Antibacterial drug composition, colloidal particles surrounded by interface membrane, preparation method and application thereof

Abstract

The present invention provides an antibacterial drug composition, colloidal particles surrounded by an interfacial film, and a preparation method and application thereof, and belongs to the technical field of antibacterial drugs. The antibacterial active drug composition or colloidal particles uses a polypeptide antibiotic composed of 3-40 amino acid molecules as an antibacterial active ingredient, a polymer-conjugated lipid as a cosolvent, and a sugar ester compound and / or a sugar acid compound or its salt as a stabilizer. Under the joint action of the stabilizer and the cosolvent, the antibacterial activity and in vivo safety of the drug are significantly improved, and the antibacterial activity of the drug against drug-resistant Gram-negative bacteria is improved; it is obtained by dissolving and mixing, and the process is simple, reproducible, and commercial production is easy to achieve. The present invention significantly reduces the toxic and side effects of the drug on the basis of not changing the in vivo PK characteristics of polymyxin drugs, and the therapeutic dose can reach 3-5 times of the conventional dose, can be used for cells, poultry, beasts and humans, and is administered by a variety of administration routes to meet clinical drug needs.

Description

Technical Field

[0001] The invention belongs to the technical field of antibacterial drugs, and in particular relates to an antibacterial drug composition, colloidal particles surrounded by an interface film, and a preparation method and application thereof. Background Art

[0002] Since the advent of the first antibiotic penicillin in 1928, the continuous discovery and use of antibiotics have effectively controlled bacterial infections that once endangered human life and health. However, in the past few decades, due to the problem of bacterial resistance caused by the long-term use of antibiotics, the number of effective antibiotics currently available has been decreasing. Antimicrobial resistance has surpassed malaria, AIDS, etc. and has become the leading cause of death in the world. In 2022, The Lancet published an article analyzing the global burden of antibiotic resistance. The study and analysis of data from 204 countries showed that antibiotic resistance is now the leading cause of death in the world, surpassing many recognized causes of death such as malaria and AIDS. In 2019, 1.27 million people died directly from antibiotic resistance, and 4.95 million deaths were related to antibiotic-resistant infections. The world urgently needs to solve the problem of antibiotic resistance. In terms of bacterial species, among the six resistant bacteria that directly caused 929,000 deaths and 3.57 million deaths, four were Gram-negative resistant bacteria (Escherichia coli, Klebsiella pneumoniae, Bacillus baumannii, and Pseudomonas aeruginosa). Matteo Bassetti and others have made predictions about global antibiotic resistance in the next 30 years. By 2050, antibiotic resistance will cause 10 million deaths per year in the world, which is higher than the number of deaths from malignant tumors. Despite this, the development of new antibiotics is still very slow, especially for the treatment of resistant Gram-negative bacteria.

[0003] Since 1999, only three new antibiotics, linezolid, daptomycin and avibactam, have been approved for marketing, but these antibiotics are ineffective against Gram-negative bacteria. On the other hand, resistant Gram-negative bacteria such as Acinetobacter baumannii and Pseudomonas aeruginosa have multiple resistance mechanisms and are widely present in intensive care unit wards, often causing infections in some immunosuppressed patients, and are a type of pathogen that seriously threatens patients' lives. The 2021 National Bacterial Resistance Monitoring Report shows that the detection rate of carbapenem-resistant Acinetobacter baumannii is 54.3%; the detection rate of carbapenem-resistant Klebsiella pneumoniae is 11.3%, an increase of 0.4% from 10.9% in 2020, and from 6.4% in 2014 to 11.3% in 2021 [2021 National Bacterial Resistance Monitoring Report]. For the above reasons, the treatment of drug-resistant bacterial infections has become one of the medical problems facing mankind in the 21st century, and the development of new antibiotics for the treatment of drug-resistant bacteria is urgent.

[0004] At present, the main drugs used in clinical practice to fight against drug-resistant bacterial infections are tigecycline, colistin, etc. Among them, tigecycline can only be used to treat multidrug-resistant Acinetobacter baumannii infections, but it is ineffective against Pseudomonas aeruginosa infections. Colistin was first discovered in 1947. Its basic structure is a quasi-cyclic decapeptide sequence, including 5 subtypes A, B, C, D, and E, among which A, C, and D are highly toxic. Polymyxin (structural formula sees Formula I) has antibacterial effects on Gram-negative bacteria such as Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Haemophilus, Enterobacter, Salmonella, Shigella, Bordetella pertussis, Pasteurella, and Vibrio. The intravenous dosage forms of polymyxin used in clinical practice are polymyxin B sulfate preparations and polymyxin E mesylate preparations, both of which can be used for nebulized inhalation; polymyxin E sulfate preparations are oral and topical dosage forms. However, there are serious adverse drug reactions, with a nephrotoxicity rate of about 40% and a neurotoxicity rate of about 10%, which severely limit the clinical application scope of the drug. There is an urgent need to develop a new dosage form that is safer, more effective and more stable.

[0005]

[0006] Currently, many studies have attempted to maintain the antibacterial activity of colistin and improve the stability and safety of the drug.

[0007] Chinese invention patent CN103735508B (publication number) discloses "polymyxin liposomes and their preparation process". This patent adopts active drug loading method to prepare polymyxin liposomes. In the preparation process, the lipid powder is obtained by vacuum evaporation or spray drying. After hydration, the liposomes are homogenized by a high-pressure homogenizer, and then the blank liposomes are loaded with drugs by pH gradient method. This technology has complex prescription process and low drug loading efficiency, and cannot achieve the goal of improving safety and antibacterial activity at the same time.

[0008] CN110974937A (publication number) discloses “a polymyxin E liposome and its preparation method and application”, which adopts the reverse phase evaporation method to prepare the polymyxin E liposome and adopts high-pressure homogenization or tank extrusion to homogenize the liposome. The preparation process easily leads to liposome rupture, resulting in a reduced yield. In addition, the drug exists in the form of a phospholipid complex in the liposome bilayer, resulting in slow drug release, which cannot meet the clinical requirements for rapid onset of antibacterial drugs.

[0009] CN105517560A (publication number) discloses "polymyxin lipid nanoparticles", which adopt emulsification solvent evaporation method or hot melt homogenization technology to prepare lipid nanoparticles. The nanoparticles prepared by dispersing the drug in the lipid material have antibiotics on the surface, resulting in different degrees of burst release of the drug due to the different sizes of the nanoparticles, and there is a problem of drug stability.

[0010] Chinese invention patent TW202019490A (publication number) discloses "therapeutic nanoparticles of coacervate complexes and their use in treating bacteria". The nanoparticles contain a cationic polypeptide and a polyanionic molecule. The mixture is dispersed by a high-pressure homogenizer to prepare the nanoparticles. The nanoparticles are easily destroyed, the yield is low, and the stability is poor;

[0011] CN113521247A (publication number) discloses “a polyion complex nanomaterial polypeptide carrier and its preparation method”. The nano-spherical polyion complex is formed by the complexation of sodium hyaluronate and polymyxin B sulfate. The nanoparticles have a large particle size (100-200nm) and do not improve the antibacterial activity of the drug.

