CN115645425B - Paeonol-glycyrrhizic acid solid dispersion with synergistic antibacterial effect, and preparation method and application thereof - Google Patents
Paeonol-glycyrrhizic acid solid dispersion with synergistic antibacterial effect, and preparation method and application thereof Download PDFInfo
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- CN115645425B CN115645425B CN202211437425.XA CN202211437425A CN115645425B CN 115645425 B CN115645425 B CN 115645425B CN 202211437425 A CN202211437425 A CN 202211437425A CN 115645425 B CN115645425 B CN 115645425B
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- Prior art keywords
- paeonol
- glycyrrhizic acid
- solid dispersion
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- acid solid
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Classifications
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- 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
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention provides a medicine-medicine solid dispersion prepared from paeonol and glycyrrhizic acid serving as active ingredients of traditional Chinese medicines, which has excellent synergistic antibacterial effect on various pathogenic microorganisms and is simple and convenient to prepare. The solid dispersion prepared by the invention has the antibacterial effect obviously superior to that of each single medicine component and the mixture thereof, and the solubility and the dissolution of the paeonol component are obviously improved, thereby being beneficial to further preparation forming and improving the bioavailability.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a paeonol-glycyrrhizic acid solid dispersion with a synergistic antibacterial effect, a preparation method of the paeonol-glycyrrhizic acid solid dispersion and application of the paeonol-glycyrrhizic acid solid dispersion in preparation of antibacterial medicines.
Background
In recent years, the abuse of antibiotics has led to the generation of drug-resistant bacteria, severely affecting the clinical therapeutic effect. Meanwhile, natural products with antibacterial activity are gradually discovered, so that the natural products are not easy to generate drug resistance, and have the advantages of multiple activities, multiple targets, low toxicity and the like. At present, researchers have proposed strategies for combining natural products with antibiotics in order to achieve the problems of weakening bacterial resistance, reducing antibiotic residues and the like. The invention selects two traditional Chinese medicine active ingredients with a certain antibacterial effect, namely paeonol and glycyrrhizic acid, and the paeonol and the glycyrrhizic acid are processed into an amorphous medicine-medicine solid dispersion, so that the synergistic antibacterial effect obviously superior to that of the original medicine is obtained.
Paeonol (PAE) is a small molecular phenolic compound extracted from root bark of Paeonol or dried root of radix Cynanchi Paniculati, and has low melting point, high volatility, slight solubility in water, and low oral bioavailability; in addition, paeonol has poor stability, and the preparation is easy to crystallize. The paeonol is taken orally to treat cardiovascular diseases, and is made into ointment for treating skin inflammation, eczema, etc. Modern researches have shown that paeonol itself has strong inhibiting effect on colibacillus, staphylococcus aureus, typhoid bacillus and the like.
Glycyrrhizic acid (Glycyrrhizic acid, GL) is the most important active ingredient of traditional Chinese medicine licorice, and consists of two molecules of glucuronic acid and one molecule of glycyrrhetinic acid. In clinical application, glycyrrhizic acid can be used for treating liver injury, chronic viral hepatitis, etc., and can be used for treating skin diseases such as inflammation by external application. Modern researches have shown that glycyrrhizic acid has definite pharmacological actions such as antibacterial and anti-inflammatory.
The pharmacy generally utilizes novel preparation technologies such as nano carriers, inclusion compounds, microcapsules, solid dispersions and the like to improve the solubility of insoluble drugs or improve the stability of the drugs. The technology generally needs to add a large amount of carriers or auxiliary materials to form, or involves a complex process method and has lower yield.
