CN112826810B - Coating agent combined with myricetin/azole drugs and used for preventing external surface infection of percutaneous catheter and application thereof - Google Patents
Coating agent combined with myricetin/azole drugs and used for preventing external surface infection of percutaneous catheter and application thereof Download PDFInfo
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- CN112826810B CN112826810B CN202110114115.3A CN202110114115A CN112826810B CN 112826810 B CN112826810 B CN 112826810B CN 202110114115 A CN202110114115 A CN 202110114115A CN 112826810 B CN112826810 B CN 112826810B
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- Prior art keywords
- myricetin
- coating agent
- film coating
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- infection
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- IKMDFBPHZNJCSN-UHFFFAOYSA-N Myricetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC(O)=C(O)C(O)=C1 IKMDFBPHZNJCSN-UHFFFAOYSA-N 0.000 title claims abstract description 114
- 229940116852 myricetin Drugs 0.000 title claims abstract description 114
- PCOBUQBNVYZTBU-UHFFFAOYSA-N myricetin Natural products OC1=C(O)C(O)=CC(C=2OC3=CC(O)=C(O)C(O)=C3C(=O)C=2)=C1 PCOBUQBNVYZTBU-UHFFFAOYSA-N 0.000 title claims abstract description 114
- 235000007743 myricetin Nutrition 0.000 title claims abstract description 114
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- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 title claims abstract description 42
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- 208000015181 infectious disease Diseases 0.000 title claims abstract description 32
- 239000011248 coating agent Substances 0.000 title claims description 48
- MCCACAIVAXEFAL-UHFFFAOYSA-N 1-[2-(2,4-dichlorophenyl)-2-[(2,4-dichlorophenyl)methoxy]ethyl]imidazole;nitric acid Chemical compound O[N+]([O-])=O.ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 MCCACAIVAXEFAL-UHFFFAOYSA-N 0.000 claims abstract description 100
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- ZFOZVQLOBQUTQQ-UHFFFAOYSA-N Tributyl citrate Chemical compound CCCCOC(=O)CC(O)(C(=O)OCCCC)CC(=O)OCCCC ZFOZVQLOBQUTQQ-UHFFFAOYSA-N 0.000 claims description 4
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- 229960001589 posaconazole Drugs 0.000 description 1
- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 210000001732 sebaceous gland Anatomy 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000007447 staining method Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 235000021476 total parenteral nutrition Nutrition 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 1
- 229960004740 voriconazole Drugs 0.000 description 1
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Abstract
The invention discloses a myricetin/azole drug combined film coating agent for preventing external surface infection of a percutaneous catheter and application thereof, belonging to the technical field of pharmaceutics. The myricetin is combined with the azole compound to help the azole compound break through a fungal biomembrane barrier by utilizing the activity of the myricetin for inhibiting the fungal candida albicans biomembrane formation, and the synergistic effect of the myricetin and the azole compound can obviously enhance the antibacterial effect. The film coating agent can be quickly dried to form a layer of transparent film after being applied to the surface of skin, is not limited by the shape and the position of a medicine application part, plays a role in physical protection, loads myricetin and miconazole nitrate, can simultaneously avoid invasion and infection of pathogens in the external environment and the skin of the user, is convenient to use, and is expected to be used for preventing relevant infection of clinical catheters.
Description
Technical Field
The invention belongs to the technical field of pharmaceutics, and relates to a myricetin/azole drug combined film coating agent for preventing external surface infection of a percutaneous catheter and application thereof.
Background
With the widespread clinical use of biomedical materials (orthopedic implants, medical catheters, cardiac pacemakers, etc.), the infection involved has become a formidable clinical problem, since the implantation of the biomaterial in the body, in addition to increasing the way the pathogens invade the body, also reduces the minimum number of pathogens needed to induce an infection in the body, both of which greatly increase the risk of infection in the body. Catheter-related infections are one of the most common nosocomial infections, complex to diagnose, and numerous risk factors. Among them, four major pathogenic bacteria causing infection of the percutaneous catheter are: coagulase-negative staphylococci, Staphylococcus aureus, Candida species, intestinal gram-negative bacilli. After the pathogenic bacteria generate a biofilm at an infected part, drug resistance can be generated through various ways (such as limited penetration of antibacterial drugs, drug-resistant gene expression and the like), and the radical treatment is difficult, so that the key for radically and effectively preventing the occurrence and development of catheter-related infection is to fundamentally solve the troublesome problem. When a catheter-related infection occurs, the current American society for infectious diseases recommends removal of the infected catheter, systemic antifungal therapy, a 14 day continuation of systemic antifungal therapy after the first negative blood culture, and re-implantation of a new catheter. On the one hand, the re-implantation of catheters is technically challenging and requires more expenditure, and on the other hand, increases the morbidity and mortality of the patient. Life threatening complications such as pneumothorax, arrhythmia, arterial puncture and hemorrhage may occur during catheterization for critically ill patients requiring intravenous administration and total parenteral nutrition. For the above-mentioned case where the catheter cannot be removed, the american society for infectious diseases suggests systemic antibiotic therapy in combination with antimicrobial lock therapy, which injects a high concentration of an antimicrobial drug into the lumen of the catheter and maintains it for a period of time for sterilization. Besides the limitations of self-administration (such as incompatibility of ethanol and polyurethane catheters, incompatibility of caspofungin and catheter-sealing heparin, etc.), the method is often reluctant to adhere microorganisms and form biofilms on the outer surface of the catheter. Therefore, there is a great need to find new strategies to prevent clinical catheter-associated biofilm infections.
