CN116473911A - Povidone iodine gel preparation for nose and preparation method and application thereof - Google Patents
Povidone iodine gel preparation for nose and preparation method and application thereof Download PDFInfo
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- CN116473911A CN116473911A CN202310058597.4A CN202310058597A CN116473911A CN 116473911 A CN116473911 A CN 116473911A CN 202310058597 A CN202310058597 A CN 202310058597A CN 116473911 A CN116473911 A CN 116473911A
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- povidone
- iodine
- nasal
- gel
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Classifications
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
- A61K31/787—Polymers containing nitrogen containing heterocyclic rings having nitrogen as a ring hetero atom
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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Abstract
The invention provides a povidone iodine gel preparation for nose, which comprises povidone iodine, in-situ gel materials, auxiliary materials and water, wherein the in-situ gel materials comprise at least one of temperature-sensitive gel materials, ion-sensitive gel materials and pH-sensitive gel materials, the povidone iodine content is 0.01-1% based on the mass percentage of the povidone iodine gel preparation for nose, the in-situ gel materials content is 0.04-40%, the auxiliary materials content is 0.01-50%, and the balance is water. The invention solves the problem that the virus is easy to fall off in the nasal cavity flushing process to cause the transmission of contact infection in the prior art. The invention also provides a preparation method and application of the nasal povidone iodine gel preparation.
Description
Technical Field
The invention relates to the technical field of povidone iodine, in particular to a povidone iodine gel preparation for nose and a preparation method and application thereof.
Background
Povidone iodine is a loose compound formed by combining elemental iodine and a polymer carrier, and has the functions of carrier and dissolution assisting, and can be used for skin disinfection, traumatic skin mucosa disinfection, chronic sphagitis and canker sore.
The pandemic of covd-19 is causing more and more losses worldwide, and the emerging SARS-CoV-2 variant exhibits a higher infection rate, possibly partially circumventing vaccine and antibody immunity. Rapid deployment of a non-invasive therapeutic route capable of preventing all SARS-CoV-2 variant infections may supplement current vaccination efforts, helping to reverse the tendency of covd-19 to pandemic.
Up to now, more than 80 variants have been identified, all with mutations in spike proteins, which promote immune evasion and in some cases may cause resistance to partial vaccine and monoclonal antibody therapies, and these variants are spreading rapidly worldwide. The omnirange variant is significantly resistant to serum neutralization in recovered patients and vaccinated subjects. The protective effect of the vaccine, although significantly increased, is diminished over time after vaccination with the booster (particularly the mix). Omimetic Rong Bianti poses a serious threat to many of the existing novel coronavirus vaccines and therapies. Thus, the continual evolution of viruses presents a formidable challenge to achieving "group immunity". Traditional drug screening and vaccine development require a significant amount of time and may not be able to catch up with the speed of the newly emerging drug-or vaccine-resistant SARS-CoV-2 strain. Clearly, there is an urgent need for alternative methods, including rapid development of therapies that are effective against a variety of concerns.
Compared with the original virus strain, the armyworm variant has the advantages of obviously reduced toxicity, and symptoms of cough, watery nasal discharge, hyposmia and the like caused by upper respiratory tract infection. More manifesting as asymptomatic or upper respiratory tract irritation only, rarely seen with classical pulmonary inflammatory manifestations. Therefore, in the current stage of epidemic situation, the upper respiratory tract including nasal cavity becomes a key part for preventing and controlling virus infection. Prevention and treatment of upper respiratory viral infections, represented by the nasal cavity, have become a major point of control. When the existing disinfectant disinfects the upper respiratory tract viruses represented by the nasal cavity, the disinfectant cannot kill all the viruses, so that the viruses can flow out of the nasal cavity along with the disinfectant, and contact infection is caused.
Therefore, there is a need to provide a new nasal povidone-iodine gel formulation, and a preparation method and application thereof, so as to solve the above-mentioned problems existing in the prior art.
Disclosure of Invention
The invention aims to provide a povidone iodine gel preparation for nose and a preparation method and application thereof, which are used for solving the problem that viruses are easy to fall off along with disinfectants in the nasal cavity washing process, so that contact infection is spread.
In order to achieve the above purpose, the povidone-iodine gel preparation for nose of the present invention comprises povidone-iodine, in-situ gel material, auxiliary material and water, wherein the in-situ gel material comprises at least one of temperature-sensitive gel material, ion-sensitive gel material and pH-sensitive gel material, the povidone-iodine content is 0.01-1% based on the mass percentage of the povidone-iodine gel preparation for nose, the in-situ gel material content is 0.04-40%, the auxiliary material content is 0.01-50%, and the balance is water.
Optionally, the pH value of the nasal povidone-iodine gel preparation is 3.5-8.0.
Optionally, the temperature sensitive gel material comprises at least one of poloxamer 407, poloxamer 188, poly-N-isopropyl acrylamide, polyoxyethylene-polylactic acid glycolic acid copolymer, methylcellulose and xylan.
Optionally, the temperature-sensitive gel material comprises any one of poloxamer 407, poloxamer 188, poly-N-isopropyl acrylamide, polyoxyethylene-polylactic acid-glycolic acid copolymer, methylcellulose and xylan, wherein the content of the poloxamer 407 is 10-40%, the content of the poloxamer 188 is 5-30%, the content of the poly-N-isopropyl acrylamide is 20-40%, the content of the polyoxyethylene-polylactic acid-glycolic acid copolymer is 15-40%, the content of the methylcellulose is 1-10%, and the content of the xylan is 0.1-3% based on the mass percentage of the povidone iodine gel preparation for nose.
Optionally, the ion-sensitive gel material comprises at least one of deacetylated gellan gum, sodium alginate, xanthan gum, welan gum, and carrageenan.
Optionally, the ion-sensitive gel material comprises any one of deacetylated gellan gum, sodium alginate, xanthan gum, welan gum and carrageenan, wherein the content of the deacetylated gellan gum is 0.04-3%, the content of the carrageenan is 0.2-9%, the content of the welan gum is 0.1-8%, the content of the xanthan gum is 0.1-8%, and the content of the sodium alginate is 0.2-10% based on the mass percentage of the nasal povidone-iodine gel preparation.
Optionally, the pH-sensitive gel material comprises at least one of cellulose acetate phthalate, carbomer, and chitosan.
Optionally, the pH-sensitive gel material includes any one of cellulose acetate phthalate, carbomer and chitosan, wherein the content of the cellulose acetate phthalate is 10-40% by mass of the nasal povidone-iodine gel preparation, the content of the carbomer is 0.1-2.0%, and the content of the chitosan is 0.1-10%.
Optionally, the in-situ gel material is a mixed gel material, and the mixed gel material comprises any one of poloxamer 407, poloxamer 188, a combination of deacetylated gellan gum, a combination of chitosan and sodium alginate, a combination of poloxamer 407 and chitosan, and a combination of poloxamer 407 and cellulose acetate phthalate.