The prior art CN113545994A discloses a plant source composite bacteriostatic agent for the cosmetic field and application thereof, wherein the plant source composite bacteriostatic agent comprises the following raw materials in percentage by mass: 1-30% of bacteriostat, 0.5-50% of synergistic agent and 20-98.5% of solvent; the bacteriostatic agent is one or two of cinnamaldehyde and paeonol, and the synergistic agent is one or more of benzalkonium chloride, magnolol, honokiol, hinokitiol, glycyrrhizic acid and its salt, citric acid and its salt, etc. The plant source composite bacteriostatic agent is safe and effective, has the effects of resisting bacteria, relieving itching and resisting sensitization, can be used as an antibacterial and antiallergic active ingredient to be applied to skin care cosmetics, and has good safety and no toxic or side effect on human bodies. However, firstly, the effect of glycyrrhizic acid in the prior art is only speculative, no verification or theoretical explanation is made on the technical effect of glycyrrhizic acid, only the specific scheme of methyl benzoate, levulinic acid and caryophyllin as a synergistic agent is given in the specification, the technical scheme of specific combination of paeonol and glycyrrhizic acid is not given, and secondly, although part of chemical substances are named as the synergistic agent in the prior art, no evidence proves that the synergistic agent can produce synergistic effect with bacteriostatic agents such as paeonol, and the description of paragraphs 41-42 of the specification shows that in fact, only superposition of bacteriostatic effect is generated between the bacteriostatic agent and the synergistic agent, and no synergistic effect is generated. Moreover, the prior art described above does not give any technical teaching for preparing solid dispersions. In summary, the above prior art does not provide a technical scheme that paeonol and glycyrrhizic acid are specifically combined into a solid dispersion, and does not provide a technical suggestion that paeonol and glycyrrhizic acid have a synergistic effect.
The prior art TW200633691A discloses an enhancer for enhancing the antibiotic activity of antibiotics, wherein the enhancer can be curcumin, emodin, glycyrrhizic acid, magnolol, paeonol and the like, and specifically provides a technical scheme of taking curcumin as a piperacillin enhancer. However, the above prior art does not suggest that the combination of glycyrrhizic acid and paeonol can produce an antibacterial synergistic effect.
The prior art (development of paeonol oral medicine film) (Liu Chanming, etc., chinese patent medicine, 8 th 1992) discloses a preparation process of paeonol oral medicine film, which comprises the steps of taking PVA film-forming material, adding proper distilled water and glycerin, heating in water bath for dissolution, filtering, and preserving heat at 75 ℃ for 15min; and adding paeonol, monoammonium glycyrrhizinate and tween-80, heating in water bath until paeonol is melted, rapidly taking down, grinding, adding above matrix, stirring while adding distilled water to adjust volume, and defoaming. The medicine directly contacts with the affected part, is absorbed by mucous membrane, exerts the anti-inflammatory and analgesic effects, can avoid the first pass effect of liver, and greatly reduces the dosage. However, monoammonium glycyrrhetate is used in the prior art, instead of glycyrrhizic acid; in addition, the prior art does not show the proportion of paeonol to monoammonium glycyrrhizinate, and does not show what technical effect is produced after monoammonium glycyrrhizinate is added.
The prior art (the combined application research of the glycyrrhizic acid diamine and the paeonol) (Luo Xin and the like, the university of vinca and traditional Chinese medicine report, 24 (6), and 12 months in 2008) discloses that the glycyrrhizic acid diamine can play a role in treating eczema dermatitis by controlling inflammatory factors and immune factors, and the paeonol has the effects of easing pain, calming and hypnotizing, resisting inflammation, relieving fever, resisting allergy, enhancing immune functions and the like. The clinical combined application of the two has obvious curative effect on acute eczema. The specific treatment method comprises 1 time/d of glycyrrhizic acid diamine (ganlixin), 40mL intravenous drip each time, and topical application of paeonol ointment. 15 d is 1 course of treatment. However, the paeonol and the diamine glycyrrhizinate are administered by different routes, the diamine glycyrrhizinate is administered by injection, and paeonol is administered topically, and no composition or solid dispersion is formed, and the use thereof is not for producing a synergistic antibacterial effect.
The medicine-medicine solid dispersion is based on intermolecular interaction between paeonol and glycyrrhizic acid, does not need to add any carrier or auxiliary materials, and has simple process and stable product.
Disclosure of Invention
The invention aims to provide paeonol-glycyrrhizic acid solid dispersion with a synergistic antibacterial effect. The solid dispersion can reduce the cost and the administration dosage under the condition of meeting the antibacterial requirement, or can enhance the antibacterial effect under the condition of the same administration dosage.
Another object of the present invention is to provide a solid dispersion which can improve dissolution, absorption and permeation properties of paeonol, can improve stability of paeonol and can inhibit crystallization of paeonol, and can be prepared simply without adding any functional auxiliary materials.
It is another object of the present invention to provide a method for preparing the above solid dispersion.