At present, the prevention measures of the relevant infection of the clinical catheter mainly comprise strict aseptic operation during the puncture of the catheter, local skin disinfection (iodine, iodophor and chlorhexidine), antimicrobial ointment coating at the outlet and the like, but the operation can only partially reduce the possibility of infection of a patient, pathogens remained in skin accessories such as a skin epidermal layer, a sebaceous gland, a hair follicle and the like cannot be killed, and the action time is short. In addition, ointments and the like can provide a warm and humid environment for pathogens, which causes skin colony proliferation, and further significantly increases the risk of catheter infection. Therefore, there is currently no mature and effective intervention for catheter-related infections. The prevention research on related infection of catheters at home and abroad mostly focuses on modifying the surface of a catheter material or introducing a bactericidal substance, the former can reduce the initial adhesion capacity of microorganisms on the surface of the material but does not have bactericidal activity, so the formation of a biofilm on the surface of the material can be delayed to a certain extent, and the latter has strict requirements on hydrophilicity, appearance structure, material variety and the like of the surface of the catheter, easily causes the shedding of the antibacterial substance in the using process, loses the antibacterial function, has a complex process and has higher cost.
Miconazole nitrate (miconazole nitrate, MN, C) 18 H 15 CI 4 N 3 O 4 ) Is an imidazole broad-spectrum antifungal medicine, can damage the fungal cell membrane and change the permeability of the fungal cell membrane by blocking the synthesis of ergosterol of the fungal cell membrane, leads the substances in the cell to leak, and plays an excellent antifungal role. However, after the fungal biofilm is generated at the focus part, the antibacterial effect of miconazole nitrate is greatly weakened, and a new method for breaking through the fungal biofilm barrier is urgently needed to be found. Myricetin (myricetin, MY, 3,5, 7-trihydroxy-2- (3,4, 5-trihydroxyphenyl) -4H-1-benzofuran-4-one, C 15 H 10 O 8 ) Is a natural flavonol compound which is widely existed in waxberry bark, ampelopsis grossedentata, grapes and other plants. A plurality of researches show that the myricetin has various pharmacological activities of oxidation resistance, tumor resistance, inflammation resistance, hypertension resistance and the like, and has wide clinical application value.
Currently, no related antibacterial application of azole drugs and myricetin as catheter-related infection coating agents is available.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide a coating agent combined with myricetin/azole drugs for preventing the infection of the external surface of a percutaneous catheter and application thereof.
In order to achieve the purpose, the invention adopts the following technical scheme to realize the purpose:
the invention discloses a film coating agent combined with myricetin/azole drugs for preventing external surface infection of a percutaneous catheter, which is prepared from main drugs and medicinal film-forming auxiliary materials: the main drug is composed of myricetin and derivatives thereof in combination with azole drugs;
in the film coating agent, the content of myricetin and derivatives thereof is 20-400 mug/ml;
the content of the azole drugs is 0.5-10 mu g/ml.
Preferably, the azole drug comprises one or more of miconazole nitrate, econazole, ketoconazole, fluconazole, itraconazole, voriconazole and posaconazole.
Preferably, the pharmaceutically acceptable film-forming auxiliary material comprises:
film forming material: acrylic resin with the mass concentration of 1-25 percent;
a plasticizer with the mass concentration of 1-20 percent;
solvent: one or more of isopropanol water solution, ethanol water solution and acetone water solution.
Preferably, the acrylic resin comprises one or more of Eudragit RS, Eudragit RL, Eudragit E, Eudragit L, Eudragit S, Eudragit NE and Eudragit RD.
Preferably, the plasticizer comprises one or more of triethyl citrate, tributyl citrate, dibutyl phthalate, dimethyl phthalate, diethyl sebacate and dibutyl sebacate.
Preferably, the volume percentage of the organic phase in the solvent is between 50% and 80%.
Preferably, the composition also comprises pharmaceutically acceptable pharmaceutical excipients, including one or more of viscosity regulator, preservative, surfactant, suspending agent, antioxidant, stabilizer and humectant.
Preferably, the film forming time of the film coating agent is 1-3 min.
The invention also discloses application of the film coating agent combined with the myricetin/azole drugs for preventing the infection of the outer surface of the percutaneous catheterization catheter in preparing a protective film for preventing the infection of a microbial biofilm on the outer surface of the percutaneous catheterization catheter.
Compared with the prior art, the invention has the following beneficial effects:
the myricetin/azole drug combined film coating agent disclosed by the invention utilizes the activity of the myricetin for inhibiting the formation of the fungal candida albicans biofilm to combine the myricetin with the azole compound, so that the azole compound is helped to break through the fungal biofilm barrier, and the synergistic effect of the myricetin and the azole compound can obviously enhance the antibacterial effect. The film coating agent can be quickly dried to form a layer of transparent film after being applied to the surface of skin, is not limited by the shape and the position of a medicine application part, plays a role in physical protection, loads myricetin and miconazole nitrate, can simultaneously avoid invasion and infection of pathogens in the external environment and the skin of the user, is convenient to use, and is expected to be used for preventing relevant infection of clinical catheters.