Optionally, the auxiliary materials comprise at least one of osmotic pressure regulator, gel regulator, pH regulator and humectant.
Optionally, the osmotic pressure regulator comprises at least one of mannitol, sorbitol, glycerol, sodium citrate, potassium chloride, propylene glycol and sodium chloride, and the content of the osmotic pressure regulator is 0.5-5% based on the mass percentage of the nasal povidone-iodine gel preparation.
Optionally, the humectant is at least one of polyethylene glycol 400, glycerin, propylene glycol, and polysorbates.
Optionally, the humectant is any one of polyethylene glycol 400, glycerin, propylene glycol and polysorbates, wherein the content of glycerin is 3-30%, the content of polyethylene glycol 400 is 5-30%, the content of propylene glycol is 5-30%, and the content of polysorbates is 0.1-8% based on the mass percentage of the nasal povidone-iodine gel preparation.
Optionally, the pH adjuster is at least one of citric acid, sodium hydroxide, triethanolamine, potassium hydroxide, hydrochloric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, and dipotassium hydrogen phosphate.
Another object of the present invention is to provide a method for preparing a nasal povidone-iodine gel formulation, comprising the steps of:
S0: providing povidone iodine, an in-situ gel material, auxiliary materials and water, wherein the in-situ gel material comprises at least one of a temperature-sensitive gel material, an ion-sensitive gel material and a pH-sensitive gel material, the auxiliary materials comprise at least one of an osmotic pressure regulator, a gel regulator, a pH regulator and a humectant, the povidone iodine content is 0.01-1% by mass of the povidone iodine gel preparation for nose, the in-situ gel material content is 0.04-40% by mass of the auxiliary materials, the auxiliary materials content is 0.01-50% by mass of the water;
s1: adding the auxiliary materials into water, and stirring until the auxiliary materials are completely dissolved to obtain a first solution;
s2: adding the in-situ gel material into the first solution, and uniformly stirring to obtain a second solution;
s3: and adding the povidone iodine into the second solution, uniformly stirring in a dark place, and sequentially carrying out ageing treatment and radiation sterilization treatment to obtain the povidone iodine gel preparation.
Yet another object of the present invention is to provide the use of a nasal povidone-iodine gel formulation for killing pathogenic microorganisms.
Optionally, the nasal povidone-iodine gel preparation enters the nasal cavity by any one of nasal spray, smearing and atomization to kill pathogenic microorganisms.
Optionally, the nasal povidone iodine gel preparation enters the nasal cavity after being atomized by an atomizer, and forms gel in the nasal cavity for killing pathogenic microorganisms.
The invention has the beneficial effects that:
1. the povidone iodine is formed by forming a micro-cavity carrier by povidone (PVP for short) and complexing iodide ions in the cavity of the microcapsule, and plays a powerful disinfection role by continuously releasing free iodine.
2. The effective iodine content of the povidone iodine gel preparation for nose is 0.5-5.0%, and the addition of the in-situ gel material has the function of stabilizing the effective iodine content, so that the effective iodine content in the povidone iodine gel preparation for nose can keep the loss of the effective iodine within 10% within 12 months of the shelf life, and the effective iodine content in the invention is the mass percent of the effective iodine in the povidone iodine gel preparation for nose to the povidone iodine gel preparation for nose unless specified.
3. Because povidone iodine is only dissolved by water, the povidone iodine is easy to agglomerate when stirred conventionally, and the dispersing time is required to be longer, the invention can solve the problems that povidone iodine is easy to agglomerate and the dispersing time is long when stirred in water by adding an in-situ gel material.
4. The pH value of the povidone-iodine gel preparation for nose is 3.5-8.0, so that the povidone-iodine gel preparation for nose does not feel irritation during use.
5. The nasal povidone iodine gel preparation has acute oral toxicity LD50 of more than 5000 mg/kg.BW to SPF grade KM mice, and belongs to actual innocuity, so the nasal povidone iodine gel preparation has acute oral toxicity.
6. The povidone iodine gel preparation for nose has good effect on killing escherichia coli, staphylococcus aureus, salmonella, pseudomonas aeruginosa and candida albicans, and can improve dermatitis, rash and tinea, promote wound healing and have the effects of lasting moisture and chapping prevention when being smeared on affected parts.
7. The nasal povidone iodine gel preparation is sprayed into the nasal cavity after being atomized by the atomizer, so that the nasal povidone iodine gel preparation can be widely distributed in the nasal cavity, and after the atomized nasal povidone iodine gel preparation forms gel in situ, the adhesion time of povidone iodine on nasal mucosa can be prolonged, thereby improving the bioavailability of povidone iodine, reducing systemic toxicity and improving the effect of povidone iodine on killing viruses.
Detailed Description
For the purpose of making the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention. Unless otherwise defined, technical or scientific terms used herein should be given the ordinary meaning as understood by one of ordinary skill in the art to which this invention belongs. As used herein, the word "comprising" and the like means that elements or items preceding the word are included in the element or item listed after the word and equivalents thereof without precluding other elements or items.
The current epidemic omnirange variant has greatly enhanced infectivity and obviously reduced toxicity, and the symptoms are concentrated and manifested as cough, watery nasal discharge, hyposmia and the like caused by upper respiratory tract infection. At the same time, the omnirange infection is also often asymptomatic or symptomatic with only upper respiratory tract irritation, with few manifestations of typical pulmonary inflammation. Therefore, in the current stage of epidemic situation, the upper respiratory tract including nasal cavity becomes a key part for preventing and controlling virus infection.
The problems can be solved by combining the disinfectant with the slow-release in-situ gel drug release technology, and the disinfectant has longer prevention and treatment effects.
The embodiment of the invention provides a povidone iodine gel preparation for nose, which comprises povidone iodine, an in-situ gel material, auxiliary materials and water, wherein the in-situ gel material comprises at least one of a temperature-sensitive gel material, an ion-sensitive gel material and a pH-sensitive gel material, the povidone iodine content is 0.01-1% based on the mass percentage of the povidone iodine gel preparation for nose, the in-situ gel material content is 0.04-40%, the auxiliary materials content is 0.01-50%, and the balance is water.
