Antibacterial drug based on cepharanthin and taurine complex and preparation method thereof

Abstract

The present invention discloses an antibacterial drug based on a complex of cepharanthin and taurine, belongs to the field of biomedical processing technology, and solves the problem that the crystal structure of the antibacterial drug prepared by cepharanthin in the prior art leads to insufficient drug efficacy. The antibacterial drug in the present invention is a dry powder obtained by mixing cepharanthin with taurine and removing water and ethanol. The dry powder has a dual effect of hydrophilicity and lipophilicity, and there is no antagonism between the components. It can have a good sterilization effect on pathogens in the case of a small amount. The present invention also discloses a preparation method of the above-mentioned antibacterial drug, firstly, cepharanthin is mixed with hydrochloric acid to prepare cepharanthin hydrochloride, and taurine is mixed with potassium hydroxide to prepare potassium taurine, and then cepharanthin hydrochloride and potassium taurine are mixed and vacuum dried to obtain the above-mentioned antibacterial drug. The preparation method in the present invention is simple, green and environmentally friendly, and the prepared antibacterial drug has a good antibacterial effect.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedical processing, and in particular, relates to an antibacterial drug based on a complex of cepharanthin and taurine and a preparation method thereof. Background Art

[0002] Cepharanthine (cep) is an alkaloid from the traditional Chinese medicinal plant Stephania tetrandra, belonging to the family of dibenzylisoquinoline alkaloids. It is currently used for leukopenia caused by tumor chemotherapy, radiotherapy and other reasons, and can enhance human immunity.

[0003] Chinese invention patent CN113046327A discloses that cephalothin has the potential to be used as a new crown treatment drug. Through the technical solution in the invention, cephalothin, selamectin, mefloquine hydrochloride, etc. were screened out, proving that cephalothin, selamectin and mefloquine hydrochloride exert inhibitory effects after xCOV enters the cell. The technical solution of the invention also explains the anti-xCOV mechanism of cephalothin. Cephalothin mainly reverses most of the disordered genes and pathways in infected cells by interfering with cell stress responses, including endoplasmic reticulum stress / unfolded protein response and heat shock shadow-mediated heat shock response. Therefore, cephalothin has broad application prospects.

[0004] In the prior art, most of the antibacterial drugs prepared by cephalothin are crystalline solids. The polycrystallinity will affect the stability, solubility, dissolution rate and bioavailability of the drug, thereby affecting the efficacy and safety of the marketed drugs. Therefore, it is of great significance to develop antibacterial drugs with better antibacterial efficacy. Summary of the invention

[0005] The purpose of this section is to summarize some aspects of embodiments of the present invention and briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section and the specification abstract and the invention title of this application to avoid blurring the purpose of this section, the specification abstract and the invention title, and such simplifications or omissions cannot be used to limit the scope of the present invention.

[0006] In order to solve the problem in the prior art that the crystal form of the antibacterial drug prepared by cephalothin affects the drug efficacy, in the technical scheme of the present invention, taurine is used to promote the development of important human tissues or organs such as the brain, nerves, heart, and reproductive organs, and can also prevent cardiovascular diseases, promote lipid absorption, enhance human immunity, reduce blood sugar concentration, prevent and treat anemia, and has anti-tumor, anti-oxidation, analgesic, anti-inflammatory and other properties. It is compounded with cephalothin to prepare antibacterial drugs, effectively preventing the antibacterial efficacy of cephalothin from being affected by the crystal form. The technical scheme of the present invention is as follows:

[0007] An antibacterial drug based on a complex of cepharanthin and taurine is prepared by mixing and stirring cepharanthin and taurine and removing water and anhydrous ethanol to obtain a dry powder.

[0008] Another object of the present invention is to provide a method for preparing the above-mentioned antibacterial drug, the specific steps of which are as follows:

[0009] Step 1: dissolving cephalaenopsis in anhydrous ethanol to obtain a solution, then adding hydrochloric acid, and sealing and stirring at room temperature to obtain cephalaenopsis hydrochloride;

[0010] Step 2: dissolving taurine in water to obtain a taurine solution, adding potassium hydroxide, and sealing and stirring at room temperature to obtain potassium taurine;

[0011] Step 3: adding cepharanthin hydrochloride to potassium taurine, mixing and stirring to obtain a mixture, heating the mixture in vacuum to remove water and anhydrous ethanol to obtain a dry powder, which is the antibacterial drug.