[0012] The nano drug delivery systems involved in the disclosed technologies are mostly prepared by thin film dispersion method, reverse phase evaporation method or high pressure homogenization method. The preparation process is complicated, and the prepared microparticles are mostly liposomes or nanoparticles, which cannot improve the safety and stability of the drug and maintain or enhance the antibacterial activity at the same time. Summary of the invention

[0013] The present invention aims at the problems existing in the prior art and provides an antibacterial drug composition, colloidal particles surrounded by an interface film, and a preparation method and application thereof. The antibacterial drug composition or colloidal particles uses a polymyxin compound as an antibacterial active ingredient, a polymer-conjugated lipid as a cosolvent, and a sugar ester compound and / or a sugar acid compound or a salt thereof as a stabilizer (synergist). By using a sugar ester compound and / or a sugar acid compound or a salt thereof as a stabilizer and a polymer-conjugated lipid as a cosolvent, the stability of the polymyxin-conjugate lipid composition is improved, the safety of polymyxin drugs is significantly improved, and the toxic and side effects of the drug are significantly reduced without changing the in vivo PK characteristics of the polymyxin drugs.

[0014] To achieve the above objectives, in a first aspect, the present invention provides an antibacterial drug composition, which comprises:

[0015] (1) Antimicrobial active ingredients;

[0016] (2) sugar ester compounds and / or sugar acid compounds or their salts;

[0017] (3) polymer-conjugated lipids;

[0018] The antibacterial active ingredient is a polypeptide antibiotic composed of 3-40 amino acid molecules.

[0019] The present invention uses polymyxin compounds as antibacterial active drugs, polymer-conjugated lipids as cosolvents, and sugar ester compounds and / or sugar acid compounds or salts thereof as stabilizers (synergists). By using sugar ester compounds and / or sugar acid compounds or salts thereof as stabilizers and polymer-conjugated lipids as cosolvents, the distribution of drugs in nanoparticles is improved and the stability of the polymyxin-conjugate lipid composition is greatly improved, thereby significantly improving the safety of polymyxin drugs, significantly reducing the toxic and side effects of drugs without changing the in vivo PK characteristics of polymyxin drugs, and can be stored for a long time at room temperature, which brings great convenience to transportation and storage.

[0020] The sugar ester compound and / or sugar acid compound or its salt used in the present invention is dispersed on the surface of the colloidal particles formed by the antimicrobial active ingredient and the polymer-conjugated lipid or dispersed in the solution through intermolecular interactions, and is surrounded on the surface of the colloidal particles in the form of an interfacial film, so that the colloidal particles have a stable shape and potential, which can not only ensure the stability of the colloidal particles, but also play an effect of reducing toxic side effects during the application of the colloidal particles or antimicrobial composition to animals.

[0021] The composition consisting of only antimicrobial active drugs and polymer-conjugated lipids has good antimicrobial activity, but its toxicity is not improved. The prior art (CN114569577A) uses antimicrobial active drugs, polymer-conjugated lipids and anionic hydrophilic monosaccharides or oligosaccharide acids to prepare nanoparticles, which have reduced toxicity and good antimicrobial activity, but compared with the simple antimicrobial active drugs, the in vitro release of the drug is slowed down and the in vivo PK characteristics are significantly changed.

[0022] In a preferred embodiment, the polypeptide antibiotic is a cyclic peptide antibiotic.

[0023] In a preferred embodiment, the polypeptide antibiotic is a polymyxin compound.

[0024] In a preferred embodiment, the polymyxin compound is selected from at least one of polymyxin B and its derivatives, polymyxin E and its derivatives, and polymyxin E sodium methanesulfonate and its derivatives.

[0025] In a preferred embodiment, the sugar ester compound is obtained by esterifying a sugar with an acid, wherein the sugar is selected from monosaccharides, oligosaccharides and polysaccharides; and the acid is an organic acid or an inorganic acid.

[0026] Monosaccharides refer to molecules that cannot be hydrolyzed into smaller sugars, including but not limited to glucose, fructose, ribose and deoxyribose. Monosaccharides can be divided into aldoses and ketoses according to the functional groups in their molecules. In addition, monosaccharides can also be classified according to the number of carbon atoms contained in their molecules, for example, trioses, tetraoses, and so on, until monosaccharides containing seven carbon atoms are called heptoses (from Chapter 9 of the 4th edition of Biochemistry, Carbohydrates and Glycobiology).

[0027] Oligosaccharides, also known as oligosaccharides, are carbohydrates composed of 2 to 10 monosaccharide units. These oligosaccharides can be classified according to the number of monosaccharide units they contain. For example, oligosaccharides composed of two monosaccharide units are called disaccharides, those composed of three monosaccharide units are called trisaccharides, and so on. It is worth noting that these oligosaccharides can be further broken down into their constituent monosaccharide units by hydrolysis. For example, disaccharides such as maltose, sucrose, and lactose can be hydrolyzed to form two monosaccharide molecules; while trisaccharides such as raffinose can be hydrolyzed to form three monosaccharide molecules (from Chapter 9 Carbohydrates and Glycobiology, Volume 1, 4th edition of "Biochemistry").

[0028] The present invention also relates to the definition and classification of polysaccharides. Polysaccharides are a type of carbohydrate that can produce more than 10 monosaccharide molecules by hydrolysis. According to the type of hydrolysis product, polysaccharides can be divided into homopolysaccharides and heteropolysaccharides. Homopolysaccharides only produce one type of monosaccharide or monosaccharide derivative when hydrolyzed, such as starch, glycogen, cellulose and chitin. In contrast, heteropolysaccharides will produce more than one monosaccharide or / and monosaccharide derivative when hydrolyzed, such as colloid, hemicellulose, peptidoglycan and glycosaminoglycan (from Chapter 9 Carbohydrates and Glycobiology, Volume 1, 4th Edition of Biochemistry).

[0029] The present invention relates to the definition and classification of organic acids. Organic acids are acidic organic compounds containing carboxyl groups, but do not include amino acids. They include but are not limited to carboxylic acids (-COOH), sulfonic acids (R-SO3H), sulfinic acids (RSOOH) and thiocarboxylic acids (RCOSH). These organic acids can react with alcohols to form compounds called esters, or combine with higher alcohols to form waxes. The types of organic acids include aliphatic monobasic, dibasic and polybasic carboxylic acids, such as tartaric acid, oxalic acid, malic acid, citric acid and ascorbic acid (i.e., vitamin C); and aromatic organic acids, such as benzoic acid, salicylic acid and caffeic acid. Except for a few that exist in a free state, most organic acids will combine with elements such as potassium, sodium, calcium to form salts, or combine with alkaloids to form salts.

[0030] Inorganic acids refer to a class of acids that do not contain carbon, or acids other than carbonic acid and alkali metals, including but not limited to hydrochloric acid (HCl), sulfuric acid (H2SO4), nitric acid (HNO3), phosphoric acid (H3PO4), boric acid (H3BO3), carbonic acid (H2CO3), etc. Generally speaking, they are inorganic compounds that can dissociate into hydrogen ions, and are compounds composed of hydrogen and non-metallic elements.