Furthermore, the film coating agent is prepared by adopting acrylic resin as a main film forming material of the film coating agent, triethyl citrate and the like as plasticizers, isopropanol aqueous solution and the like as solvents, and has the advantages of simple preparation process, high film forming speed, strong toughness, no easy falling, no toxicity, no stimulation, good water resistance, air permeability and adhesiveness, low production cost, safety, good stability and convenience for realizing industrial production.
Furthermore, the invention selects the combination of myricetin and miconazole nitrate to generate a synergistic effect, can break through the microbial biomembrane barrier, has obvious antibacterial effect, effectively prevents the infection related to the microbial biomembrane, and has profound clinical practical significance and application value when the myricetin and miconazole nitrate film coating agent is applied to the prevention of the clinical catheter related infection.
Drawings
FIG. 1 shows the appearance of myricetin + miconazole nitrate film coating agent before and after application; wherein A is in a liquid form before the myricetin and miconazole nitrate coating agent is applied; b is a solid form of the myricetin and miconazole nitrate coating agent applied to the dried human arm (yellow arrow is myricetin and miconazole nitrate coating agent, blue arrow is myricetin and miconazole nitrate coating agent and congo red);
FIG. 2 is the result of viscosity investigation after application of each group of coating agents; wherein A is a blank coating agent; b is myricetin film coating agent; c is miconazole nitrate film coating agent; d is myricetin + miconazole nitrate film coating agent;
FIG. 3 is the result of the investigation of the sealing effect of each group of coating agents; wherein, (a) is the water loss weight of each experimental group at different time points; (B) sealing action of each group of coating agent;
FIG. 4 is a standard curve of HPLC method; wherein, (A) is a myricetin standard curve; (B) is a standard curve of miconazole nitrate;
FIG. 5 shows the results of HPLC method specificity investigation; wherein A is spectrum of myricetin (500 μ g/ml) reference solution at 360nm wavelength; b is spectrum of myricetin (500 μ g/ml) control solution at 230nm wavelength; c is a spectrum of a miconazole nitrate (500 mu g/ml) reference solution at the wavelength of 230 nm; d is a spectrum of a miconazole nitrate (500 mu g/ml) reference substance solution at the wavelength of 360 nm; e is a spectrum of the blank film coating agent under the wavelength of 360 nm; f is a spectrum of the blank film coating agent at the wavelength of 230 nm;
FIG. 6 is a HPLC method for determining the drug content of myricetin + miconazole nitrate film coating agent after being placed for different periods of time at 40 ℃;
FIG. 7 shows the residence of coumarin-6-loaded plastics on the skin of mice at different times;
FIG. 8 is a fluorescent microscope showing the adhesion of Candida albicans to the outer surface of the PE catheter; wherein A is a conduit group; b is a molding set; c is a blank film coating agent group; d is myricetin (400 μ g/ml) coating agent group; e is miconazole nitrate (10 mu g/ml) film coating agent group; f is a film coating agent combination of myricetin (400 mu g/ml) and miconazole nitrate (10 mu g/ml);
FIG. 9 is an electron scanning microscope for observing the adhesion of Candida albicans on the outer surface of the PE catheter; wherein A is a conduit group; b is a molding set; c is a blank film coating agent group; d is myricetin (400 μ g/ml) coating agent group; e is miconazole nitrate (10 mu g/ml) film coating agent group; f is a film coating agent combination of myricetin (400 mu g/ml) and miconazole nitrate (10 mu g/ml);
FIG. 10 shows the PAS staining method for the residual Candida albicans in the skin tissue around the tube placement of each group of mice; wherein A is a normal control group; b is a catheter group; c is a molding set; d is a blank film coating agent group; e is a myricetin (400 mu g/ml) film coating agent group; f is a film coating agent group of miconazole nitrate (10 mu g/ml); g is a film coating agent combination of myricetin (400 mu G/ml) and miconazole nitrate (10 mu G/ml);
FIG. 11 is an H & E staining of histopathological changes in the skin surrounding the catheterization of each group of mice; wherein A is a normal control group; b is a catheter group; c is a molding set; d is a blank film coating agent group; e is a myricetin (400 mu g/ml) film coating agent group; f is a film coating agent group of miconazole nitrate (10 mu g/ml); g is a film coating agent combination of myricetin (400 mu G/ml) and miconazole nitrate (10 mu G/ml);
FIG. 12 shows the cytotoxicity test results of myricetin/miconazole nitrate after being used alone or in combination; wherein (A) is human umbilical vein endothelial cells; (B) is a human renal epithelial cell;
FIG. 13 shows the results of skin irritation test for a blank film coating agent and a combination film coating agent of myricetin and miconazole nitrate; wherein a is a normal control group; b is a group of single administration blank film coating agents for intact skin; c is a film coating agent group combining myricetin (400 mu g/ml) and miconazole nitrate (10 mu g/ml) for single administration on the whole skin; d is a single administration blank film coating agent group for the damaged skin; e is a film coating agent group combining myricetin (400 mu g/ml) and miconazole nitrate (10 mu g/ml) for single administration on damaged skin; f is a group of blank film coating agents continuously administered for multiple times to the intact skin; g is a film coating agent group combining myricetin (400 mu g/ml) and miconazole nitrate (10 mu g/ml) which are continuously and repeatedly administered to the intact skin; h is a blank film coating agent group continuously and repeatedly administered to the damaged skin; i is a film coating agent group combining myricetin (400 mu g/ml) and miconazole nitrate (10 mu g/ml) continuously and repeatedly administered to the damaged skin.