The invention also aims to provide the application of the solid dispersion in preparing medicines, namely, the solid dispersion is used as a preparation intermediate to be further prepared into various oral or external antibacterial preparations such as gel, tablets, capsules and the like, so that the solid dispersion is convenient for clinical application.
Specifically, the invention provides the following technical scheme:
a solid dispersion with synergistic antibacterial effect comprises paeonol and glycyrrhizic acid as active ingredients of traditional Chinese medicine, wherein no functional auxiliary material is added, and the molar ratio of paeonol to glycyrrhizic acid is 1:10-10:1.
Preferably, the molar ratio of paeonol to glycyrrhizic acid is in the range of 1:5-5:1.
More preferably, the molar ratio of paeonol to glycyrrhizic acid is in the range of 1:3-3:1.
Most preferably, the molar ratio of paeonol to glycyrrhizic acid is 1:1.
The invention also provides a method for preparing the solid dispersion, namely a solvent evaporation method, a grinding method and a melting method. Preferably, the preparation method is a solvent evaporation method.
The solvent evaporation method is to weigh a proper amount of paeonol and glycyrrhizic acid, completely dissolve in the solvent, uniformly mix, naturally volatilize the solvent at room temperature, and crush to obtain paeonol-glycyrrhizic acid solid dispersion. Preferred solvents are ethanol and methanol.
The grinding method comprises weighing paeonol and appropriate amount of glycyrrhizic acid, placing in beaker, adding appropriate amount of zirconia beads with appropriate size, grinding for 3 hr, and sieving with 80 mesh sieve to obtain paeonol-glycyrrhizic acid solid dispersion.
The melting method comprises weighing paeonol and appropriate amount of glycyrrhizic acid, heating glycyrrhizic acid to molten state, cooling to a certain temperature, adding paeonol, mixing, rapidly solidifying in ice bath, pulverizing, and sieving with 80 mesh sieve to obtain paeonol-glycyrrhizic acid solid dispersion.
The inventor verifies through experiments that the solid dispersion obtained by the solvent evaporation method has the highest product yield, the preparation process is simple, and the obtained product has the best synergistic antibacterial effect.
Preferably, the solid dispersion of the invention has obvious synergistic antibacterial effect on klebsiella pneumoniae, staphylococcus aureus, drug-resistant staphylococcus aureus and propionibacterium acnes.
The solid dispersion obtained by the invention is in an amorphous form, and is more stable than paeonol raw material medicines, better in dissolution performance and higher in dissolution rate. Without limitation, the inventors believe that the above-described effect of increasing stability and solubility may be related in part to the reason that glycyrrhizic acid can self-assemble in water to form micelles, and can improve the solubility and bioavailability of other poorly soluble molecules by solubilization or the like. However, it should be noted that the above solubilization may not be related to the synergistic antibacterial effect between glycyrrhizic acid and paeonol, because experiments by the inventor prove that other ways of increasing the solubility of paeonol, such as using other surfactants or nanoemulsions, are adopted in combination with other common antibacterial agents other than glycyrrhizic acid, and the antibacterial effect is also significantly worse than that of paeonol-glycyrrhizic acid pharmaceutical compositions under the same conditions, and no synergistic effect is generated.
The paeonol-glycyrrhizic acid solid dispersion provided by the invention is simple to prepare, low in cost and good in reproducibility.
The invention takes the solid dispersion as a preparation intermediate, further prepares a plurality of preparations, and is prepared from the solid dispersion and pharmaceutic adjuvant.
In summary, the inventors have found through unexpected studies that the preparation of a solid dispersion by mixing the components of paeonol and glycyrrhizic acid can produce a remarkable synergistic antibacterial effect, which is significantly greater than that of paeonol or glycyrrhizic acid alone, and also greater than that of a simple mixture of paeonol and glycyrrhizic acid. Besides, the solubility and bioavailability of the active ingredients can be obviously increased, and the stability is obviously enhanced. In addition, any auxiliary materials are not needed in the process of preparing the solid dispersion, so that the cost is saved.
Description of the drawings:
FIG. 1 is a graph of paeonol-glycyrrhizic acid solid dispersion PXRD and stability test results in example 1; wherein A is a solid dispersion PXRD pattern; b is a stability diagram.