[0031] In a preferred embodiment, the acid is selected from phosphoric acid, carboxylic acid, sulfuric acid, sulfurous acid, organic sulfonic acid, sulfinic acid, thiocarboxylic acid.

[0032] In a preferred embodiment, the sugar acid compound is selected from monosaccharides, oligosaccharides or polysaccharides containing acidic groups.

[0033] In a preferred embodiment, the acidic group is selected from a phosphoric acid group, a phosphonic acid group, a carboxyl group, a sulfate group, a sulfite group or a sulfonic acid group.

[0034] In a preferred embodiment, the sugar units of the monosaccharides, oligosaccharides and polysaccharides have 4-7 carbon atoms and are selected from furanose and / or pyranose.

[0035] In a preferred embodiment, the sugar ester compound or its salt is selected from at least one of glucose pentasulfate potassium, D-arabinose-5-phosphate disodium salt, mannose sodium phosphate, trehalose 6-phosphate dipotassium salt, sucrose potassium octasulfate, sucrose sodium octasulfate, sucrose potassium heptasulfate, sucrose sodium heptasulfate, sucrose potassium hexasulfate, sucrose sodium hexasulfate, sucrose potassium pentasulfate, sucrose sodium pentasulfate, sucrose 6'-monophosphate dipotassium salt, heparin disaccharide IS, sodium, chondroitin disaccharide ΔDI-6S sodium salt, cyclodextrin sodium sulfate, β-cyclodextrin sodium phosphate, carboxymethyl-β-cyclodextrin sodium, pentosan sulfate sodium, N-acetyl-O-sulfated heparin (heparin IV-A) sodium salt, chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate, and heparin.

[0036] In a preferred embodiment, the sugar acid compound or its salt is selected from at least one of sucrose 6,6'-dicarboxylic acid, potassium lactobionate, lactobionic acid, sodium lactobionic acid, maltobionic acid, β-maltose heptaacetic acid, potassium alginate, L-guluronic acid pentasaccharide sodium salt, and hyaluronic acid.

[0037] In a preferred embodiment, the polymer-conjugated lipid is a polyethylene glycol-conjugated lipid.

[0038] In a preferred embodiment, the polyethylene glycol-conjugated lipid is a PEG-conjugated phospholipid.

[0039] In a preferred embodiment, the PEG-conjugated phospholipid is selected from at least one of PEG-conjugated phosphatidylcholines, PEG-conjugated phosphatidylethanolamines, PEG-conjugated phosphatidylglycerols, and PEG-conjugated phosphatidylserines.

[0040] In a preferred embodiment, the polyethylene glycol-conjugated lipid is selected from at least one of distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG), dimyristoylphosphatidylethanolamine-polyethylene glycol (DMPE-PEG), dipalmitoylphosphatidylethanolamine-polyethylene glycol (DPPE-PEG), dilauroylphosphatidylethanolamine-polyethylene glycol (PEG-DLPE), and dioleoylphosphatidylethanolamine-polyethylene glycol (DOPE-PEG).

[0041] In a preferred embodiment, the molar ratio of the antimicrobial active ingredient to the polymer-conjugated lipid is 1:1.5-1:15, and the molar ratio of the antimicrobial active ingredient to the sugar ester compound and / or sugar acid compound or its salt is 1:0.1-1:50.

[0042] In a preferred embodiment, the amount of polymer-conjugated lipid is 10-99% (w / w) of the total formulation.

[0043] In a second aspect, the present invention provides colloidal particles surrounded by an interfacial membrane, wherein the interfacial membrane is a sugar ester compound and / or a sugar acid compound or a salt thereof;

[0044] The colloidal particles comprise: an antimicrobial active ingredient, a sugar ester compound and / or a sugar acid compound or a salt thereof and a polymer-conjugated lipid;

[0045] The antibacterial active ingredient is a polypeptide antibiotic composed of 3-40 amino acid molecules;

[0046] The molar ratio of the antimicrobial active ingredient to the polymer-conjugated lipid is 1:1.5-1:15, and the molar ratio of the antimicrobial active ingredient to the sugar ester compound and / or sugar acid compound or its salt is 1:0.1-1:50;

[0047] The colloidal particles have a stable potential, and the Zeta potential is -40 to 10 mV;

[0048] The average particle size of the colloidal particles is 5-1000 nm.

[0049] In a preferred embodiment, the polypeptide antibiotic is a cyclic peptide antibiotic.

[0050] In a preferred embodiment, the polypeptide antibiotic is a polymyxin compound.

[0051] In a preferred embodiment, the polymyxin compound is selected from at least one of polymyxin B and its derivatives, polymyxin E and its derivatives, and polymyxin E sodium methanesulfonate and its derivatives.

[0052] In a preferred embodiment, the sugar ester compound is an ester compound formed by a sugar and an acid, the sugar is selected from monosaccharides, oligosaccharides and polysaccharides, and the acid is an organic acid or an inorganic acid; the sugar acid compound is a monosaccharide, oligosaccharide or polysaccharide containing an acidic group.

[0053] In a preferred embodiment, the acid is selected from phosphoric acid, carboxylic acid, sulfuric acid, sulfurous acid, organic sulfonic acid, sulfinic acid, and thiocarboxylic acid; and the acidic group is selected from phosphoric acid, phosphonic acid, carboxyl, sulfate, sulfite, or sulfonic acid.

[0054] In a preferred embodiment, the sugar ester compound or its salt is selected from the group consisting of potassium glucose pentasulfate, disodium D-arabinose-5-phosphate, sodium mannose phosphate, dipotassium trehalose 6-phosphate, potassium sucrose octasulfate, sodium sucrose octasulfate, potassium sucrose heptasulfate, sodium sucrose heptasulfate, potassium sucrose hexasulfate, sodium sucrose hexasulfate, potassium sucrose pentasulfate, sodium sucrose pentasulfate, dipotassium sucrose 6'-monophosphate, sodium heparin disaccharide IS, chondroitin disaccharide ΔDI-6S sodium salt, cyclodextrin sulfur At least one of sodium sulfate, β-cyclodextrin sodium phosphate, carboxymethyl-β-cyclodextrin sodium, pentosan sulfate sodium, N-acetyl-O-sulfated heparin (heparin IV-A) sodium salt, chondroitin sulfate, dermatan sulfate, keratan sulfate, heparan sulfate, and heparin; the sugar acid compound or its salt is selected from at least one of sucrose 6,6'-dicarboxylic acid, potassium lactobionate, lactobionic acid, sodium lactobionic acid, maltobionic acid, β-maltose heptacetic acid, potassium alginate, L-guluronic acid pentasaccharide sodium salt, and hyaluronic acid.

[0055] In a preferred embodiment, the polyethylene glycol-conjugated phospholipid is selected from at least one of PEG-conjugated phosphatidylcholines, PEG-conjugated phosphatidylethanolamines, PEG-conjugated phosphatidylglycerols, and PEG-conjugated phosphatidylserines.