Detailed Description
In order to make the technical solutions of the present invention better understood, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
It should be noted that the terms "first," "second," and the like in the description and claims of the present invention and in the drawings described above are used for distinguishing between similar elements and not necessarily for describing a particular sequential or chronological order. It is to be understood that the data so used is interchangeable under appropriate circumstances such that the embodiments of the invention described herein are capable of operation in other sequences than those illustrated or described herein. Furthermore, the terms "comprises," "comprising," and "having," and any variations thereof, are intended to cover a non-exclusive inclusion, such that a process, method, system, article, or apparatus that comprises a list of steps or elements is not necessarily limited to those steps or elements expressly listed, but may include other steps or elements not expressly listed or inherent to such process, method, article, or apparatus.
The invention is described in further detail below with reference to the accompanying drawings:
preparation of myricetin and miconazole nitrate film coating agent
Acrylic resin (Eudragit RS PO) is used as a main film forming material of the film coating agent, triethyl citrate is used as a plasticizer, an isopropanol water solution is used as a solvent, and main drugs of myricetin and miconazole nitrate are added to prepare the drug-loaded film coating agent. The method comprises the following steps:
precisely weighing acrylic resin (2% -15%, w/v) in a prescription amount into a reagent bottle, adding a proper amount of isopropanol water solution (70% -78%, v/v), sealing, shaking and uniformly mixing, after the solution is clarified, adding triethyl citrate (2% -15%, w/v) in a prescription amount, and uniformly mixing to prepare a blank film coating agent.
Accurately adding main drugs of myricetin (80-1000 mug/ml) and miconazole nitrate (2-25 mug/ml) in the prescription amount into the blank film coating agent, and uniformly mixing to dissolve the main drugs to obtain the drug-carrying film coating agent.
1) Preparation of miconazole nitrate mother liquor
0.015g of miconazole nitrate is accurately weighed into a sample bottle, 30ml of isopropanol aqueous solution (75 percent, v/v) is added and dissolved, and then miconazole nitrate mother liquor (500 mu g/ml) is obtained and stored at 4 ℃ for standby.
2) Preparation of blank film coating agent
2.7434g of acrylic resin (Eudragit RS PO) was weighed out accurately into a sample bottle, and 30ml of an aqueous isopropanol solution (75%, v/v) was added and dissolved by shaking. Adding plasticizer triethyl citrate 1.037ml, mixing well to obtain blank coating agent, and storing at 4 deg.C for use.
3) Preparation of myricetin and miconazole nitrate film coating agent
Accurately adding 0.012g of myricetin and 0.6ml of miconazole nitrate mother liquor into 30ml of blank film coating agent, and uniformly mixing to obtain the myricetin/miconazole nitrate film coating agent, and storing at 4 ℃ for later use.
Evaluation of Myricetin + miconazole nitrate film coating agent
1. Appearance character
The myricetin and miconazole nitrate film coating agent prepared by the prescription is transparent and light yellow before application, has good fluidity, does not have the phenomena of flocculation, caking, sedimentation and the like, can quickly form a layer of uniformly dispersed, transparent and good-adhesion film after being applied to arms, has good toughness and does not have damage and cracking, and the result is shown in figure 1.
2. Investigation of film formation time
Dripping 50 mul of the coating agent on a glass slide, standing at room temperature, observing the film forming condition of the coating agent every 30s, and taking the time required when no liquid flows as the film forming time. Each sample was run in duplicate for 3 groups and averaged. The film forming time of the myricetin and miconazole nitrate film coating agent prepared by the prescription is 1min 30s, which shows that the film forming time of the myricetin and miconazole nitrate film coating agent prepared by the invention is less than 3min, the film forming speed is high, and the medicine requirement can be met.
3. Viscosity investigation
50 mul of each coating agent is dripped on a glass slide, the glass slide is kept still and dried at the temperature (32 ℃) simulating the drug application environment, the glass slide is taken out at 5min, 30min, 1h, 4h and 24h respectively, the cotton is lightly pressed, the amount of cotton fiber left on the coating agent is observed and recorded, so as to reflect the viscosity of the coating agent, and the experiment is repeated three times. The viscosity investigation result of the myricetin/miconazole nitrate coating agent prepared by the prescription is shown in figure 2, the viscosity is obviously reduced along with the prolonging of the application time, almost no viscosity exists after 4 hours, clothes and external foreign matters cannot be adhered, and the daily use feeling is good. Fully shows that the viscosity of the myricetin and miconazole nitrate coating agent prepared by the invention is obviously reduced along with the prolonging of the application time, the medicine application part can be kept dry and comfortable, and clothes and external foreign matters cannot be adhered.
4. Examination of Water-retaining Effect
75. mu.l of each film-forming agent was dropped onto a filter paper disc (radius: 1cm), and the disc was allowed to stand at a temperature simulating the environment of administration (32 ℃ C. of the skin surface temperature) to dry the film to a constant weight. Adding 10ml of ultrapure water into a penicillin bottle, covering the opening of the penicillin bottle with a filter paper wafer coated with the film coating agent, sealing the film to seal the penicillin bottle, putting the penicillin bottle into a simulated ring (32 ℃) environment thermostat, weighing the penicillin bottle in 0, 12, 24, 36, 48, 60 and 72 hours respectively, calculating the water loss weight so as to reflect the water retention effect of the film coating agent, and repeating the experiment for three times. The investigation result is shown in figure 3, and the myricetin and miconazole nitrate film coating agent prepared by the prescription has good water retention effect, can hydrate the corneocytes, expand the clearance of the corneocytes, and enable the medicines myricetin and miconazole nitrate to enter the corneous layer to exert the antibacterial effect. Fully proves that the myricetin and miconazole nitrate coating agent prepared by the invention has good water retention effect.