Specifically, by adding the in-situ gel material, the povidone iodine gel preparation for the nose is enabled to enter the nasal cavity and form gel in situ, so that the povidone iodine gel preparation for the nose is effectively attached to the nasal mucosa, the residence time of povidone iodine in the nose is prolonged, the delivery of povidone iodine by a nasal mucociliary transmission system is reduced, the effect of povidone iodine on killing viruses in the nasal mucosa is improved, the ratio of the povidone iodine gel preparation for the nose to be swallowed by the gastrointestinal tract is reduced, the bioavailability of the povidone iodine gel preparation for the nose in the nasal mucosa is improved, meanwhile, the irritation of the povidone iodine gel preparation for the nose can be reduced, the povidone iodine gel preparation for the nose can be well prevented from being pushed to the back wall of the pharynx rapidly, the compliance of a patient, especially a child patient, the effect of povidone iodine killing viruses in the nasal cavity is realized, the immune function of the nasal cavity is improved, the repeated infection of viruses is reduced, the purpose of effectively preventing and treating the povidone iodine gel preparation for the nose can be improved through the gel. The content of the in-situ gel material is controlled to be 0.04-40%, compared with the povidone iodine, the in-situ gel material has the functions of in-situ slow release, moisture preservation and drug loading in the nasal cavity; the in-situ gel material comprises at least one of a temperature-sensitive gel material, an ion-sensitive gel material and a pH-sensitive gel material, so that the povidone-iodine gel preparation for the nose has long-term lasting and low-toxicity pharmacological effects, a more uniform povidone-iodine gel preparation can be obtained, coronaviruses can be effectively killed, the povidone-iodine gel preparation for the nose enters the interior of the nose in a solution mode, gel is formed in situ, and the residence time of povidone-iodine in the nose is prolonged. The invention solves the problem that viruses are easy to fall off along with disinfectants in the nasal cavity washing process, so that contact infection is transmitted.
The nasal povidone iodine gel preparation has good tissue compatibility, and the unique property of converting a solution into gel ensures that the nasal povidone iodine gel preparation has the advantages of simple preparation, convenient use, strong affinity with a medicine application part, particularly a mucous membrane tissue, long residence time and the like, and has good controlled drug release performance.
In some embodiments, the nasal povidone-iodine gel formulation has a pH of 3.5-8.0. In some embodiments, the nasal povidone-iodine gel formulation including the pH-sensitive gel material has a pH of 3.5-5.0 and the nasal povidone-iodine gel formulation not including the pH-sensitive gel material has a pH of 5.0-8.0. Specifically, the pH value of the povidone iodine gel preparation for nose is controlled to be 3.5-8.0, which is favorable for forming gel in situ after the povidone iodine gel preparation for nose is dripped into the nasal cavity, so as to prolong the adhesion time of povidone iodine in nasal mucosa, thereby improving the bioavailability.
In some embodiments, the temperature sensitive gel material comprises at least one of poloxamer 407, poloxamer 188, poly N-isopropyl acrylamide, polyoxyethylene-poly (lactic-co-glycolic acid), methylcellulose, and xylan. Specifically, the temperature-sensitive gel material has a critical phase transition temperature, can change phase with the change of the ambient temperature, is free flowing solution at room temperature, and gels into a semisolid gel state at the nasal cavity temperature.
In some specific embodiments, the number average molecular weight of the poly (N-isopropylacrylamide) is 20,000-60,000, the poly (N-isopropylacrylamide) is a NiPAAM copolymer, the English language of the polyoxyethylene-polylactic acid glycolic acid copolymer is abbreviated as PEG-PLGA, and the number average molecular weight of the polyoxyethylene-polylactic acid glycolic acid copolymer is 400-20,000.
In some embodiments, the temperature-sensitive gel material comprises any one of poloxamer 407, poloxamer 188, poly (N-isopropyl acrylamide), polyoxyethylene-polylactic acid-glycolic acid copolymer, methylcellulose and xylan, wherein the content of poloxamer 407 is 10-40%, the content of poloxamer 188 is 5-30%, the content of poly (N-isopropyl acrylamide) is 20-40%, the content of polyoxyethylene-polylactic acid-glycolic acid copolymer is 15-40%, the content of methylcellulose is 1-10%, and the content of xylan is 0.1-3% based on the mass percentage of the nasal povidone-iodine gel preparation.
In some embodiments, the ion-sensitive gel material comprises at least one of deacetylated gellan gum, sodium alginate, xanthan gum, welan gum, and carrageenan. In particular, the ion-sensitive gel material is a free flowing solution at room temperature that will interact with K in body fluids + 、Na + 、Ca 2+ The plasma complexes, whereby conformational changes occur to form a gel.
In some embodiments, the ion-sensitive gel material comprises any one of deacetylated gellan gum, sodium alginate, xanthan gum, welan gum and carrageenan, wherein the content of the deacetylated gellan gum is 0.04-3%, the content of the carrageenan is 0.2-9%, the content of the welan gum is 0.1-8%, the content of the xanthan gum is 0.1-8%, and the content of the sodium alginate is 0.2-10% based on the mass percentage of the nasal povidone-iodine gel preparation.
In some embodiments, the pH-sensitive gel material comprises at least one of cellulose acetate phthalate, carbomer, and chitosan. The pH sensitive gel material is gel formed by phase transition due to different pH values in vitro and in vivo, the pH value of nasal mucus is generally between 5.5 and 7.0, a large number of dissociable groups are contained in a polymer molecular skeleton in the pH sensitive gel material, the gelation behavior is a result of molecular chain extension and mutual entanglement caused by repulsive interaction between charges, cellulose acetate phthalate, carbomer and chitosan are designed according to physiological pH environment in a nasal cavity, the pH value of the cellulose acetate phthalate, carbomer and chitosan is 3.5 to 5.0, the cellulose acetate phthalate, carbomer and chitosan are free flowing solutions, and the acidic groups on the polymer chains are neutralized when the pH value is increased to 5.5 to 6.5, and the molecular chains are extended and entangled to form gel due to mutual repulsion of charges.
In some embodiments, the pH-sensitive gel material includes any one of cellulose acetate phthalate, carbomer and chitosan, wherein the content of the cellulose acetate phthalate is 10-40% and the content of the carbomer is 0.1-2.0% and the content of the chitosan is 0.1-10% based on the mass percentage of the povidone-iodine gel preparation for nose.
In some embodiments, the in-situ gel material is a mixed gel material, and the mixed gel material comprises any one of poloxamer 407, poloxamer 188, a combination of deacetylated gellan gum, a combination of chitosan and sodium alginate, a combination of poloxamer 407 and chitosan, and a combination of poloxamer 407 and cellulose acetate phthalate.
In some embodiments, the adjunct includes at least one of an osmotic pressure regulator, a gel regulator, a pH regulator, and a humectant. In particular, the nasal povidone-iodine gel preparation is made to be a free flowing solution under natural conditions, and gel is formed more quickly under physiological conditions.
In some embodiments, the osmotic pressure regulator comprises at least one of mannitol, sorbitol, glycerol, sodium citrate, potassium chloride, propylene glycol and sodium chloride, and the content of the osmotic pressure regulator is 0.5-5% based on the mass percentage of the nasal povidone-iodine gel preparation.
In some embodiments, the humectant is at least one of polyethylene glycol 400, glycerin, propylene glycol, and polysorbates. In some embodiments, the polysorbates are selected from at least one of Tween-20, tween-40, tween-60, tween-65, tween-80, and Tween-85.