[0012] Preferably, in the first step of the above preparation method, the molar ratio of cepharanthin to hydrochloric acid is 1:1, and the sealed stirring time is 2 hours.

[0013] Preferably, in the second step of the above preparation method, the molar ratio of taurine to potassium hydroxide is 1:1, and the sealed stirring time is 2 hours.

[0014] Preferably, in the third step of the above preparation method, the mixing and stirring time is 5 hours, and the mixing and stirring temperature is 60°C, the vacuum heating time of the mixture is 5 hours, and the vacuum heating temperature is 60°C.

[0015] Preferably, in the above preparation method, the reaction process of cepharanthin and hydrochloric acid is as follows:

[0016]

[0017] Preferably, in the above preparation method, the reaction process of taurine and potassium hydroxide is as follows:

[0018]

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] The antibacterial drug prepared in the present invention can improve the solubility, stability and permeability of the drug, solve the polymorphism problem of the drug, and exert the therapeutic effect of the drug to a greater extent. Figure 1 ) It can be seen that pure cephalaenopsis begins to decompose at 137°C, while the complex [cep][tau] begins to decompose at 309°C, indicating that after adding taurine, the thermal stability of the complex [cep][tau] is greatly improved compared with pure cephalaenopsis.

[0021] The antibacterial drug prepared in the present invention can promote the permeability of the drug. The product obtained by the present invention has both hydrophilicity and lipophilicity: taurine has hydrophilicity, and the hydrophilic group can promote the paracellular transport of the drug; cepharanthin has lipophilicity, and the lipophilic group promotes the transcellular transport of the drug by improving the permeability of the cell membrane. In addition, taurine contains hydrogen bonds, which interact with the phospholipid bilayer, thereby better increasing the permeability of the drug.

[0022] The antibacterial drug prepared in the present invention has a higher absorption rate. Taurine is a conditionally essential amino acid, which has important functions such as anti-aging, regulating crystal osmotic pressure and anti-oxidation, and is an important food nutrition enhancer and infant formula milk powder additive. It can be quickly absorbed in the body, thereby enhancing the absorption of the drug in the digestive tract and reducing the toxicity of the drug. In addition, taurine can promote the generation of antioxidant substances in the body, which helps to regulate the body's acid-base balance.

[0023] The antibacterial drug of the present invention pairs taurine having an immunomodulatory effect with cephalothin which can prevent and treat leukopenia, which not only makes the product have dual medicinal effects but also plays a synergistic and synergistic role.

[0024] The antibacterial drug of the present invention increases the crystallinity of the raw material drug cepharanthin and improves the quality of the drug. Figure 2 ) It can be seen that after adding taurine, the crystallinity of the complex [cep][tau] is higher than that of pure cepharanthin, which is of great significance for improving the quality of drugs.

[0025] The method for preparing the drug of the present invention is simple in process, low in preparation cost, and green and environmentally friendly. In addition, the product [cep][tau] of the present invention has significant sterilization activity against Staphylococcus aureus and Klebsiella pneumoniae. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 Schematic diagram of thermogravimetric analysis curves of cepharanthin, taurine and the antibacterial drug prepared by using cepharanthin and taurine in the present invention;

[0027] Figure 2 X-ray diffraction patterns of cepharanthin, taurine and the antibacterial drug prepared by using cepharanthin and taurine in the present invention;

[0028] Figure 3 Schematic diagram of the sterilization effect of cepharanthin, taurine and the antibacterial drug prepared by using cepharanthin and taurine on Staphylococcus aureus in the present invention;

[0029] Figure 4It is a schematic diagram of the sterilization effect of cepharanthin, taurine and the antibacterial drug prepared by cepharanthin and taurine on Klebsiella pneumoniae in the present invention. DETAILED DESCRIPTION

[0030] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with the accompanying drawings.