5. Stability survey
The myricetin and miconazole nitrate film coating agent is sealed and stood in an environment of 40 ℃, the change of the drug content is detected by HPLC (high performance liquid chromatography) for 0, 1, 2, 5, 10, 20 and 30 days respectively, so that the stability of the preparation is reflected, and the experiment is repeated for three times. As shown in figure 6, the myricetin and miconazole nitrate film coating agent prepared by the prescription has good stability, the property is stable within 60 days at 40 ℃, and the medicine content is not changed obviously. The myricetin and miconazole nitrate coating agent prepared by the invention has stable property within 60 days, and has no drug degradation.
The methodology for the HPLC detection described above was constructed as follows:
a) preparation of myricetin and miconazole nitrate stock solution
Accurately weighing 0.0105g of miconazole nitrate in a sample bottle, adding a proper amount of methanol to dissolve the miconazole nitrate, transferring the miconazole nitrate into a 10ml measuring flask, and carrying out constant volume on the methanol to obtain the miconazole nitrate stock solution. Accurately weighing 0.0420g of myricetin in another sample bottle, adding 1ml of miconazole nitrate stock solution and a proper amount of methanol, dissolving, uniformly mixing, transferring to a 10ml measuring flask, and fixing the volume with the methanol to obtain the myricetin + miconazole nitrate stock solution.
b) HPLC standard curve plotting
Respectively sucking the myricetin + miconazole nitrate stock solutions with different volumes, and adding methanol to fix the volume to obtain myricetin + miconazole nitrate reference substance solutions with concentrations of 224 mug/ml, 5.6 mug/ml, 192 mug/ml, 4.8 mug/ml, 160 mug/ml, 4.0 mug/ml, 128 mug/ml, 3.2 mug/ml, 96 mug/ml and 2.4 mug/ml respectively. The peak area is measured by a high performance liquid chromatograph, the sample injection volume is 10 mu l, the flow rate is 1.0ml/min, the mobile phase procedure is shown in the following table 1, the detection wavelength of myricetin is 360nm, the detection wavelength of miconazole nitrate is 230nm, the peak area is used as a vertical coordinate, the drug concentration is used as a horizontal coordinate to draw a standard curve, and the result is shown in an attached figure 4.
TABLE 1 HPLC METHOD FLOW PHASE PROGRAM
c) HPLC methodology specificity review
The myricetin (500. mu.g/ml) and miconazole nitrate (500. mu.g/ml) control solutions were filtered through a 0.22 μm filter, and 10. mu.l of each sample was injected. Taking 500 μ l blank coating agent, adding 750 μ l ultrapure water according to the coating agent sample treatment method, mixing, centrifuging (15000rpm, 10min), collecting supernatant, filtering at 0.22 μm, and injecting 10 μ l sample. The detection is carried out according to the HPLC conditions, and the specificity of HPLC methodology is examined. The results are shown in FIG. 5, which shows that the specificity of this method is good.
d) HPLC methodology precision investigation
Continuously injecting 5 samples of myricetin + miconazole nitrate stock solutions with high, medium and low concentrations in one day, and calculating the precision in one day. And injecting high, medium and low myricetin + miconazole nitrate stock solutions respectively in five days, and calculating the daytime precision. The results of the precision survey in the day are shown in Table 2, and the RSD (%) of the low, medium and high concentrations of myricetin are 0.8167%, 1.1854% and 0.0989% respectively; the low, medium and high concentration RSD (%) of miconazole nitrate are 1.7754%, 1.2650% and 1.0150%, respectively. The results of the day precision test are shown in Table 3, and the RSD (%) of the low, medium and high concentrations of myricetin are 1.8481%, 0.6913% and 1.3365% respectively; the low, medium and high concentration RSD (%) of miconazole nitrate are 1.5815%, 0.4492% and 1.7980%, respectively. The HPLC method is excellent in precision.
TABLE 2 in-day precision of HPLC method
TABLE 3 daytime precision of HPLC method
e) HPLC methodology sample recovery survey
Taking blank film coating agent, respectively adding different volumes of myricetin + miconazole nitrate stock solutions to make the final concentrations of myricetin be 480 mug/ml (high), 400 mug/ml (medium) and 320 mug/ml (low), respectively, and the final concentrations of miconazole nitrate be 12 mug/ml (high), 10 mug/ml (medium) and 8 mug/ml (low). Adding 750 μ l of ultrapure water according to the method for treating the film coating agent sample, mixing uniformly, centrifuging (15000rpm, 10min), taking the supernatant, filtering at 0.22 μm, injecting 10 μ l of sample for detection, calculating the blank matrix sample recovery rate according to the formula (1), and repeating the experiment for three times. The results are shown in table 4, where RSD (%) is less than 2%, which indicates that the HPLC method meets the requirements for subsequent drug content determination.
