries out linear regression with Excel, according to recurrence Equation extrapolates the concentration for generating lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor when fa inhibits, respectively ICfa(A)With ICfa(B)Value.For drug combination, then with inhibiting rate (IR) to the concentration (μM) of lipase inhibitor in drug combination Logarithm (log (c)) mapping, and carries out linear regression with Excel, combined system when extrapolating fa inhibition according to regression equation The concentration of interior lipase inhibitor, i.e. ICfa(mixA), further according to the ratio of the amount of substance in combined system, when extrapolating fa inhibition The concentration of hydroxy-3-methylglutaryl CoA reductase inhibitor, i.e. IC in combined systemfa(mixB)。

The drug combination index (CI) generated when fa inhibits is calculated according to the following formula

It when CI < 1, as acts synergistically, CI value is smaller, acts synergistically stronger.

The results are shown in Table 7.

Table 7

Embodiment 2 contains the composition being made of lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor The preparation of oral solid formulation

Prescription (1000 unit dose)

Preparation method

50g composition and recipe quantity auxiliary material are taken, is sieved with 100 mesh sieve.Take composition, lactose, microcrystalline cellulose, the poly- dimension of crosslinking Ketone is mixed well with starch；The hydroxypropyl methylcellulose for taking recipe quantity, be configured to according to hydroxypropyl methylcellulose meter concentration be 10% it is molten The softwood processed into above-mentioned mixed material is added with newborn acid for adjusting pH to 3.0~4.0 in liquid, is pelletized with 16 meshes, and 80 DEG C of dryings 3~ 4h.With 16 mesh sieves, the superfine silica gel powder of recipe quantity is added and magnesium stearate mixes mixing, filling capsule is to get capsule；

50g composition and recipe quantity auxiliary material are taken, is sieved with 100 mesh sieve.Take composition, lactose, microcrystalline cellulose, the poly- dimension of crosslinking Ketone is mixed well with starch；The hydroxypropyl methylcellulose for taking recipe quantity, be configured to according to hydroxypropyl methylcellulose meter concentration be 10% it is molten The softwood processed into above-mentioned mixed material is added with newborn acid for adjusting pH to 3.0~4.0 in liquid, is pelletized with 16 meshes, and 80 DEG C of dryings 3~ 4h.With 16 mesh sieves, the superfine silica gel powder of recipe quantity is added and magnesium stearate mixes mixing, dispenses to get granule；

50g composition and recipe quantity auxiliary material are taken, is sieved with 100 mesh sieve.Take composition, lactose, microcrystalline cellulose, the poly- dimension of crosslinking Ketone is mixed well with starch；The hydroxypropyl methylcellulose for taking recipe quantity, be configured to according to hydroxypropyl methylcellulose meter concentration be 10% it is molten The softwood processed into above-mentioned mixed material is added with newborn acid for adjusting pH to 3.0~4.0 in liquid, is pelletized with 16 meshes, and 80 DEG C of dryings 3~ 4h.With 16 mesh sieves, the superfine silica gel powder of recipe quantity is added and magnesium stearate mixes mixing, tabletting both obtains tablet.

Claims (10)

1. a kind of composition being made of lipase inhibitor and hydroxy-3-methylglutaryl CoA reductase inhibitor.

2. composition according to claim 1, which is characterized in that the lipase inhibitor is to replace selected from orlistat with west One of Li Sita；It is furthermore preferred that the lipase inhibitor is orlistat.

3. composition according to claim 1, which is characterized in that the hydroxy-3-methylglutaryl CoA reductase inhibitor is choosing From one of Atorvastatin, Rosuvastatin, Simvastatin, Fluvastatin, Pravastatin, Lovastatin and Pitavastatin Or its pharmaceutically acceptable salt；It is furthermore preferred that the hydroxy-3-methylglutaryl CoA reductase inhibitor is to cut down him selected from pungent One in spit of fland, rosuvastain calcium, Atorvastatin calcium, Lovastatin, pravastatin sodium, Pitavastatin Calcium and fluvastatin sodium Kind.

4. composition according to claim 1~any one of 3, which is characterized in that the lipase inhibitor and hydroxyl first penta The ratio of the amount of the substance of two acyl coenzyme A reductase inhibitors is between 0.008:1~158.489:1.

5. the pharmaceutical preparation containing composition according to claim 1~any one of 4.

6. pharmaceutical preparation according to claim 5, which is characterized in that the pharmaceutical preparation is oral solid formulation.It is furthermore preferred that Oral solid formulation of the present invention is selected from one of capsule, tablet and granule.

7. composition according to claim 1~any one of 4 or the drug system according to any one of claim 5~6 Agent is preparing the purposes in the drug for treating bacterial infection.

8. composition according to claim 1~any one of 4 or the drug system according to any one of claim 5~6 Agent is preparing the purposes in the drug for treating anaphylactia.

9. composition according to claim 1~any one of 4 or the drug system according to any one of claim 5~6 Agent is preparing while being used to treat the purposes in bacterial infection and the drug of anaphylactia.

10. according to claim 7 and any one of 9 purposes, which is characterized in that the bacterial infection is by selected from viscous Caused by one of actinomyces, bacteroides fragilis, brevibacterium epidermidis, clostridium difficile, clostridium tetani, paratyphosus A bacillus Infection.

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