FIG. 2 is a graph showing the equilibrium solubility and in vitro dissolution of paeonol-glycyrrhizic acid solid dispersion according to example 1; wherein a is an equilibrium solubility profile (< 0.05 compared to bulk drug group; (< 0.05 compared to physical mixture group); b is an in vitro dissolution profile (mean±sd; n=3).
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is evident that the embodiments described are only some embodiments of the present invention, but not all embodiments.
Detailed Description
Example 1: weighing appropriate amount of paeonol and glycyrrhizic acid (molar ratio of 1:1), completely dissolving in methanol, mixing, naturally volatilizing solvent at room temperature, and pulverizing to obtain paeonol-glycyrrhizic acid solid dispersion.
Example 2: weighing appropriate amount of paeonol and glycyrrhizic acid (molar ratio of 1:10), respectively dissolving in 70% ethanol, mixing, concentrating at 40deg.C under reduced pressure, naturally volatilizing at room temperature, pulverizing, sieving to obtain paeonol-glycyrrhizic acid solid dispersion, adding appropriate amount of starch, mixing, dry granulating, and directly encapsulating to obtain paeonol-glycyrrhizic acid capsule.
Example 3: weighing appropriate amount of paeonol and glycyrrhizic acid (molar ratio of 10:1), completely dissolving in methanol, mixing, concentrating at 40deg.C under reduced pressure, naturally volatilizing at room temperature, pulverizing, sieving to obtain paeonol-glycyrrhizic acid solid dispersion, adding appropriate amount of microcrystalline cellulose, mixing, and directly encapsulating to obtain paeonol-glycyrrhizic acid capsule.
Example 4: weighing appropriate amount of paeonol and glycyrrhizic acid (molar ratio of 1:5), respectively dissolving in 70% ethanol, mixing, concentrating at 45deg.C under reduced pressure, naturally volatilizing at room temperature, pulverizing, sieving to obtain paeonol-glycyrrhizic acid solid dispersion, adding appropriate amount of starch, mixing, and directly tabletting to obtain paeonol-glycyrrhizic acid tablet.
Example 5: weighing a proper amount of paeonol and glycyrrhizic acid (the molar ratio is 5:1), completely dissolving in methanol, uniformly mixing, naturally volatilizing the solvent at room temperature, and pulverizing to obtain paeonol-glycyrrhizic acid solid dispersion; weighing a proper amount of the composition, dissolving in a proper amount of water, adding a proper amount of hydroxypropyl methylcellulose for dispersion, fully swelling and uniformly mixing to obtain paeonol-glycyrrhizic acid gel.
Example 6: weighing a proper amount of paeonol and glycyrrhizic acid (the molar ratio is 1:3), firstly heating glycyrrhizic acid to a molten state in a water bath kettle at 80 ℃, cooling to about 40 ℃, adding paeonol, stirring for 5min to uniformly mix, placing in an ice bath to rapidly solidify after uniformly mixing, crushing and sieving with a 80-mesh sieve to obtain the paeonol-glycyrrhizic acid solid dispersion.
Example 7: weighing a proper amount of paeonol and glycyrrhizic acid (the molar ratio is 3:1), placing into a beaker, adding a proper amount of zirconia beads with proper size, grinding for 3 hours together, and sieving with a 80-mesh sieve to obtain the paeonol-glycyrrhizic acid solid dispersion.
Example 8: weighing a proper amount of paeonol and glycyrrhizic acid (the molar ratio is 1:1), placing into a mortar, adding a proper amount of methanol, grinding for 1h, naturally volatilizing the solvent at room temperature, crushing and sieving with a 80-mesh sieve to obtain paeonol-glycyrrhizic acid solid dispersion, adding a proper amount of hydroxypropyl methylcellulose into 95% ethanol, uniformly stirring, uniformly spreading on a smooth glass plate, placing into a 40 ℃ oven, drying for 2 h, and removing to obtain the paeonol-glycyrrhizic acid oral instant film.