TABLE 4 HPLC sample recovery
6. Examination of skin Retention
Adding coumarin-6 (final concentration of 400 μ g/ml) into the blank film coating agent, mixing well to obtain coumarin-6-carrying film coating agent, and storing at 4 deg.C in dark place for use.
Male BALB/c mice are used as experimental objects, the body mass is 12-15G, the mice are randomly divided into seven groups A-G, 10 mice are fed in cages. The skin on the right side of the back of each group of mice is unhaired, 20 mul of coating agent carrying coumarin-6 is given, and the coating agent is placed into a cage after being dried to form a film, and is freely raised in a dark place. Each group of mice was sacrificed by cervical dislocation at 0h (group A), 4h (group B), 8h (group C), 12h (group D), 24h (group E), 48h (group F) and 72h (group G), the dorsal skin tissue was subjected to OCT embedding, rapidly frozen at-80 ℃ and longitudinally sectioned (5 μm) with a microtome, and the film-coating agent remaining in the mouse skin tissue was observed under a fluorescence microscope. FIG. 7 shows that the fluorescence intensity of the film coating agent is very strong after 0-12h, which shows that the film coating agent has good adhesion and retention effects on the back skin of a mouse, the residue of the film coating agent gradually decreases with the passage of time, and a small amount of film coating agent still remains on the surface of the back skin and in pores of the back skin of the mouse after 72h of application, so that the action time of the drug is greatly prolonged.
Thirdly, investigation of prevention effect of myricetin and miconazole nitrate film coating agent on candida albicans biofilm infection
Constructing a clinically representative animal model, administering the myricetin and miconazole nitrate film coating agent to a specific administration part, and selecting a proper index to evaluate the prevention effect after administering for certain times and time. The myricetin and miconazole nitrate film coating agent has the advantages of convenient administration, accurate dosage, long drug action time, difficult abrasion by clothes and the like.
The specific experimental method is as follows:
1) preparation of Candida albicans suspension
The Candida albicans used in the experiment is SC5314(pCaExp-EGFP), and can express green fluorescent protein. 3-5 single colonies of Candida albicans with a diameter of about 1mm are picked from YPD agar medium, added into YPD liquid medium, streptomycin is added, and the mixture is placed in a constant temperature incubator for 30 ℃ shaking (200rpm) to culture overnight to obtain Candida albicans suspension in logarithmic phase. Taking a glass test tube with a diameter equivalent to 0.5 McLeod turbidimetric tube, adding appropriate amount of bacterial suspension for turbidimetric analysis, and adjusting the concentration of Candida albicans suspension to 1 × 10 with sterile physiological saline 8 CFU/ml, spare.
2) Grouping animals
The experimental animals are male BALB/c mice, the body mass is 12-15G, the experimental animals are randomly divided into 7 groups of A-G, each group comprises 10 animals, and the animals are raised in cages. The pipe used for the experiment was a Polyethylene (PE) hose with an outer diameter of 0.63mm and an inner diameter of 0.28 mm.
Group A was a normal control group (no catheter insertion, no Candida albicans inoculation), group B was a catheter group (catheter insertion, no Candida albicans inoculation), group C was a molding group (catheter insertion, Candida albicans inoculation), group D was a blank film coating group (catheter insertion, Candida albicans inoculation, prevention with blank film coating), group E was a myricetin (400. mu.g/ml) film coating group (catheter insertion, Candida albicans inoculation, prevention with myricetin single film coating), group F was a miconazole nitrate (10. mu.g/ml) film coating group (catheter insertion, Candida albicans inoculation, prevention with miconazole nitrate single film coating), and group G was a myricetin (400. mu.g/ml) + miconazole nitrate (10. mu.g/ml) film coating group (catheter insertion, candida albicans inoculation, prevention with myricetin + miconazole nitrate combined film coating).
3) Construction of mouse medical catheter Candida albicans biofilm infection model
3.5% chloral hydrate solution is injected into the abdominal cavity according to the weight of 0.1ml/10g, the mouse is anesthetized, and the prone position is fixed. Taking the skin on the right side of the back for unhairing, sterilizing by using 75% ethanol, and after the ethanol is volatilized: the group B is directly inserted into a PE conduit (the outer side end is sealed) with the length of about 1cm, and the PE conduit is placed back into the cage after being fixed; dripping 20 μ l Candida albicans suspension into group C, slightly absorbing, inserting into PE catheter (outer end sealed), fixing, and placing back into cage; and dripping 20 mul of candida albicans suspension into the group D-G to enable the candida albicans suspension to be absorbed slightly, dripping 20 mul of each group of coating agent, inserting a PE catheter (the outer side end is sealed) after the candida albicans suspension is dried into a film, dripping 20 mul of each group of coating agent, dripping 20 mul of candida albicans suspension into the film after the candida albicans suspension is dried into the film, and fixing the film in a cage after the candida albicans suspension is absorbed slightly. Each group of mice was freely housed.