[0031] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein, and those skilled in the art may make similar generalizations without violating the connotation of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0032] The present invention proposes a low-cost, simple and safe preparation method for a complex of cepharanthin and taurine based on modern pharmaceutical technology. The active pharmaceutical ingredient (i.e., cepharanthin) is mixed with an organic inner salt (i.e., taurine), which solves the problem of cepharanthin crystal polymorphism, improves the stability, permeability and solubility of cepharanthin in physiological media, changes its pharmacokinetic properties and delivery mode, and solves the problems of low drug solubility and limited dosage in the pharmaceutical industry. At the same time, the present invention also studies the effect of the complex of cepharanthin and taurine on common pathogens of clinical infection. The specific scheme is as follows:

[0033] The cepharagnan and hydrochloric acid are mixed in equal moles. The cepharagnan is dissolved in a certain amount of anhydrous ethanol to obtain a solution, and then an equal mole of hydrochloric acid is added, and the solution is sealed and stirred at room temperature for 2 hours to obtain the cepharagnan hydrochloride.

[0034] Taurine and potassium hydroxide are mixed in equal moles. Taurine is dissolved in water to obtain a taurine solution, and then an equal mole of potassium hydroxide is added, and the mixture is sealed and stirred at room temperature for 2 hours to obtain potassium taurine.

[0035] Cephalaenopsis hydrochloride was added to potassium taurine, and the mixture was sealed and stirred at 60°C for 5 h. The mixture was heated at 60°C in vacuum on a Schlenk line for 5 h to remove water and anhydrous ethanol to obtain a dry complex powder named [cep][tau].

[0036] In order to more clearly demonstrate the technical solution of the present invention, the present invention provides the following embodiments.

[0037] The term "one embodiment" or "embodiment" as used herein refers to a feature, structure or characteristic that may be included in at least one implementation of the present invention. The term "in one embodiment" that appears in different places in this specification does not necessarily refer to the same embodiment, nor does it refer to a separate or selective embodiment that is mutually exclusive with other embodiments. The specific embodiments are as follows.

[0038] Example 1

[0039] First, 50.0 mg of cephalaenopsis was dissolved in 0.50 mL of anhydrous ethanol, and then 80.76 μL of hydrochloric acid was added, and the mixture was sealed and stirred at room temperature for 2 h to obtain cephalaenopsis hydrochloride. In this embodiment, the reaction process of cephalaenopsis and hydrochloric acid is as follows:

[0040]

[0041] Next, 10.16 mg of taurine was dissolved in 0.207 mL of water, and 5.33 mg of potassium hydroxide was added, and the mixture was sealed and stirred at room temperature for 2 h to obtain potassium taurine. In this embodiment, the chemical reaction of taurine and potassium hydroxide is as follows:

[0042]

[0043] Finally, the above-mentioned cepharanthin hydrochloride was added to potassium taurine, and the mixture was sealed and stirred at 60°C for 5 hours. The mixture was vacuum heated at 60°C on a double-row vacuum line for 5 hours to remove water and anhydrous ethanol to obtain a dry powder. The powder was an antibacterial drug prepared by combining cepharanthin and taurine. In this embodiment, the powder was named [cep][tau].

[0044] In this embodiment, the oil-water partition coefficient logP of taurine is -2.769, which is a hydrophilic drug; while the oil-water partition coefficient logP of cepharanthin is 6.290, which is a lipophilic drug. Therefore, the antibacterial drug prepared by the method in this embodiment has both hydrophilicity and lipophilicity. In this embodiment, taurine is hydrophilic, and the hydrophilic group can promote the paracellular transport of the drug; cepharanthin is lipophilic, and the lipophilic group promotes the transcellular transport of the drug by improving the permeability of the cell membrane. And taurine contains hydrogen bonds, which interact with the phospholipid bilayer, thereby better increasing the permeability of the drug.