Example 9: paeonol-glycyrrhizic acid in-vitro medicine combination antibacterial effect test
MIC was measured by microdilution, and concentration of Klebsiella pneumoniae, staphylococcus aureus, drug-resistant Staphylococcus aureus, and Propionibacterium acnes was adjusted to 3×10 5 Inoculating CFU/mL into 96-well sterile culture plate, adding appropriate amount of paeonol and glycyrrhizic acid in table 1, changing their ratio, solid dispersion prepared from paeonol and common solid dispersion carrier (polyethylene glycol PEG6000 or poloxamer F68) and physical mixture of paeonol and glycyrrhizic acid or different adjuvants,dissolving in DMSO, diluting with each time, adding into the bacterial suspension, and respectively setting negative control and positive control. Culturing in a constant temperature incubator at 37 ℃ for 18-24 h, observing growth conditions, adding 10 mu L of prepared TTC solution, continuously culturing in the incubator at 37 ℃ for 2 h under the dark condition, observing dyeing change, and obtaining the MIC of the medicine which is the lowest medicine concentration group without being dyed red.
MBC was measured by streaking, inoculating a bacterial culture solution of a MIC experiment 96-well plate, which was not subjected to bacterial growth, to a solid medium, culturing in a constant temperature incubator at 37℃for 16-18 hours, observing the results, counting colonies, and performing parallel operation 3 times on each bacterium with a minimum concentration of drug of less than 5 colonies as MBC of the bacterium.
Table 1 MIC and MBC values (mg/mL) for each group of samples against Staphylococcus aureus
Table 1 shows that the MIC and MBC values of paeonol-glycyrrhizic acid solid dispersions prepared under different molar ratios are significantly lower than those of the two raw material medicaments and the physical mixture thereof, and the paeonol-glycyrrhizic acid solid dispersions show excellent synergistic antibacterial effect; wherein the MIC of the solid dispersion obtained in the molar ratio of 1:1 is less than 0.46 mg/mL, the MBC is less than 0.73 mg/mL, and the synergistic antibacterial effect is optimal; under the condition of the same fixed molar ratio of the two medicines, the paeonol-glycyrrhizic acid solid dispersion prepared by adopting the solvent volatilization method has an antibacterial effect which is obviously better than that of a sample prepared by adopting the grinding method, and the MIC and MBC values of the paeonol-glycyrrhizic acid solid dispersion are respectively 4.8 and 6.0 times of those of the paeonol-glycyrrhizic acid solid dispersion prepared by adopting the grinding method; the weight ratio of paeonol to carrier is basically consistent with that of paeonol to glycyrrhizic acid (molar ratio 1:1) by adopting a solvent volatilization method respectively to prepare two solid dispersions of polyethylene glycol PEG 6000\poloxamer F68, but the MIC value is about 10 times different, and the antibacterial effect of the two solid dispersions is almost consistent with that of a physical mixture, so that the improvement of the dissolution performance of the solid dispersions on paeonol is not a key factor of the paeonol-glycyrrhizic acid solid dispersions in playing a synergistic antibacterial effect.
TABLE 2 MIC (mg/mL) of each group of sample concentrations for different bacterial solutions
Table 2 shows that the combination of paeonol and glycyrrhizic acid shows excellent synergistic antibacterial effect against Klebsiella pneumoniae, staphylococcus aureus, drug resistant Staphylococcus aureus and Propionibacterium acnes.
Example 10: characterization of paeonol-glycyrrhizic acid solid dispersion properties
The appropriate amount of the solid dispersion obtained in example 1 was scanned by a powder X-ray diffractometer (PXRD) under the following measurement conditions: the scanning angle is 2 theta, the step length is 0.02 DEG, the scanning speed is 8 DEG/min, and the scanning range is 3-85 deg. The results are shown in FIG. 1A.
FIG. 1A shows that the characteristic peak of the product formed in Experimental example 1 disappears, and is in an amorphous form, i.e., paeonol-glycyrrhizic acid amorphous solid dispersion.
Example 11: paeonol equilibrium solubility determination
In the embodiment of the invention, the solubility test of paeonol-glycyrrhizic acid solid dispersion is referred to the edition 2020 of Chinese pharmacopoeia: taking excessive paeonol raw material, solid dispersion and physical mixture with different proportions, placing into a constant temperature gas bath table (37 ℃ C., 100 r/min), shaking 72 h, taking out, immediately centrifuging, taking out supernatant, passing through a 0.22 μm microporous filter membrane, measuring the absorption peak area by HPLC, and calculating the equilibrium solubility of paeonol, wherein the result is shown in figure 2A.
Fig. 2A shows that the solid dispersion prepared in example 1 has significantly improved paeonol solubility, and the solubility increases as the paeonol ratio decreases.