In some embodiments, the humectant is any one of polyethylene glycol 400, glycerin, propylene glycol and polysorbates, wherein the glycerin content is 3-30%, the polyethylene glycol 400 content is 5-30%, the propylene glycol content is 5-30% and the polysorbates content is 0.1-8% based on the mass percentage of the nasal povidone-iodine gel preparation.
In some embodiments, the pH adjuster is at least one of citric acid, sodium hydroxide, triethanolamine, potassium hydroxide, hydrochloric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, and dipotassium hydrogen phosphate.
In some embodiments, the gel modifier comprises at least one of pectin, hydroxypropyl cellulose, and carboxymethyl cellulose. The content of the gel regulator is 0.05-1% based on the mass percentage of the nasal povidone-iodine gel preparation.
The embodiment of the invention also provides a preparation method of the povidone-iodine gel preparation for nose, which comprises the following steps:
S0: providing povidone iodine, an in-situ gel material, auxiliary materials and water, wherein the in-situ gel material comprises at least one of a temperature-sensitive gel material, an ion-sensitive gel material and a pH-sensitive gel material, the auxiliary materials comprise at least one of an osmotic pressure regulator, a gel regulator, a pH regulator and a humectant, the povidone iodine content is 0.01-1% by mass of the povidone iodine gel preparation for nose, the in-situ gel material content is 0.04-40% by mass of the auxiliary materials, the auxiliary materials content is 0.01-50% by mass of the water;
s1: adding the auxiliary materials into water, and stirring until the auxiliary materials are completely dissolved to obtain a first solution;
s2: adding the in-situ gel material into the first solution, and uniformly stirring to obtain a second solution;
s3: and adding the povidone iodine into the second solution, uniformly stirring in a dark place, and sequentially carrying out ageing treatment and radiation sterilization treatment to obtain the povidone iodine gel preparation.
Specifically, the prepared povidone iodine gel preparation for nose enters the nasal cavity after being atomized by an atomizer and then forms gel in situ, so that the adhesion time of povidone iodine on the nasal mucosa can be prolonged, the bioavailability of the povidone iodine gel preparation for nose is improved, the systemic toxicity is reduced, the local bioavailability of the povidone iodine gel preparation for nose is improved, the viruses are killed internally, and the transmission and the repeated infection of the viruses are reduced. The preparation method is simple, convenient, safe and reliable.
Embodiments of the present invention also provide for the use of a nasal povidone-iodine gel formulation for killing pathogenic microorganisms. In some embodiments, the pathogenic microorganisms include viruses of the genus coronavirus, herpes simplex virus, enteroviruses, bacteria of the genus escherichia and staphylococcus. Some more specific examples, the pathogenic microorganisms include SARS-CoV-2, HIV-1, CVB3, pseudomonas aeruginosa, candida albicans, and Staphylococcus aureus.
In some embodiments of the invention, the nasal povidone-iodine gel formulation is introduced into the nasal cavity by any one of nasal spray, paint, and spray to kill pathogenic microorganisms.
In some embodiments of the invention, the nasal povidone-iodine gel formulation is atomized by an atomizer and then enters the nasal cavity, forming a gel in the nasal cavity for killing pathogenic microorganisms. The nasal povidone iodine gel preparation is atomized by the atomizer and then enters the nasal cavity, and the atomized nasal povidone iodine gel preparation can be filled in the whole nasal cavity, so that the nasal povidone iodine gel preparation has a better effect of killing viruses, and the atomized nasal povidone iodine gel preparation enters the whole nasal cavity and forms gel in situ, so that the problem that the viruses are easy to fall off along with a disinfectant in the nasal cavity in the flushing process to cause contact infection transmission is solved.
The test methods in the following examples, in which specific conditions are not specified, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise indicated, the contents of the examples are mass percentages.
Examples
Povidone iodine was purchased from the midbody chemical engineering, inc. Of south-Huai; poloxamers are purchased from basf; PEG-PLGA was purchased from Siamirili biotechnology Co., ltd; methylcellulose, glycerol, propylene glycol, tween-20, sodium dihydrogen phosphate, and potassium dihydrogen phosphate were all purchased from Shanghai source leaf Biotechnology Co., ltd; citric acid, triethanolamine, sorbitol, and mannitol were all purchased from sigma aldrich (Shanghai) trade limited; sodium chloride and potassium chloride were purchased from Shanghai Ala Biochemical technologies Co., ltd; deacetylated gellan gum is purchased from Shanghai Jiadelier chemical technologies Co., ltd; sodium alginate was purchased from Hebeili Hua Biotechnology Co., ltd; hydroxypropyl cellulose and carboxymethyl cellulose are both purchased from Shanghai Biotechnology Inc.; pectin was purchased from shandong duckweed poly biotechnology limited; carbomers were purchased from Hebei Klaville Biotech Co; chitosan was purchased from Sichuan Huayuan Shengtai Biotechnology Co.
Examples 1-8 are preparations of nasal povidone-iodine gel formulations containing temperature-sensitive gel materials whose compositions are shown in table 1. The preparation method of the nasal povidone-iodine gel preparation of the temperature-sensitive gel materials of examples 1 to 8 comprises the following steps:
and adding a proper amount of pH regulator into the formula amount of purified water, and stirring until the pH regulator is completely dissolved. Adding the osmotic pressure regulator with the formula amount, and uniformly stirring to form uniform first solution;
dissolving humectant in the first solution, stirring to dissolve completely to obtain the second solution;
and adding povidone iodine with the formula amount into the second solution, mixing, uniformly stirring in a dark place, aging for 2-12 hours at normal temperature, and performing irradiation sterilization treatment to obtain the povidone iodine gel preparation for nose.
TABLE 1
Phase transition temperature measurement: the nasal povidone-iodine gel formulations obtained in examples 1 to 8 and comparative examples 1 to 2 were subjected to phase transition temperature measurement according to the method prescribed by the third method rotational viscometer measurement method in the fourth section rule 0633 viscometry method of the pharmacopoeia of the people's republic of China 2020.
Specifically, the nasal povidone-iodine gel formulations obtained in examples 1-8 and comparative examples 1-2 were continuously measured for viscosity by heating from 20 ℃ to 40 ℃, the heating rate was 0.1 ℃/min, and the gel phase transition temperature was the temperature at which the viscosity was sharply increased, and the measurement results are shown in table 2.
TABLE 2
Note that: the phase transition temperatures cannot be measured in table 2/representative.
As is clear from Table 2, the nasal povidone-iodine gel formulations obtained in examples 1-8 showed a significant increase in viscosity over the body temperature range of normal persons, and the nasal povidone-iodine gel formulations obtained in comparative examples 1-2 did not show a phase transition temperature, and the nasal povidone-iodine gel formulations of examples 2-6 showed good phase transition at 36.+ -. 1 ℃.
Nasal cavity retention test: the nasal povidone-iodine gel formulations obtained in example 2 and comparative example 1 were subjected to an aerosol administration in a single nostril of a rat, and after a certain period of administration, the nasal cavity was rinsed with physiological saline at 4 ℃ to measure the retention of povidone-iodine in the nasal cavity, and each group was tested 3 times, and the measurement results are shown in table 3.