[0056] In a preferred embodiment, the polyethylene glycol-conjugated phospholipid is selected from at least one of the polyethylene glycol-conjugated lipids selected from distearoylphosphatidylethanolamine-polyethylene glycol, dimyristoylphosphatidylethanolamine-polyethylene glycol, dipalmitoylphosphatidylethanolamine-polyethylene glycol, dilauroylphosphatidylethanolamine-polyethylene glycol, and dioleoylphosphatidylethanolamine-polyethylene glycol.

[0057] In a third aspect, the present invention provides a method for preparing the aforementioned antibacterial pharmaceutical composition or colloidal particles, which is obtained by mixing the antibacterial active ingredients, sugar ester compounds and / or sugar acid compounds or their salts and polymer-conjugated lipids with an aqueous solvent.

[0058] In a preferred embodiment, the aqueous solvent comprises 0-90% (v / v) ethanol solution, buffered saline solution or sucrose solution.

[0059] In a preferred embodiment, the antimicrobial active ingredient and the polymer-conjugated lipid are first mixed with an aqueous solvent, and then the sugar ester compound and / or sugar acid compound or its salt is added and mixed evenly; or the antimicrobial active ingredient, sugar ester compound and / or sugar acid compound or its salt and the polymer-conjugated lipid are mixed evenly with an aqueous solvent.

[0060] In a preferred embodiment, microchannel mixing is not employed.

[0061] In a fourth aspect, the present invention provides the use of the aforementioned antibacterial pharmaceutical composition or colloidal particles in the preparation of an antibacterial product that acts on cells.

[0062] In a preferred embodiment, the cell is a mammalian cell.

[0063] In a fifth aspect, the present invention provides the use of the aforementioned antibacterial pharmaceutical composition or colloidal particles in the preparation of an antibacterial product for administration to a mammalian subject.

[0064] In a sixth aspect, the present invention provides the use of the aforementioned antibacterial pharmaceutical composition or colloidal particles in the preparation of an antibacterial product for administration to poultry subjects.

[0065] In a seventh aspect, the present invention provides the use of the aforementioned antibacterial pharmaceutical composition or colloidal particles in the preparation of an antibacterial product for administration to humans.

[0066] Compared with the prior art, the present invention has the following beneficial effects:

[0067] 1. The antimicrobial active pharmaceutical composition or the colloidal particles surrounded by the interfacial film of the present invention uses polymyxin compounds as antimicrobial active ingredients, polymer-conjugated lipids as cosolvents, and sugar ester compounds and / or sugar acid compounds or their salts as stabilizers (enhancers). Under the combined action of the stabilizer and cosolvent, the antibacterial activity of the antimicrobial drug is significantly improved, while the safety of the drug in vivo is significantly improved. The antibacterial activity of polymyxin drugs against drug-resistant Gram-negative bacteria is improved to a certain extent, and the antibacterial activity against Gram-negative bacteria in vitro is more than twice that of ordinary preparations.

[0068] 2. The antibacterial drug composition or the colloidal particles surrounded by the interface membrane provided by the present invention significantly reduces the toxic and side effects of the drug without changing the in vivo PK characteristics of the polymyxin drugs. Compared with the method of reducing the toxic and side effects by structurally modifying the colistin to change the in vivo pharmacokinetic characteristics of the drug, the technology provided by the present invention is safer and more effective.

[0069] 3. The antibacterial drug composition or the colloidal particles surrounded by the interface film proposed in the present invention are prepared by only two steps of dissolution and mixing, without the need to adopt traditional processes such as organic solvent thin film dispersion method and high-pressure homogenization. The process is simple, has good reproducibility, and is easy to realize commercial production.

[0070] 4. The antibacterial drug composition or the colloidal particles surrounded by the interface membrane proposed in the present invention have good stability and can be stored for a long time (up to more than 18 months) at room temperature, thus solving the problems faced in transportation and storage.

[0071] 5. The therapeutic dose of the antibacterial drug composition or the colloidal particles surrounded by the interface membrane proposed in the present invention for animals can reach 3-5 times the conventional dose, greatly meeting the clinical drug demand.

[0072] 6. The antibacterial drug composition or the colloidal particles surrounded by the interface membrane provided by the present invention can be used in cells, birds, animals and humans, and has a wide range of uses.

[0073] 7. The antibacterial drug composition or the colloidal particles surrounded by the interface membrane of the present invention can be administered through a variety of routes to meet the needs of users. BRIEF DESCRIPTION OF THE DRAWINGS

[0074] Figure 1 : Bactericidal effect of the antibacterial drug composition of Examples 3, 6, and 13 and the colistin sulfate API in a mouse thigh muscle infection model - bacterial load in mouse thigh muscle;

[0075] Figure 2 : The blood drug concentration-time curve of the antibacterial drug composition of Examples 9 and 12 and the colistin sulfate bulk drug administered intravenously to SD rats;

[0076] Figure 3 : Drug tissue distribution 0.5 h after intravenous administration of the antibacterial drug composition of Example 3 and the colistin sulfate bulk drug (data are the average of three animals, ng / g or ng / mL; Mean);

[0077] Figure 4 : In vitro release curves of colistin sulfate bulk drug, the antibacterial drug compositions of Examples 3, 12, 20 and Comparative Examples 3-6. DETAILED DESCRIPTION

[0078] The present invention will be further described in detail below in conjunction with specific examples. The following examples are not intended to limit the present invention, but are only intended to illustrate the present invention. The experimental methods used in the following examples are generally conventional, unless otherwise specified, and the materials, reagents, etc. used in the following examples are commercially available, unless otherwise specified.

[0079] The formulas of Examples 1-22 and Comparative Examples 1-5 are as follows:

[0080] Example 1

[0081] 5 mg of colistin sulfate and 76 mg of MPEG2000-DSPE were dissolved in 10 ml of purified water, 30 mg of maltobionic acid was added and dissolved, and the mixture was stirred and mixed for 20 minutes. The obtained mixed solution was sterilized and filtered to obtain the antibacterial drug composition.

[0082] Example 2

[0083] 5 mg of polymyxin B sulfate, 23 mg of sodium lactobionate and 36 mg of MPEG2000-DMPE were dissolved in 10 ml of purified water, and the mixture was stirred for 20 minutes. The obtained mixed solution was sterilized and filtered to obtain the antibacterial drug composition.

[0084] Example 3

[0085] 5 mg of colistin sulfate and 66 mg of MPEG2000-DMPE were dissolved in 10 ml of purified water, 5 mg of sucrose potassium octasulfate was added and dissolved, and the mixture was stirred and mixed for 20 minutes. The obtained mixed solution was sterilized and filtered to obtain the antibacterial drug composition.

[0086] Example 4

[0087] 5 mg of colistin sulfate, 5 mg of doxycycline hydrochloride and 184 mg of MPEG2000-DPPE were dissolved in 20 ml of purified water, 19 mg of sucrose hexasulfate potassium was added and dissolved and stirred for 20 minutes, and the obtained mixed solution was sterilized and filtered to obtain the antibacterial drug composition.