Example 12: evaluation of paeonol in vitro dissolution Performance
The dissolution rate of the paeonol-glycyrrhizic acid solid dispersion in the embodiment of the invention is referred to a small cup method of the 2020 edition of Chinese pharmacopoeia: the release medium was water at a temperature of 37.+ -. 0.5 ℃ and a small amount of paeonol and a considerable amount of the physical mixture and solid dispersion (example 1) were accurately weighed in a 250mL beaker, 2mL was sampled and passed through a 0.22 μm microporous filter membrane while supplementing an isothermal equal volume of the dissolution medium, the absorption peak area thereof was measured by HPLC, the cumulative dissolution for each time period was calculated, and the dissolution curve was drawn, and the results are shown in fig. 2B.
Figure 2B shows that the in vitro release rates of paeonol and glycyrrhizic acid are significantly faster.
While the foregoing description illustrates and describes the preferred embodiments of the present invention, it is to be understood that the invention is not limited to the forms disclosed herein, but is not to be construed as limited to other embodiments, and is capable of numerous other combinations, modifications and environments and is capable of changes or modifications within the scope of the inventive concept as described herein, either as a result of the foregoing teachings or as a result of the knowledge or technology in the relevant art. And that modifications and variations which do not depart from the spirit and scope of the invention are intended to be within the scope of the appended claims.
Claims (7)
1. A paeonol-glycyrrhizic acid solid dispersion with synergistic antibacterial effect is characterized in that: the paeonol-glycyrrhizic acid composition comprises paeonol and glycyrrhizic acid, wherein the molar ratio of paeonol to glycyrrhizic acid is 1:1-1:5; the preparation method is a solvent evaporation method, and the solvent used in the preparation process is ethanol, methanol or a mixed solvent containing water;
the antibacterial agent is used for inhibiting or killing staphylococcus aureus, drug-resistant staphylococcus aureus, klebsiella pneumoniae and/or propionibacterium acnes.
2. The paeonol-glycyrrhizic acid solid dispersion according to claim 1, characterized in that: the molar ratio of paeonol to glycyrrhizic acid is 1:1-1:3.
3. The paeonol-glycyrrhizic acid solid dispersion according to claim 2, characterized in that: the molar ratio of paeonol to glycyrrhizic acid is 1:1.
4. The paeonol-glycyrrhizic acid solid dispersion according to claim 1, characterized in that: the paeonol-glycyrrhizic acid solid dispersion is in an amorphous state, and has no characteristic diffraction peak under the detection of a powder X-ray diffractometer.
5. A method for preparing paeonol-glycyrrhizic acid solid dispersion according to claim 1, characterized in that:
the preparation method is a solvent evaporation method, and the solvent used in the preparation process is ethanol, methanol or a mixed solvent containing water.
6. Use of the paeonol-glycyrrhizic acid solid dispersion according to claim 1 for the preparation of an antibacterial drug, characterized in that: the antibacterial agent is used for inhibiting or killing staphylococcus aureus, drug-resistant staphylococcus aureus, klebsiella pneumoniae and/or propionibacterium acnes.
7. Use according to claim 6, characterized in that: the medicine is an oral preparation
Or external preparation, wherein the oral preparation is tablet, capsule, granule, powder or oral liquid,
the external preparation is a solution, gel, patch or ointment.
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Citations (3)
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JP2002363091A (en) * | 2001-06-08 | 2002-12-18 | Noevir Co Ltd | Skin care preparation |
KR20030043520A (en) * | 2001-11-28 | 2003-06-02 | 주식회사 엘지생활건강 | Oral compositions against halitosis |
CN113545994A (en) * | 2021-06-16 | 2021-10-26 | 广州艾卓生物科技股份有限公司 | Plant source composite bacteriostatic agent and application thereof |
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JP2002363091A (en) * | 2001-06-08 | 2002-12-18 | Noevir Co Ltd | Skin care preparation |
KR20030043520A (en) * | 2001-11-28 | 2003-06-02 | 주식회사 엘지생활건강 | Oral compositions against halitosis |
CN113545994A (en) * | 2021-06-16 | 2021-10-26 | 广州艾卓生物科技股份有限公司 | Plant source composite bacteriostatic agent and application thereof |
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