TABLE 3 Table 3
As is clear from Table 3, the nasal povidone-iodine gel preparation of example 2 has a significantly higher retention capacity in the nasal cavity than the nasal povidone-iodine gel preparation of comparative example 1, and the nasal povidone-iodine gel preparation of comparative example 1 has a retention amount of about 35% after administration because of the fluidity of the nasal povidone-iodine gel preparation, which is rapidly cleared from the nasal cavity, for 5 minutes; the nasal povidone-iodine gel preparation of example 2 was adhered to the nasal mucosa by rapid gelation after reaching the administration site, and therefore, after administration for 60 minutes, the retention in the nasal cavity was still approximately 31%. The nasal povidone-iodine gel preparation of example 2 is beneficial to improving the retention time of the drug in the nasal cavity, provides opportunities for the drug to be fully absorbed and transported, and can overcome the gravity effect of the drug when the drug is administered in an upright state of the human body, and the nasal povidone-iodine gel preparation of the invention has more obvious advantages in practical application.
Examples 9-16 are preparations of nasal povidone-iodine gel formulations containing ion-sensitive gel materials whose compositions are shown in table 4. The preparation method of the nasal povidone-iodine gel preparation containing the ion-sensitive gel material of examples 9-16 comprises the following steps:
and adding a proper amount of pH regulator into the formula amount of purified water, and stirring until the pH regulator is completely dissolved. Adding the osmotic pressure regulator with the formula amount, and uniformly stirring to form uniform first solution;
dissolving humectant in the first solution, stirring to dissolve completely to obtain the second solution;
and adding povidone iodine with the formula amount into the second solution, mixing, uniformly stirring in a dark place, aging for 2-12 hours at normal temperature, and performing irradiation sterilization treatment to obtain the povidone iodine gel preparation for nose.
TABLE 4 Table 4
Phase transition temperature measurement: the nasal povidone-iodine gel formulations of examples 9-16 were subjected to a phase transition temperature measurement according to the method specified by the third method rotational viscometer measurement in the fourth section rule 0633 viscometry of the pharmacopoeia of the people's republic of China 2020.
Specifically, the viscosity of the nasal povidone-iodine gel formulations of examples 9-16 was measured before and after mixing with an artificial nasal solution at a ratio of 1:1 (v/v), and the results are shown in Table 5. Wherein, the artificial nose liquid is configured in the following way: naCl1.975g, caCl20.64g, KCl0.92g was weighed separately, dissolved in an appropriate amount of purified water, adjusted to a pH of 6.4.+ -. 1, and fixed to a volume of 250mL with purified water, see Table 5.
TABLE 5
As can be seen from Table 5, the nasal povidone-iodine gel formulations of examples 9-16 all had an increased viscosity after contact with the artificial nasal fluid, and had a significant phase transition, wherein the nasal povidone-iodine gel formulations of examples 9, 10, 13, and 15 had a viscosity of < 5000 mPa.s after phase transition and had slightly poorer adhesion; the nasal povidone-iodine gel preparations of examples 11, 12, 14 and 16 have a viscosity of 5000-7000 mpa·s after phase transition, and have a good viscosity.
Nasal cavity retention test: the nasal povidone-iodine gel formulations of example 11 and comparative example 1 were used for the test, and the nasal drug was administered by nasal drip to one nostril of a rat, and after a certain period of administration, the nasal cavity was rinsed with physiological saline at 4 ℃ to measure the retention of the drug in the nasal cavity, and each group was tested 3 times, and the test results are shown in table 6.
TABLE 6
| Time/min | EXAMPLE 11 percent Retention | Comparative example 1 percent retention |
| 0 | 100％ | 100％ |
| 5 | 79.8％ | 31.2％ |
| 15 | 68.7％ | 24.4％ |
| 30 | 51.2％ | 14.1％ |
| 60 | 29.9％ | 7.9％ |
| 120 | 19.7％ | 5.4％ |
| 240 | 8.5％ | / |
| 480 | 3.7％ | / |
As can be seen from Table 6, the nasal povidone-iodine gel formulation of example 11 had significantly higher retention capacity in the nasal cavity than the nasal povidone-iodine gel formulation of comparative example 1. After nasal administration, the nasal povidone-iodine gel preparation of comparative example 1 rapidly cleared from the nasal cavity due to fluidity of the nasal povidone-iodine gel preparation, and the retention was only about 40% after administration for 5 minutes; the nasal povidone-iodine gel preparation of example 11 was rapidly gelled to adhere to the nasal mucosa after reaching the administration site, and therefore, the retention in the nasal cavity was still about 30% after administration for 60 minutes. The nasal povidone-iodine gel preparation of example 11 is beneficial to improving the retention time of the drug in the nasal cavity, provides opportunities for the drug to be fully absorbed and transported, and can overcome the gravity effect of the drug when the drug is administered in an upright state of the human body, and the advantages of the nasal povidone-iodine gel preparation of the invention in practical application are more obvious.
Examples 17-24 are preparations of nasal povidone-iodine gel formulations containing pH-sensitive gel materials whose compositions are shown in table 7. The preparation method of the nasal povidone-iodine gel preparation containing the pH-sensitive gel material of examples 17 to 24 comprises the following steps:
And adding a proper amount of pH regulator into the formula amount of purified water, and stirring until the pH regulator is completely dissolved. Adding the osmotic pressure regulator with the formula amount, and uniformly stirring to form uniform first solution;
dissolving humectant in the first solution, stirring to dissolve completely to obtain the second solution;
and adding povidone iodine with the formula amount into the second solution, mixing, uniformly stirring in a dark place, aging for 2-12 hours at normal temperature, and performing irradiation sterilization treatment to obtain the povidone iodine gel preparation for nose.
TABLE 7
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Phase transition temperature measurement: the nasal povidone-iodine gel formulations containing the pH-sensitive gel material of examples 17-24 were subjected to phase transition temperature measurement according to the method prescribed by the third method rotational viscosimeter assay in the fourth edition of the general rule 0633 viscosimeter assay of the fourth edition of the pharmacopoeia of the people's republic of China.
Specifically, the viscosity of the nasal povidone-iodine gel formulations of examples 17-24 was measured and the viscosity of the nasal drops were measured at a ratio of 1:1 (v/v) with an artificial nasal drop having a pH of 6.4.+ -. 1, and the results are shown in Table 8. Wherein, the artificial nose liquid is configured in the following way: naCl1.975g, caCl20.64g, KCl0.92g is weighed separately, dissolved in a proper amount of purified water, the pH is adjusted to 6.4+/-1, and the volume is fixed to 250mL by adopting the purified water.