[0088] Example 5

[0089] 5 mg of polymyxin B sulfate, 15 mg of lactobionic acid and 61 mg of MPEG5000-DSPE were dissolved in 10 ml of purified water, and the mixture was stirred for 20 minutes. The obtained mixed solution was sterilized and filtered to obtain the antibacterial drug composition.

[0090] Example 6

[0091] 5 mg of colistin sulfate, 10 mg of heparin disaccharide IS sodium salt and 81 mg of MPEG2000-DOPE were dissolved in 10 ml of purified water, and the mixture was stirred for 20 minutes. The obtained mixed solution was sterilized and filtered to obtain the antibacterial drug composition.

[0092] Example 7

[0093] 5 mg of colistin sulfate, 15 mg of N-acetyl-O-sulfated heparin (heparin IV-A) sodium salt and 49 mg of MPEG2000-DMPE were dissolved in 10 ml of purified water, stirred and mixed for 20 minutes, and the obtained mixed solution was sterilized and filtered to obtain the antibacterial drug composition.

[0094] Example 8

[0095] 5 mg of colistin sulfate, 15 mg of sodium chondroitin sulfate and 94 mg of MPEG2000-DLPE were dissolved in 10 ml of purified water, and the mixture was stirred for 20 minutes. The obtained mixed solution was sterilized and filtered to obtain the antibacterial drug composition.

[0096] Example 9

[0097] 5 mg of colistin sulfate, 8 mg of β-cyclodextrin sodium sulfate and 73 mg of MPEG2000-DPPE were dissolved in 10 ml of purified water, and the mixture was stirred for 20 minutes. The obtained mixed solution was sterilized and filtered to obtain the antibacterial drug composition.

[0098] Example 10

[0099] 5 mg of colistin sulfate, 7 mg of sodium pentosan sulfate and 71 mg of MPEG2000-DSPE were dissolved in 10 ml of purified water, and the mixture was stirred for 20 minutes. The obtained mixed solution was sterilized and filtered to obtain the antibacterial drug composition.

[0100] Embodiment 11

[0101] 5 mg of colistin sulfate, 11 mg of L-guluronic acid pentasaccharide sodium salt and 95 mg of MPEG2000-DOPE were dissolved in 10 ml of purified water, and the mixture was stirred for 20 minutes. The obtained mixed solution was sterilized and filtered to obtain the antibacterial drug composition.

[0102] Example 12

[0103] 5 mg of colistin sulfate and 16 mg of MPEG2000-DSPE were dissolved in 10 ml of purified water, 36 mg of sodium hyaluronate (3 kDa) was added and dissolved and stirred for 20 minutes, and the obtained mixed solution was sterilized and filtered to obtain the antibacterial drug composition.

[0104] Embodiment 13

[0105] 5 mg of colistin sulfate and 86 mg of MPEG2000-DSPE were dissolved in 10 ml of purified water, 14 mg of sodium hyaluronate (10 kDa) was added and dissolved and stirred for 20 minutes, and the obtained mixed solution was sterilized and filtered to obtain the antibacterial drug composition.

[0106] Embodiment 14

[0107] 5 mg of polymyxin E sodium methanesulfonate and 112 mg of MPEG2000-DMPE were dissolved in 10 ml of purified water, 9 mg of β-cyclodextrin sodium phosphate was added and dissolved, and the mixture was stirred and mixed for 20 minutes. The obtained mixed solution was sterilized and filtered to obtain the antibacterial drug composition.

[0108] Embodiment 15

[0109] 5 mg of polymyxin E sodium methanesulfonate and 54 mg of MPEG2000-DOPE were dissolved in 10 ml of purified water, 6 mg of sucrose 6,6'-dicarboxylic acid was added and dissolved and stirred for 20 minutes, and the obtained mixed solution was sterilized and filtered to obtain the antibacterial drug composition.

[0110] Example 16

[0111] 5 mg of polymyxin B sulfate and 53 mg of MPEG2000-DSPE were dissolved in 10 ml of purified water, 12 mg of L-guluronic acid pentasaccharide sodium salt was added and dissolved and stirred for 20 minutes, and the obtained mixed solution was sterilized and filtered to obtain the antibacterial drug composition.

[0112] Embodiment 17

[0113] 5 mg of polymyxin B sulfate and 67 mg of MPEG2000-DLPE were dissolved in 10 ml of purified water, 15 mg of sucrose 6'-monophosphate dipotassium salt was added and dissolved and stirred for 20 minutes, and the obtained mixed solution was sterilized and filtered to obtain the antibacterial drug composition.

[0114] Embodiment 18

[0115] 5 mg of polymyxin B sulfate and 108 mg of MPEG5000-DPPE were dissolved in 10 ml of purified water, 9 mg of trehalose 6-dipotassium phosphate was added and dissolved, and the mixture was stirred and mixed for 20 minutes. The obtained mixed solution was sterilized and filtered to obtain the antibacterial drug composition.

[0116] Embodiment 19

[0117] 5 mg of polymyxin B sulfate and 147 mg of MPEG5000-DSPE were dissolved in 10 ml of purified water, 10 mg of potassium alginate was added and dissolved, and the mixture was stirred and mixed for 20 minutes. The obtained mixed solution was sterilized and filtered to obtain the antibacterial drug composition.

[0118] Embodiment 20

[0119] 5 mg of colistin sulfate and 49 mg of MPEG2000-DSPE were dissolved in 10 ml of purified water, 5 mg of potassium glucose pentasulfate was added and dissolved, and the mixture was stirred for 20 minutes. The obtained mixed solution was sterilized and filtered to obtain the antibacterial drug composition.

[0120] Embodiment 21

[0121] 5 mg of colistin sulfate and 65 mg of MPEG2000-DMPE were dissolved in 10 ml of purified water, 24 mg of chondroitin disaccharide ΔDI-6S sodium salt was added and dissolved and stirred for 20 minutes, and the obtained mixed solution was sterilized and filtered to obtain the antibacterial drug composition.

[0122] Embodiment 22

[0123] 5 mg of colistin sulfate and 121 mg of MPEG2000-DMPE were dissolved in 10 ml of purified water, 15 mg of sodium carboxymethyl-β-cyclodextrin was added and dissolved, and the mixture was stirred and mixed for 20 minutes. The obtained mixed solution was sterilized and filtered to obtain the antibacterial drug composition.

[0124] Comparative Example 1

[0125] 5 mg of colistin sulfate and 14 mg of sodium hyaluronate (10 kDa) were dissolved in 10 ml of purified water, and the mixture was stirred for 20 minutes. The obtained mixed solution was sterilized and filtered.

[0126] Comparative Example 2

[0127] Dissolve 5 mg of colistin sulfate and 86 mg of MPEG2000-DSPE in 10 ml of purified water, stir and mix for 10-30 minutes, and sterilize and filter the resulting mixed solution.

[0128] Comparative Example 3

[0129] Dissolve 5 mg of colistin sulfate and 66 mg of MPEG2000-DMPE in 10 ml of purified water, add 5 mg of poly-L-glutamate sodium salt to dissolve and stir for 20 minutes, and sterilize and filter the resulting mixed solution.