4) Evaluation of preventive Effect
a) Fluorescent observation of candida albicans on catheter surface
After 3 days of molding, mice in groups B to G were sacrificed by cervical dislocation, and the catheters were taken out and observed under a fluorescence microscope for Candida albicans adhering to the outer surfaces of the catheters. The external surface of the PE catheter of the catheter group B is not adhered by candida albicans, the external surfaces of the PE catheter of the group C, the group D, the group E and the group F are adhered by mature and compact candida albicans biofilms, and the external surfaces of the PE catheter of the group G and the group F are adhered by miconazole nitrate (10 mug/ml), wherein only a small amount of candida albicans is adhered to the external surface of the PE catheter of the group G and the group G are combined by the group G and the group 10 mug/ml, so that the effect of preventing the infection of the biofilm is remarkable, and the antibacterial effect of the miconazole nitrate is enhanced by adding the myricetin (figure 8).
b) Scanning electron microscope observation of catheter surfaces
After 3 days of molding, mice in groups B to G were sacrificed by cervical dislocation, and the catheters were taken out and observed under a scanning electron microscope for Candida albicans adhering to the outer surfaces of the catheters. As a result, the external surface of the PE catheter of the catheter group B has no Candida albicans adhesion, the external surface of the PE catheter of the group C has mature and compact Candida albicans biofilm adhesion, the external surface of the PE catheter of the group D has mature and compact Candida albicans adhesion, the external surface of the PE catheter of the group E has 400 mu G/ml myricetin and 10 mu G/ml miconazole nitrate coating groups, the external surface of the PE catheter of the group G has small amount of Candida albicans adhesion and the external surface of the PE catheter of the group G has combined myricetin and miconazole nitrate coating groups has good prevention effect (figure 9).
b) Observation of Candida albicans remaining in skin tissue around cannula on back of mouse
After 3 days of molding, mice in groups A to G were sacrificed by cervical dislocation, and the peripheral skin tissue of the tube was fixed, dehydrated, paraffin-embedded, and then sectioned (4 μm), stained with glycogen PAS, and observed for Candida albicans remaining in the peripheral skin tissue. The skin tissues of mice in the group A normal control group and the group B ductal group are not shown with candida albicans, the skin tissues of mice in the group C construction module, the group D blank coating agent group, the group E myricetin (400 mu G/ml) coating agent group and the group F miconazole nitrate (10 mu G/ml) coating agent group are all treated with candida albicans residue, and the skin tissues of mice in the group G myricetin (400 mu G/ml) + miconazole nitrate (10 mu G/ml) combined coating agent group are not shown with candida albicans residue, so that the myricetin + miconazole nitrate combined coating agent can effectively prevent the candida albicans residue in the skin tissues of the mice (figure 10).
c) Histopathological change observation around back intubation tube of mouse
3 days after molding, mice in groups A to G were sacrificed by cervical dislocation, tissues around the cannula were fixed, dehydrated, paraffin-embedded, sectioned (4 μm), stained with hematoxylin-eosin (H & E), and changes in surrounding histopathology were observed. The skin tissues of mice in the group A normal control group and the group B ductal group are normal, the skin tissues of mice in the group C construction module, the group D blank coating agent group, the group E myricetin (400 mu G/ml) coating agent group and the group F miconazole nitrate (10 mu G/ml) coating agent group can be subjected to epidermal hyperplasia and inflammatory cell infiltration in different degrees, and the skin tissues of mice in the group G myricetin (400 mu G/ml) and miconazole nitrate (10 mu G/ml) combined coating agent group are not obviously different from those in the group A, B (figure 11).
Investigation of medication safety of myricetin and miconazole nitrate film coating agent
The cytotoxicity and tissue toxicity of the myricetin and miconazole nitrate coating agent are evaluated at in vivo and in vitro levels respectively, and the medication safety of the myricetin and miconazole nitrate coating agent is inspected. The myricetin and miconazole nitrate film coating agent prepared by the invention has no cytotoxicity and tissue toxicity, and the toxicity of miconazole nitrate can be counteracted by adding myricetin, so that the administration safety is good.
The method specifically comprises the following steps:
a) investigation of cytotoxicity
Taking two kinds of cells in logarithmic growth phase with Human Umbilical Vein Endothelial Cells (HUVEC) and human kidney epithelial cells 293T as experimental subjects, respectively, and adjusting the cell suspension concentration to 1.5 × 10 5 293T of 4X 10 per ml 5 The cells/ml were inoculated into a 96-well flat-bottomed plate at 100. mu.l/well, incubated at 37 ℃ with 5% CO 2 The cells were cultured in a cell incubator overnight. After the cells adhere to the wall, the old culture solution is discarded, 100 mul of sterile PBS is rinsed for 1 time in each hole, 100 mul of liquid medicine with each concentration is respectively sucked and added into the corresponding holes, and the mixture is treated at 37 ℃ and 5 percent CO 2 And (3) incubating under the condition, detecting the activity of the cells by using an MTT method for 24h and 48h respectively, namely adding 20 mu l of MTT (5mg/ml) into each hole, incubating for 4h in a dark place at 37 ℃, carefully absorbing supernatant in the holes, adding 150 mu l of dimethyl sulfoxide into each hole to dissolve formazan crystal, uniformly mixing, and then, measuring the absorbance of each hole at 490nm by using an enzyme labeling instrument. Duplicate wells of 6 were set for each drug concentration and the experiment was repeated 3 times. Blank medium was used as a blank control, and the drug-free group was used as a growth control. The results show that miconazole nitrate (10 mug/ml) has certain toxicity to HUVEC and 293T cells in 24h and 48h, myricetin (400 mug/ml) has certain growth promoting effect on HUVEC and 293T cells, when miconazole nitrate and myricetin are combined, the growth promoting effect is shown on 293T cells in 24h and 48h, the promoting effect is shown on HUVEC cells in 24h, and low toxicity is shown in 48h (the cell activity is that the cell activity is92.8847%) (fig. 12).