TABLE 8
As can be seen from Table 8, the viscosity of the nasal povidone-iodine gel formulations of example 19 and example 24 was less than or equal to 5000 mPa.s; the viscosity of the nasal povidone-iodine gel preparations of example 18 and example 23 is equal to or more than 7000mpa·s; the nasal povidone-iodine gel formulations of examples 17, 20, 21 and 22 have a viscosity of between 5000 and 7000 mPa-s, and have a moderate viscosity and excellent phase transition properties.
Nasal cavity retention test: the nasal povidone-iodine gel formulations of example 21 and comparative example 2 were used for the test, and the nasal drug was administered by nasal drip to one nostril of a rat, and after a certain period of administration, the nasal cavity was rinsed with physiological saline at 4 ℃ to measure the retention of the drug in the nasal cavity, and the results of each test were shown in table 9.
TABLE 9
| Time/min | Example 21 percent Retention | Comparative example 2 percent retention |
| 0 | 100％ | 100％ |
| 5 | 89.2％ | 34.5％ |
| 15 | 72.9％ | 27.8％ |
| 30 | 60.9％ | 17.1％ |
| 60 | 37.5％ | 10.8％ |
| 120 | 16.4％ | 4.5％ |
| 240 | 8.7％ | / |
| 480 | 3.8％ | / |
As can be seen from Table 9, the nasal povidone-iodine gel formulation of example 21 had significantly higher retention capacity in the nasal cavity than the nasal povidone-iodine gel formulation of comparative example 2. After nasal administration, the nasal povidone-iodine gel preparation of comparative example 2 rapidly cleared from the nasal cavity due to the fluidity of the drug solution, and was administered for 5 minutes with a retention of only about 35%; the nasal povidone-iodine gel preparation of example 21 was rapidly gelled to adhere to the nasal mucosa after reaching the administration site, and therefore, the retention in the nasal cavity was still about 35% after administration for 60 minutes. The in situ gel of example 21 is beneficial to improving the retention time of the drug in the nasal cavity, provides opportunities for the drug to be fully absorbed and transported, and can overcome the gravity effect of the drug when the drug is administered in an upright state of the human body, and the advantages of the nasal povidone-iodine gel preparation of the invention in practical application are more obvious.
Stability determination of povidone-iodine nasal gel formulation:
test sample: nasal povidone-iodine gel formulations of example 1, example 2, example 11, example 21, comparative example 1 and comparative example 2 were used; the test method comprises the following steps: according to the disinfection technical Specification (2002 edition), the available iodine content is measured at 25℃and the rate of decrease is calculated; test time: the test results are shown in Table 10, after the test pieces are placed in a constant temperature and humidity box at 54 ℃ for accelerated aging and 14 days.
Table 10
| Example 1 | Example 2 | Example 11 | Example 21 | Comparative example 1 | Comparative example 2 | |
| Effective iodine content decrease rate | 7.5％ | 7.6％ | 7.8％ | 7.4％ | 22.3％ | 25.5％ |
As can be seen from Table 10, under the accelerated test conditions, the decrease rate of the effective iodine content of the nasal povidone-iodine gel formulations of comparative examples 1-2 after 14 days of accelerated aging is more than 20%, and the stability of the nasal povidone-iodine gel formulations of examples 1, 2, 11 and 21 is inferior to that of the nasal povidone-iodine gel formulations of examples 1, 2 and 11, respectively, and the decrease rate of the effective iodine content of the nasal povidone-iodine gel formulations after 14 days of accelerated aging is less than 10%, so that the requirements of one year of effective period are satisfied.
Sterilization test effect of povidone-iodine gel preparation for nose:
because the invention is applied to disinfection of human skin and skin mucous membrane, the test examines whether the nasal povidone iodine gel preparation can be sterilized rapidly.
Nasal povidone-iodine gel formulations of example 2, example 11, example 21 were tested;
test strain: coli, staphylococcus aureus, salmonella, pseudomonas aeruginosa and candida albicans, all provided by the food safety strain collection center of the food safety engineering technology research and development center of Guangdong province;
culture medium: tryptone soy agar medium (TSA): tryptone 1.5%, soyase 0.5%, sodium chloride 0.5%, agar 1.6%, water 1L, pH 7.2+ -0.2, and autoclaving at 121deg.C for 20min;
neutralizing agent: 1.0% sodium thiosulfate+0.2% tween-80+1000 ml PBS;
organic interferents: 3% bovine serum albumin;
main instrument, tool: steam sterilizing pot, ultra clean bench, constant temperature incubator, culture dish, glass bottle, measuring cylinder, and pipetting gun;
the test method comprises the following steps:
according to the quantitative bacterial suspension killing test in the disinfection technical Specification, the bacterial concentration is 10 8 0.5ml of cfu/ml of test strain is added into a small test tube, 0.5ml of organic interference substance is added, the mixture is uniformly mixed, 4.0ml of sample to be tested is added, and the mixture is uniformly mixed and acts for 0.5min, 1.0min and 1.5min respectively. 0.5ml of the neutralizing agent is added into 4.5ml of the neutralizing agent, and the mixture is uniformly mixed and acted for 10min. 1.0ml of the culture dish is taken, 15-20 ml of culture medium is added, the culture medium is uniformly shaken, and the culture is inverted and carried out in a constant temperature incubator at 37 ℃ for 48 hours.
The test steps are as follows:
(1) Preparing a proper amount of tryptone soybean agar culture medium (TSA), normal saline, neutralizer and purified water, placing the culture dishes with the required number together with the gun heads in a sterilizing pot for sterilization at 121 ℃ for 20min, taking out and placing the culture dishes on an ultra-clean workbench for standby (placing the culture medium in water bath at 40-45 ℃);
(2) Preparing bacterial suspension for test with concentration of 1×10 8 cfu/ml～5×10 8 cfu/ml；
(3) Taking a sterile test tube for disinfection test, firstly adding 0.5ml of test bacterial suspension, then adding 0.5ml of organic interference substance, uniformly mixing, placing in a water bath at 20 ℃ for 5min, sucking 4.0ml of povidone iodine gel preparation for nose by using a sterile suction tube, injecting into the sterile test tube, quickly uniformly mixing and immediately timing;
(4) Respectively sucking 0.5ml of mixed solution of the test bacteria and the nasal povidone iodine gel preparation into 4.5ml of sterilized neutralizer for uniformly mixing until the test bacteria and the nasal povidone iodine gel preparation interact for each preset time;
(5) After the mixed solution of each tube of test bacteria and the nasal povidone iodine gel preparation is added with a neutralizing agent for 10min, respectively sucking 1.0ml of sample solution, adding a sterilized culture dish, adding 15-20 ml of culture medium, shaking uniformly, and inversely culturing for 48h in a constant-temperature incubator at 37 ℃;
(6) Meanwhile, the diluted solution is used for replacing the nasal povidone iodine gel preparation, and a parallel test is carried out to be used as a positive control;
(7) Meanwhile, the diluent, the neutralizer and the culture medium are used for parallel experiments, and the parallel experiments are used as negative control.