[0130] Comparative Example 4

[0131] Dissolve 5 mg of colistin sulfate and 16 mg of MPEG2000-DSPE in 10 ml of purified water, add 36 mg of sodium carboxymethyl cellulose to dissolve and stir for 20 minutes, and sterilize and filter the resulting mixed solution.

[0132] Comparative Example 5

[0133] Dissolve 5 mg of sodium hyaluronate (8 kDa) in 25 ml of 50% ethanol solution for later use; add polysulfate colistin B to 100 microliters of water to dissolve it, then add 1 ml of PLGA-dichloromethane solution containing 5 mg of PLGA, mix well to obtain an oil-in-water emulsion; add the oil-in-water emulsion to the obtained sodium hyaluronate-ethanol aqueous solution to generate an antibiotic precipitate; stir the obtained antibiotic precipitate dispersion at room temperature for 10 minutes (speed of 500 r / min), and then vacuum evaporate at 30° C. to remove residual organic solvent, collect the obtained colloidal dispersion, and disperse it in ultrapure water to a final volume of 5 ml.

[0134] Comparative Example 6

[0135] That is, the prior art CN114569577A embodiment 1:

[0136] 20 mg of colistin sulfate and 32 mg of polyglutamic acid were dissolved in 10 ml of water to obtain solution 1; 600 mg of MPEG5000-DSPE (distearoylphosphatidylethanolamine-methoxypolyethylene glycol 5000) was dissolved in 30 ml of water to obtain solution 2. Solution 1 was injected into solution 2 at a speed of 12 ml / min to mix, and the mixed solution was sterilized and filtered to obtain solution 2.

[0137] Test example

[0138] 1. Particle size and PDI: The average particle size and polydispersity index (PDI) of the antibacterial drug composition solution in the embodiment were measured by dynamic light scattering using a Malvern ZetaSizer Nano ZS90. The measuring angle was 90°, the refractive index of the dispersant was 1.330, and the test temperature was 25°C.

[0139] 2. Zeta potential: The zeta potential of the antibacterial drug composition solution in the example was measured using Malvern ZetaSizer Nano ZS90 based on electrophoretic light scattering (ELS) technology. The refractive index of the dispersant was 1.330 and the test temperature was 25°C.

[0140] 3. Encapsulation efficiency: 2.5 ml of the antibacterial drug composition in the embodiment and the comparative example was loaded into an ultrafiltration centrifuge tube (Amicon Ultra-4 Centrifugal Filters, molecular cutoff 30 kD), centrifuged at 5000 rpm / min, and the HLPC method was used to determine the amount of free drug in the centrifuge tube and the amount of encapsulated drug retained on the filter membrane. 4.46 g / L sodium sulfate solution (pH 2.4)-acetonitrile (78:22) was used as the mobile phase, the detection wavelength was 215 nm, the flow rate was 1.0 ml / min, and the injection volume was 20 μl. The retained drug amount M1 and the free drug amount M2 were measured. The encapsulation efficiency calculation formula is: Encapsulation efficiency (EE%) = retained drug amount / (retained drug amount+free drug amount)×100%.

[0141] The particle size, PDI, potential, encapsulation efficiency and freeze-drying stability data of the antibacterial drug compositions of the examples and comparative examples are shown in Tables 1-2.

[0142] Table 1 Performance data of antibacterial drug composition

[0143]

[0144]

[0145] Table 2 Freeze-dried stability data of antibacterial drug composition

[0146]

[0147] As can be seen from Table 1-2, the average particle size, PDI, and Zeta potential of the antibacterial drug composition of the embodiment are all small, indicating that it has a small and uniform particle size, low toxicity, and a good encapsulation rate (>90%). The above parameters have no significant changes after freeze-drying and re-dissolving. The relevant parameters of comparative examples 1-6 are significantly inferior to those of the embodiment, especially after freeze-drying and re-dissolving of comparative examples 3-4, each parameter has changed significantly. It can be seen that the antibacterial drug composition within the scope of the present invention not only has a small and uniform particle size, low toxicity and ideal encapsulation rate, but also can ensure the stability of performance after long-term storage.

[0148] Effect example

[0149] 1. In vitro antibacterial test

[0150] (1) In vitro antibacterial activity of colistin sulfate

[0151] A total of 42 strains of clinically isolated Gram-negative bacilli were collected, including 11 strains of Escherichia coli (carbapenem-resistant strains), 10 strains of Klebsiella pneumoniae (carbapenem-resistant strains), 10 strains of Acinetobacter baumannii (carbapenem-resistant strains) and 11 strains of Pseudomonas aeruginosa (carbapenem-resistant strains). Colistin sulfate and Examples 1, 3, 4, 7, 8, 9, 10, 11, 12 and Comparative Examples 3, 4, 5, 6 were investigated for drug sensitivity tests on the above 42 resistant strains, and the results are shown in Tables 3-7.

[0152] Table 3 In vitro drug susceptibility test of the tested drugs against 11 strains of drug-resistant Escherichia coli (MIC mg / L)

[0153]

[0154] Table 4 In vitro drug susceptibility test of the tested drugs against 10 strains of drug-resistant Klebsiella pneumoniae (MIC mg / L)

[0155]

[0156] Table 5 In vitro drug susceptibility test of the tested drugs against 10 strains of drug-resistant Acinetobacter baumannii (MIC mg / L)

[0157]

[0158] Table 6 In vitro drug susceptibility test of the tested drugs against 11 strains of drug-resistant Pseudomonas aeruginosa (MIC mg / L)

[0159]

[0160] Table 7 In vitro drug susceptibility test of the tested drugs against 42 strains of resistant Gram-negative bacilli (MIC mg / L)

[0161]

[0162]

[0163] As shown in the above results, the antibacterial activity of the antibacterial drug composition of the embodiment of the present invention against different carbapenem strains is better than that of comparative examples 3-6 and slightly better than colistin sulfate, indicating that the antibacterial drug composition of the present invention has good antibacterial activity against carbapenem-resistant strains.

[0164] (2) Antibacterial activity test of polymyxin B sulfate

[0165] A total of 44 strains of clinically isolated Gram-negative bacilli were collected, including 12 strains of Escherichia coli (sensitive to carbapenems), 12 strains of Klebsiella pneumoniae (sensitive to carbapenems), 10 strains of Acinetobacter baumannii (sensitive to carbapenems) and 10 strains of Pseudomonas aeruginosa (sensitive to carbapenems) for drug sensitivity tests. Polymyxin B sulfate, Examples 2, 5, 16, 18, and 19 were used to test the drug sensitivity of the above 44 drug-resistant strains, and the results are shown in Tables 8-11.

[0166] Table 8 In vitro drug susceptibility test of the tested drugs against 23 strains of Escherichia coli (MIC mg / L)

[0167]

[0168] Table 9 In vitro drug susceptibility test of 12 strains of Klebsiella pneumoniae susceptible to carbapenems (MIC mg / L)

[0169]

[0170] Table 10 In vitro drug susceptibility test of 10 strains of Acinetobacter baumannii susceptible to carbapenems (MIC mg / L)

[0171]

[0172] Table 11 In vitro drug susceptibility test of 10 strains of Pseudomonas aeruginosa sensitive to carbapenems (MIC mg / L)

[0173]

[0174] As shown in the above results, the antibacterial activity of the antibacterial drug composition of the embodiment of the present invention against different carbapenem strains is better than or equivalent to polymyxin B sulfate. This shows that the antibacterial drug composition of the present invention has good antibacterial activity against carbapenem-sensitive strains.