b) Investigation of tissue toxicity
The male BALB/c mice are used as experimental objects, the body mass is 12-15g, the mice are randomly divided into a normal control group, an intact skin single administration stimulation group, a damaged skin single administration stimulation group, an intact skin continuous multiple administration stimulation group and a damaged skin continuous multiple administration stimulation group, 10 mice are fed in cages. The single administration of the damaged skin stimulates the group of mice to inject 3.5 percent of chloral hydrate solution into the abdominal cavity according to the mass of 0.1ml/10g for anesthesia, the prone position is fixed, the left and right skin on the back is depilated symmetrically, a # is drawn on the skin by using a surgical knife or a syringe needle, the damage degree of the two skin is kept consistent, 20 mul of blank coating agent is given to the left skin, 20 mul of myricetin (400 mu g/ml) and miconazole nitrate (10 mu g/ml) are given to the right skin, and the mice are placed back into a cage for free feeding after the coating agent is dried to form a film; the mice in the stimulation group with multiple times of damaged skin are administered 1 time per day for 7 days after the first administration according to the operation of the stimulation group with single administration. After the four groups of mice are administered for 24 hours in the last time, the film coating agent remained on the skin is slightly wiped off by sterile water warmed to 37 ℃, and the skin on the two sides of the back of the mice is observed by naked eyes for 0 hour, 24 hours, 48 hours and 72 hours respectively to have the phenomena of erythema, edema and the like. Each group of mice was sacrificed by 72H cervical dislocation, dorsal skin tissues were fixed in 4% paraformaldehyde aqueous solution, dehydrated, paraffin-embedded, sectioned (4 μm), H & E stained, and histopathological changes of the skin were observed to reflect the histotoxicity of the coating agent. As shown in figure 13, the blank film coating agent, the myricetin (400 mug/ml), the miconazole nitrate (10 mug/ml) combined film coating agent have no irritation to the intact and damaged skin of a mouse after single or continuous multiple times of administration, and the administration safety is good.
In conclusion, the myricetin and miconazole nitrate film coating agent provided by the invention has the advantages that the main drug (myricetin and miconazole nitrate) can break through the microbial biofilm barrier, the antibacterial effect is obvious, and the myricetin and miconazole nitrate film coating agent can be used as an effective prevention strategy for clinically relevant microbial biofilm infection when the problem of clinical drug resistance is increasingly serious. The preparation method of the film coating agent is simple, the experimental conditions are mild, special equipment is not needed, the investment cost is low, and the used reagents are conventional reagents, so that the industrial implementation is facilitated, and the method is environment-friendly. When the invention is used for the skin at the position of the medical catheter tube, the invention is not limited by the shape and the position of the drug, has fast film forming speed, strong toughness, no toxicity or stimulation, is not easy to drop, is not easy to be polluted by clothes to cause drug loss, has good water resistance, air permeability and adhesiveness, convenient drug administration, good stability, easy control of dosage and long drug administration time, can simultaneously avoid the invasion and infection of pathogens in the external environment and the skin per se, and provides an idea for the skillful problem of the clinical catheter related infection prevention.
The above-mentioned contents are only for illustrating the technical idea of the present invention, and the protection scope of the present invention is not limited thereby, and any modification made on the basis of the technical idea of the present invention falls within the protection scope of the claims of the present invention.
Claims (6)
1. A film coating agent combined with myricetin/azole drugs for preventing the infection of the outer surface of a percutaneous catheter is characterized by being prepared from main drugs and medicinal film forming auxiliary materials: the main drug is composed of myricetin and miconazole nitrate;
in the film coating agent, the content of myricetin is 20-400 mug/ml;
the content of azole drugs is 0.5-10 mu g/ml;
the film forming time of the film coating agent is 1-3 min;
the medicinal film-forming auxiliary material comprises:
film-forming materials: acrylic resin with the mass concentration of 1-25%;
the mass concentration of the plasticizer is 1% -20%;
solvent: one or more of isopropanol water solution, ethanol water solution and acetone water solution.
2. The film coating agent of claim 1, wherein the acrylic resin comprises one or more of Eudragit RS, Eudragit RL, Eudragit E, Eudragit L, Eudragit S, Eudragit NE and Eudragit RD.
3. The film coating agent for preventing infection of the outer surface of a percutaneous catheter combined with a myricetin/azole drug according to claim 1, wherein the plasticizer comprises one or more of triethyl citrate, tributyl citrate, dibutyl phthalate, dimethyl phthalate, diethyl sebacate and dibutyl sebacate.
4. The film coating agent of a combined myricetin/azole drug for preventing external surface infection of a percutaneous catheter as claimed in claim 1, wherein the volume percentage of the organic phase in the solvent is 50-80%.
5. The film coating agent of a combination myricetin/azole drug for preventing external surface infection of a percutaneous catheter according to claim 1, further comprising pharmaceutically acceptable pharmaceutical excipients, including one or more of a viscosity regulator, a preservative, a surfactant, a suspending agent, an antioxidant, a stabilizer and a humectant.
6. The use of a coating agent of any one of claims 1-5 in combination with a myricetin/azole drug for preventing infection of the outer surface of a percutaneous catheter for the preparation of a protective film for preventing infection of a microbial biofilm on the outer surface of a percutaneous catheter.
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