The test results are shown in tables 11 and 12.
TABLE 11
| Strain name | Total number of colonies of positive control group |
| Staphylococcus aureus | 2.50×10 7 |
| Pseudomonas aeruginosa | 1.43×10 7 |
| Candida albicans | 1.69×10 6 |
Table 12
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As can be seen from tables 11 and 12, the nasal povidone-iodine gel formulations of example 2, example 11 and example 21 have good effect in killing staphylococcus aureus, pseudomonas aeruginosa and candida albicans.
One complete skin irritation test conditions for nasal povidone-iodine gel formulations:
test sample: nasal povidone-iodine gel formulations of example 2, example 3, example 6, comparative example 1 and comparative example 2;
test animals: common new zealand rabbits, 3 per group, body weight range: 2.0-2.5kg;
the test method comprises the following steps: the second part 2.3.3 of the 2002 edition of the disinfection technical Specification;
test conditions: the ambient temperature is 20-26 ℃ and the relative humidity is 40-70%;
the test steps are as follows: the hairs on both sides of the spine of the back of the rabbit are shaved off before the test, and the hair removal range is about 3cm multiplied by 3cm on the left and right. The next day 0.5mL of the experimental sample is directly smeared on one side of skin, covered by a layer of non-stimulated plastic film, fixed by a non-stimulated adhesive tape, the other side of skin is used as a blank control, a closed test is adopted, the application time is 4 hours, after the experiment is finished, the residual test object is removed by warm water,
Evaluation of results: skin response results of the tested parts are observed respectively in 1h, 24h and 48h after the test object is removed, skin response scoring is carried out according to a skin stimulation response scoring table, skin stimulation intensity is judged according to a skin stimulation intensity grading standard table according to the highest integral average value of each observation point in 1h, 24h and 48h, and the test results are shown in table 13.
TABLE 13
As can be seen from Table 13, the nasal povidone-iodine gel formulations of comparative example 1, comparative example 2, example 3, example 6 were all non-irritating in one complete skin irritation test.
Nasal povidone-iodine gel formulations were tested for multiple complete skin irritation:
test sample: nasal povidone-iodine gel formulations of example 2, example 3, example 6, comparative example 1 and comparative example 2;
test animals: common new zealand rabbits, 21, 3 per group, body weight range: 2.0-2.5kg;
test method and evaluation: the second part 2.3.3 of the 2002 edition of the disinfection technical Specification;
test conditions: the ambient temperature is 20-26 ℃ and the relative humidity is 40-70%;
the test steps are as follows: the method comprises the steps of (1) removing hairs on two sides of a spine of a back of a New Zealand rabbit with a depilatory 24 hours before a test, wherein the skin is not damaged, the hair removal range is about 3cm multiplied by 3cm on the left and right sides, 0.5mL of a test sample is coated on the left skin on the next day, the right skin is used as a blank control, the test sample is washed with water for 4 hours after the application, residues are removed, the test sample is applied once a day, the test sample is continuously applied for 14 days, the observation result is 24 hours after each application, and the stimulation reaction scoring is carried out on the formation condition of red spots and edema of animal skin according to a skin stimulation reaction scoring table, so that the application and result observation of a test object are convenient, the hairs are sheared when necessary, and the treatment method of a control area is the same as that of a test area;
The evaluation rule: the average daily integral (stimulation index) for each animal was calculated according to the following formula and the skin irritation intensity of the test subjects was rated on a skin irritation intensity scale.
Average integral per animal per day = Σ (total integral of erythema and edema per animal for 14 days)/(number of animals tested x 14), test results are shown in table 14.
TABLE 14
As can be seen in Table 14, the nasal povidone-iodine gel formulations of comparative examples 1, 2, 3 and 6 were non-irritating in the multiple full skin irritation test to New Zealand rabbits, and met the requirements of the "sterilizing technical Specification" (2002 edition).
Acute oral toxicity test conditions of nasal povidone-iodine gel formulations:
test sample: the nasal povidone-iodine gel formulation of example 2;
animal species strain: SPF grade KM mice; 10 males, 10 females and the weight range is 18-22g;
the inspection method comprises the following steps: the second part 2.3.1 of the 2002 edition of the disinfection technical Specification;
dose level: according to the method requirement, a primary limit method (namely, 20 animals take 5000 mg/kg.BW weight dose orally);
the test steps are as follows: before the test, the experimental animals are fasted overnight without limiting drinking water; during the test, weighing animal weight, randomly grouping, and orally and gastric lavaging for 1 time, wherein the amount of each time of gastric lavage is 0.2ml/10g of body weight, and after gastric lavage, continuously fasting for 3 hours, and then administering normal diet; each animal was individually and comprehensively recorded after exposure to the toxicant and death conditions of the experimental animal were observed, after which the experimental animal was carefully examined once a day, and the body weight was weighed on the first, seventh and fourteenth days of administration D0, D7 and D14, and the observation period was 14 days.
Evaluation of results: in evaluating the results, LD50 was calculated from the data, and the results were determined according to an oral toxicity classification table, and are shown in Table 15.
TABLE 15
Note that: all animals tested did not show obvious poisoning symptoms and death during the 14 day observation period.
As is clear from Table 15, under the present test conditions, the nasal povidone-iodine gel preparation of example 2 was practically nontoxic in terms of acute oral toxicity LD50 > 5000 mg/kg.BW for SPF-grade KM mice.
Acute eye irritation test conditions for nasal povidone-iodine gel formulations:
test sample: nasal povidone-iodine gel formulations of example 8, example 12, comparative example 1;
test animals:
1. common animal house, experimental animal use license number: SYXK (Yue) 2016-0156;
2. animal species strain: common grade New Zealand rabbits; female 12; body weight range: 2.0-2.2kg; animal pass number: 44007600007442;
3. animal origin: the experimental animal is provided by the Dongshihua experimental animal farm (experimental animal production license number: SCXK (Guangdong) 2019-0023);
the inspection method comprises the following steps: the second part 2.3.4 of the 2002 edition of the disinfection technical Specification;
detection conditions: the ambient temperature is 22-25 ℃ and the relative humidity is 40-70%;
The test steps are as follows: 24 hours before the test, the eyes of the experimental animal were routinely inspected, 0.1mL of the test sample was instilled into conjunctival sac during the test, the eyes were passively closed for 4s to prevent the sample from being lost, and the eyes were rinsed with physiological saline after 30 s. On the other side, eyes were examined 1h, 24h, 48h, 72h, 7d, and 14d after the end of the test with normal saline as a control, and a 14d termination test was observed, changes in cornea and iris were examined with 2% sodium fluorescein solution at the time of observation, and the integral of eye irritation reaction was recorded in each examination according to the eye damage scoring criteria.