[0175] 2. In vivo efficacy study: bactericidal effect study in mouse thigh muscle infection model

[0176] The efficacy of Examples 3, 6, 13 and the colistin sulfate API was studied in a mouse thigh muscle infection model constructed with carbapenem-resistant Acinetobacter baumannii ATCC BAA-1605. The results are shown in the attached Figure 1 .

[0177] The dosage regimen and experimental results are shown in Table 12:

[0178] Table 12 Dosage regimen for the bactericidal effect study of the tested drugs in the mouse thigh muscle infection model

[0179]

[0180]

[0181] The results show that at the same low therapeutic dose, the antibacterial effects of Examples 3, 6, and 13 are substantially equivalent to those of the control compound colistin sulfate; when the therapeutic dose of the antibacterial pharmaceutical composition of the present invention is further increased, the antibacterial effect thereof is also enhanced in a dose-dependent manner, which provides a good pharmacodynamic basis for further research on polymyxin nanoformulations.

[0182] 3. Pharmacokinetic study:

[0183] (1) Blood drug concentration study

[0184] The changes in the blood drug concentrations of Examples 9, 12 and the colistin sulfate raw material at different times after a single intravenous administration to SD rats were investigated.

[0185] Experimental animals: 12 male SD rats (including 3 blank rats), 6-7 weeks old, purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd.

[0186] The dosage regimen is shown in Table 13, and the results are shown in Tables 14-15 and Attached Figure 2 :

[0187] Table 13 Dosage regimen for pharmacokinetic study of the tested drugs in rats

[0188]

[0189] Table 14 Summary of clinical observations after intravenous administration of the test drugs in SD rats

[0190]

[0191] Table 15 Summary of pharmacokinetic parameters of the test drugs given intravenously to SD rats

[0192]

[0193] As can be seen from Table 14, after intravenous administration of the test drug to rats, the rats' tolerance to the antibacterial drug compositions of Examples 9 and 12 was significantly stronger than that to colistin sulfate, indicating that the antibacterial drug composition provided by the present technology is less toxic to rats than colistin sulfate.

[0194] As can be seen from Table 15, the drug-time curves of Example 9 and Example 12 are basically consistent with colistin sulfate, and the three test substances are all two-compartment models.

[0195] (2) Tissue distribution

[0196] The tissue distribution of Example 3 and the colistin sulfate raw material drug after a single intravenous administration in SD rats was investigated.

[0197] Experimental animals: 9 male and female SD rats (including blank rats), 7 weeks old, purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd.

[0198] The dosage regimen is shown in Table 16, and the test results are shown in Attachment Figure 3 :

[0199] Table 16 Dosage regimen for single intravenous administration of test drug tissue distribution study in SD rats

[0200]

[0201] Note: There are 6 animals, including 3 females and 3 males.

[0202] After a single intravenous administration, both test substances (colistin sulfate and Example 3) were mainly concentrated in the kidneys of rats, followed by the lungs, and slightly distributed in other tissues, but there were no significant differences (p < 0.05).

[0203] 4. Toxicology study: Maximum tolerated dose of a single dose

[0204] The maximum tolerated dose (MTD) of single administration of Examples 1-22 and Comparative Examples 1-6 on ICR mice was investigated. The main reference indicators of this experiment were the morbidity / death of animals, clinical observations, and weight changes.

[0205] Experimental animals: ICR mice: male, 6-8 weeks old, weighing 25-30 g, purchased from Shanghai Lingchang Experimental Animal Co., Ltd.; the dosing regimen is shown in Table 17, and the test results are shown in Table 18:

[0206] Table 17 Dosing regimen for the maximum tolerated dose of the test drug administered to mice

[0207]

[0208] Table 18 Summary of the maximum tolerated dose of the tested drugs in mice after single administration

[0209] Example MTD (mg / kg) Colistin sulfate 10 Polymyxin B sulfate 10 Polymyxin E sodium methanesulfonate 15 Example 1 60 Example 2 60 Example 3 60 Example 4 60 Example 5 60 Example 6 60 Example 7 60 Example 8 60 Example 9 60 Example 10 60 Embodiment 11 60 Example 12 60 Embodiment 13 60 Embodiment 14 60 Embodiment 15 60 Example 16 50 Embodiment 17 60 Embodiment 18 60 Embodiment 19 60 Embodiment 20 50 Embodiment 21 60 Embodiment 22 50 Comparative Example 1 15 Comparative Example 2 20 Comparative Example 3 60 Comparative Example 4 30 Comparative Example 5 65 Comparative Example 6 60

[0210] It can be seen from Table 18 that the MTD of the antibacterial pharmaceutical composition of the embodiment is significantly better than that of colistin sulfate, polymyxin B sulfate and polymyxin E sodium methanesulfonate, indicating that the antibacterial pharmaceutical composition of the present invention has a higher maximum tolerated dose of a single administration.

[0211] 5. In vitro release curve

[0212] The in vitro release curves of colistin sulfate API, Examples 3, 12, 20 and Comparative Examples 3, 4, 5, 6 were investigated.

[0213] Take 1.5 ml of colistin sulfate, the antibacterial drug composition of the above examples or comparative examples, and place them in dialysis bags (molecular retention capacity is 100 kD). Place the dialysis bag in a centrifuge tube containing 18.5 ml PBS (pH 7.4, 10 mM phosphate + 150 mM NaCl), and shake it in a 37°C constant temperature water bath oscillator (100 rpm). Take samples at regular intervals and transfer the dialysis bag to fresh medium. Use HPLC to determine the concentration of free drugs outside the dialysis bag, and then calculate the release of colistin sulfate or the antibacterial drug composition at each time point. See the release curve diagram. Figure 4 .

[0214] from Figure 4 It can be seen that the antibacterial drug composition provided by Examples 3, 12, and 20 can be released stably and sustainably in PBS (pH 7.4, 10mM phosphate + 150mM NaCl) buffer, and the release trend of Examples 3, 12, and 20 is similar to that of colistin sulfate, and the cumulative release is significantly better than that of Comparative Examples 3-6. There are obvious differences in the release curves of Examples 3, 12, and 20 and Comparative Examples 3-6. It can be seen that the selection of stabilizers has a great influence on the release effect of antibacterial active ingredients. The stabilizer defined by the present invention can effectively ensure the release efficiency of antibacterial active ingredients, achieve sustainable and stable release, and ensure a high release. In addition, the release effect of the antibacterial drug composition of the present invention is better than that of the prior art CN114569577A.