[0045] In addition, in this embodiment, taurine is a β-amino acid widely distributed in various tissues and organs of animals, and is one of the most abundant free amino acids in organisms, playing an important role in the development of the body. It can be quickly absorbed in the body, thereby enhancing the absorption of the composite drug in the digestive tract and reducing the toxicity of the drug. In addition, taurine can promote the production of antioxidant substances in the body and help regulate the body's acid-base balance.

[0046] In this example, the antibacterial drug prepared above was subjected to thermogravimetric analysis, and the effect was as follows: Figure 1 As shown. Figure 1It can be seen that the antibacterial drug prepared based on the composite of cepharanthin and taurine in this embodiment can improve the thermal stability of the drug. From the thermogravimetric analysis curve, it can be seen that pure cepharanthin begins to decompose at 137°C, while the composite [cep][tau] begins to decompose at 309°C, indicating that after adding taurine, the thermal stability of the composite [cep][tau] is greatly improved compared with pure cepharanthin.

[0047] In addition, in this embodiment, the antibacterial drug prepared above was subjected to X-ray powder diffraction analysis. Figure 2 As shown, the antibacterial drug prepared by compounding cepharanthin and taurine in this embodiment can increase the crystallinity of the drug and improve the quality of the drug. After taurine is added to cepharanthin, the crystallinity of [cep][tau] is higher than that of pure cepharanthin, which is of great significance for improving the quality of the drug.

[0048] In this embodiment, the above-prepared antibacterial drug was used to study the inhibition of Staphylococcus aureus and Klebsiella pneumoniae. Figure 3 and Figure 4 As shown, both cephalothin and the antibacterial drug prepared in this embodiment have a good sterilization effect on Staphylococcus aureus and Klebsiella pneumoniae. According to the antibacterial experiment, taurine alone has no inhibitory effect on Staphylococcus aureus and Klebsiella pneumoniae. At the same time, when taurine is used in combination with cephalothin (i.e. [cep][tau]), compared with cephalothin alone, the inhibitory effect of [cep][tau] on the two bacteria is not reduced. Therefore, it can be seen that taurine has no antagonistic effect on cephalothin.

[0049] The above content is a further detailed description of the present invention in combination with specific implementation methods. It cannot be determined that the specific implementation of the present invention is limited to these descriptions. For ordinary technicians in the technical field to which the present invention belongs, several simple deductions or substitutions can be made without departing from the concept of the present invention, which should be regarded as belonging to the scope of protection determined by the claims submitted for the present invention.

Claims

1. A method for preparing an antibacterial drug based on cepharanthin and taurine, characterized in that: The specific steps are as follows: Step 1: dissolving cephalaenopsis in anhydrous ethanol to obtain a solution, then adding hydrochloric acid, and sealing and stirring at room temperature to obtain cephalaenopsis hydrochloride; Step 2: dissolving taurine in water to obtain a taurine solution, adding potassium hydroxide, and sealing and stirring at room temperature to obtain potassium taurine; Step 3: adding cepharanthin hydrochloride to potassium taurine, mixing and stirring to obtain a mixture; then heating the mixture in vacuum to remove water and anhydrous ethanol to obtain a dry powder, which is the antibacterial drug; This antibacterial drug has inhibitory effects on Staphylococcus aureus and Klebsiella pneumoniae.

2. The method for preparing the antibacterial drug according to claim 1, characterized in that: In the first step, the molar ratio of cepharanthin to hydrochloric acid was 1:1, and the sealed stirring time was 2 h.

3. The method for preparing the antibacterial drug according to claim 1, characterized in that: In the second step, the molar ratio of taurine to potassium hydroxide was 1:1, and the sealed stirring time was 2 h.

4. The method for preparing the antibacterial drug according to claim 1, characterized in that: In the third step, the mixing and stirring time is 5 h, and the mixing and stirring temperature is 60 °C. The vacuum heating time of the mixture is 5 h, and the vacuum heating temperature is 60 °C.

5. The method for preparing the antibacterial drug according to claim 1, characterized in that: The reaction process of cepharanthin and hydrochloric acid is as follows: 。 6. The method for preparing the antibacterial drug according to claim 1, characterized in that: The reaction process of taurine and potassium hydroxide is as follows: 。

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