[0215] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. An antibacterial drug composition, characterized in that: Its composition includes: (1) Antimicrobial active ingredients; (2) sugar ester compounds and / or sugar acid compounds or their salts; (3) polymer-conjugated lipids; The antibacterial active ingredient is a polypeptide antibiotic composed of 3-40 amino acid molecules; The polypeptide antibiotic is a polymyxin compound; the polymyxin compound is selected from at least one of polymyxin B, polymyxin E, and polymyxin E sodium methanesulfonate; The sugar ester compound or its salt is selected from at least one of glucose pentasulfate potassium, trehalose 6-phosphate dipotassium salt, sucrose octasulfate potassium, sucrose octasulfate sodium, sucrose heptasulfate potassium, sucrose heptasulfate sodium, sucrose hexasulfate potassium, sucrose pentasulfate, sucrose 6'-monophosphate dipotassium salt, heparin disaccharide IS, sodium salt, chondroitin disaccharide ΔDI-6S sodium salt, cyclodextrin sodium sulfate, β-cyclodextrin sodium phosphate, carboxymethyl-β-cyclodextrin sodium, pentosan sulfate sodium, N-acetyl-O-sulfated heparin (heparin IV-A) sodium salt, and chondroitin sulfate; The sugar acid compound or its salt is selected from at least one of sucrose 6,6'-dicarboxylic acid, potassium lactobionate, lactobionic acid, sodium lactobionic acid, maltobionic acid, potassium alginate, L-guluronic acid pentasaccharide sodium salt, and sodium hyaluronate; The polymer-conjugated lipid is a polyethylene glycol-conjugated lipid; The preparation method of the antibacterial drug composition is as follows: the antibacterial active ingredients, sugar ester compounds and / or sugar acid compounds or their salts and polymer-conjugated lipids are mixed with a water-containing solvent to obtain the antibacterial drug composition.

2. The antibacterial drug composition according to claim 1, characterized in that: The polyethylene glycol-conjugated lipid is a PEG-conjugated phospholipid.

3. The antibacterial drug composition according to claim 2, characterized in that: The PEG-conjugated phospholipid is selected from at least one of PEG-conjugated phosphatidylcholines, PEG-conjugated phosphatidylethanolamines, PEG-conjugated phosphatidylglycerols, and PEG-conjugated phosphatidylserines.

4. The antibacterial drug composition according to claim 2, characterized in that: The polyethylene glycol-conjugated lipid is selected from at least one of distearoylphosphatidylethanolamine-polyethylene glycol, dimyristoylphosphatidylethanolamine-polyethylene glycol, dipalmitoylphosphatidylethanolamine-polyethylene glycol, dilauroylphosphatidylethanolamine-polyethylene glycol, and dioleoylphosphatidylethanolamine-polyethylene glycol.

5. The antibacterial drug composition according to claim 1, characterized in that: The amount of polymer-conjugated lipids used was 10-99% (w / w) of the total formulation.

6. A colloidal particle surrounded by an interfacial film, characterized in that The interface film is a sugar ester compound and / or a sugar acid compound or a salt thereof; The colloidal particles comprise: an antimicrobial active ingredient, a sugar ester compound and / or a sugar acid compound or a salt thereof and a polymer-conjugated lipid; The antibacterial active ingredient is a polypeptide antibiotic composed of 3-40 amino acid molecules; The colloidal particles have a stable potential, and the Zeta potential is -40~10mV; The average particle size of the colloidal particles is 5-1000nm; The polypeptide antibiotic is a polymyxin compound; the polymyxin compound is selected from at least one of polymyxin B, polymyxin E, and polymyxin E sodium methanesulfonate; The sugar ester compound or its salt is selected from at least one of glucose pentasulfate potassium, trehalose 6-phosphate dipotassium salt, sucrose octasulfate potassium, sucrose octasulfate sodium, sucrose heptasulfate potassium, sucrose heptasulfate sodium, sucrose hexasulfate potassium, sucrose pentasulfate, sucrose 6'-monophosphate dipotassium salt, heparin disaccharide IS, sodium salt, chondroitin disaccharide ΔDI-6S sodium salt, cyclodextrin sodium sulfate, β-cyclodextrin sodium phosphate, carboxymethyl-β-cyclodextrin sodium, pentosan sulfate sodium, N-acetyl-O-sulfated heparin (heparin IV-A) sodium salt, and chondroitin sulfate; The sugar acid compound or its salt is selected from at least one of sucrose 6,6'-dicarboxylic acid, potassium lactobionate, lactobionic acid, sodium lactobionic acid, maltobionic acid, potassium alginate, L-guluronic acid pentasaccharide sodium salt and sodium hyaluronate; The preparation method of the colloidal particles is as follows: the antibacterial active ingredients, sugar ester compounds and / or sugar acid compounds or their salts and polymer-conjugated lipids are mixed with a water-containing solvent to obtain the colloidal particles.

7. The colloidal particles according to claim 6, characterized in that The polymer-conjugated lipid is selected from at least one of PEG-conjugated phosphatidylcholines, PEG-conjugated phosphatidylethanolamines, PEG-conjugated phosphatidylglycerols, and PEG-conjugated phosphatidylserines.

8. The colloidal particles according to claim 6, characterized in that The polymer-conjugated lipid is selected from at least one of distearoylphosphatidylethanolamine-polyethylene glycol, dimyristoylphosphatidylethanolamine-polyethylene glycol, dipalmitoylphosphatidylethanolamine-polyethylene glycol, dilauroylphosphatidylethanolamine-polyethylene glycol, and dioleoylphosphatidylethanolamine-polyethylene glycol.

9. The method for preparing the antibacterial pharmaceutical composition according to any one of claims 1 to 5 or the colloidal particles according to any one of claims 6 to 8, characterized in that: The antimicrobial active ingredient, the sugar ester compound and / or the sugar acid compound or its salt and the polymer-conjugated lipid are mixed with an aqueous solvent to obtain the product.

10. The preparation method according to claim 9, characterized in that: First, the antimicrobial active ingredient and the polymer-conjugated lipid are mixed with an aqueous solvent, and then the sugar ester compound and / or sugar acid compound or its salt is added and mixed evenly; or the antimicrobial active ingredient, sugar ester compound and / or sugar acid compound or its salt and the polymer-conjugated lipid are mixed evenly with an aqueous solvent.

11. The preparation method according to claim 9 or 10, characterized in that: No microchannel mixing is used.

12. Use of the antibacterial pharmaceutical composition according to any one of claims 1 to 5 or the colloidal particles according to any one of claims 6 to 8 in the preparation of an antibacterial product acting on cells.

13. The use according to claim 12, characterized in that The cell is a mammalian cell.

14. Use of the antibacterial pharmaceutical composition according to any one of claims 1 to 5 or the colloidal particles according to any one of claims 6 to 8 in the preparation of an antibacterial product for administration to a mammalian subject.

15. Use of the antibacterial pharmaceutical composition according to any one of claims 1 to 5 or the colloidal particles according to any one of claims 6 to 8 in the preparation of an antibacterial product for administration to poultry subjects.

16. Use of the antibacterial pharmaceutical composition according to any one of claims 1 to 5 or the colloidal particles according to any one of claims 6 to 8 in the preparation of an antibacterial product for human administration.

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