Evaluation of results: the acute irritation response of the cornea, iris and conjunctiva of the rabbit eye was scored, and the average scores of each animal in three different observation times (24 h, 48h and 72 h) of cornea damage, iris damage, conjunctival congestion and conjunctival edema were calculated, and the average scores and recovery time of the cornea, iris and conjunctival congestion and conjunctival edema of the animal eye were respectively used, and the irritation intensity of the test object to the eyes was judged according to the eye irritation response grading standard, if the irritation response did not appear within 72 hours, or on day 7 or 14, the eye irritation response was completely recovered, and the test was terminated in advance, and the test results are shown in table 16.
Table 16
Note that: "-" indicates that no trial was performed and the average score was the sum of the 24, 48, 72h scores for each group of animals divided by the observed number 3.
As can be seen from Table 16, the nasal povidone-iodine gel preparation has no irritation to the eye of New Zealand rabbits, and meets the requirements of the disinfection technical Specification (2002 edition).
Experiment of inactivating virus with povidone-iodine gel preparation for nose:
experimental equipment:
1. test virus strain: poliovirus type 1 (PV-1, vaccine strain), HIV-1 (HIV-1) American strain, rabies virus (CTN-1 strain), hand-foot-mouth virus (EV-71 strain), herpes virus (VZV strain), influenza virus (H1N 1 strain), and novel coronavirus SARS-CoV-2;
2. host cell: vero cells, MT4 cells;
3. the disinfectant comprises the following active ingredients: povidone iodine;
4. cell culture flasks and 96-well plates;
5. a constant temperature water bath box, a carbon dioxide incubator, a biosafety cabinet, an adjustable pipettor and sterile equipment;
6. cell maintenance medium, cell complete medium and fetal bovine serum;
7. deionized water and standard hard water;
8.3% bovine serum albumin organic interfering substance;
9. neutralizing agent solution: 10g/L histidine, 3.0% Tween-80 and 3 g/lecithin in PBS;
10. Experimental group: example 21, control: comparative example 1, commercially available iodophor
The experimental method comprises the following steps:
1. human coronavirus 229E, human coronavirus NL63, SARS-CoV (causing severe acute respiratory syndrome), novel coronaviruses SARS-CoV-2, MERS-CoV (causing middle east respiratory syndrome), H1N1, HIV-1 virus suspension with 3% bovine serum albumin organic interference material are respectively diluted 10 times for standby;
2. neutralization agent identification test: and removing residual disinfectant by adopting a neutralization dilution method. The nasal povidone iodine gel preparation is used as a stock solution for experiments, the acting time is 3min, the experimental temperature is 20+/-1 ℃, and the experiments are repeated for 3 times;
3. various virus inactivation tests: removing residual disinfectant by a neutralization dilution method, taking the nasal povidone iodine gel preparation as a stock solution for test, wherein the action time is 1.5min, 3min and 4.5min, the test temperature is 20+/-1 ℃, and the test is repeated for 3 times; the experimental results are shown in Table 17.
TABLE 17
| Virosomes | Example 11 | Comparative example 1 | Commercial iodophor |
| 229E | 5.97 | 3.98 | 3.54 |
| NL63 | 6.05 | 4.09 | 4.76 |
| SARS-CoV | 5.76 | 4.53 | 4.95 |
| MERS-CoV | 6.09 | 3.97 | 3.98 |
| H1N1 | 7.65 | 4.17 | 4.91 |
| HIV-1 | 5.23 | 3.76 | 5.02 |
| SARS-CoV-2 | 5.67 | 4.43 | 4.76 |
As is clear from Table 17, the nasal povidone-iodine gel formulations of example 11 and comparative example 1 and commercial iodophor were subjected to 3 repeated tests at a test temperature of 20+ -1deg.C, and the nasal povidone-iodine gel formulation of example 11 was stock solution and acted for 3 minutes, and the average inactivation pair number of the novel coronaviruses SARS-CoV-2, MERS-CoV (causing severe acute respiratory syndrome), H1N1 and HIV-1 virus was more than about 5, which further revealed that the nasal povidone-iodine gel formulation of the present invention was far superior to the nasal povidone-iodine gel formulation of comparative example 1 and commercial iodophor in terms of virus inactivation effect.
The neutralizing agent used by the neutralization dilution method can effectively neutralize the nasal povidone-iodine gel preparation, and the neutralizing agent solution and the neutralizing product solution have no influence on human coronavirus 229E, human coronavirus NL63, SARS-CoV (causing severe acute respiratory syndrome), novel coronavirus SARS-CoV-2, MERS-CoV (causing middle east respiratory syndrome), H1N1, HIV-1 virus and cell growth; the nasal povidone-iodine gel preparation acts for 3min at the test temperature of 20+/-1 ℃ and has inactivation pair values of more than 5.00 for human coronavirus 229E, human coronavirus NL63, SARS-CoV (causing severe acute respiratory syndrome), novel coronavirus SARS-CoV-2, MERS-CoV (causing middle east respiratory syndrome), H1N1 and HIV-1 viruses; the nasal povidone-iodine gel preparation provided by the invention is proved to be effective in inactivating viruses and superior to the existing disinfectants in effect.
The nasal povidone-iodine gel preparation has an effective inactivation effect on human coronavirus 229E, human coronavirus NL63, SARS-CoV (causing severe acute respiratory syndrome), novel coronaviruses SARS-CoV-2, MERS-CoV (causing middle east respiratory syndrome), H1N1 and HIV-1 viruses, and can be used on the surface of human skin, the surface of mucous membrane, spraying or wiping. Can be used immediately, and can effectively block the possible process of invasion of viruses into human bodies through skin, mucous membranes.
The nasal povidone iodine gel preparation of the invention can not cause toxicity, irritation and mutagenic damage in the skin and mucous membrane disinfection process.
The disinfection of the povidone iodine gel preparation for nose has high-quality instantaneity and durability, can achieve the effects of sterilizing and inactivating viruses without frequent repeated use, and can not cause skin and mucous membrane damage after repeated use.
While embodiments of the present invention have been described in detail hereinabove, it will be apparent to those skilled in the art that various modifications and variations can be made to these embodiments. It is to be understood that such modifications and variations are within the scope and spirit of the present invention as set forth in the following claims. Moreover, the invention described herein is capable of other embodiments and of being practiced or of being carried out in various ways.
Claims (18)
1. The nasal povidone-iodine gel preparation is characterized by comprising povidone-iodine, an in-situ gel material, auxiliary materials and water, wherein the in-situ gel material comprises at least one of a temperature-sensitive gel material, an ion-sensitive gel material and a pH-sensitive gel material, the povidone-iodine content is 0.01-1% based on the mass percentage of the nasal povidone-iodine gel preparation, the in-situ gel material content is 0.04-40%, the auxiliary materials content is 0.01-50%, and the balance is water.
2. The nasal povidone-iodine gel formulation of claim 1, wherein the pH of the nasal povidone-iodine gel formulation is 3.5-8.0.
3. The nasal povidone-iodine gel formulation of claim 1, wherein the temperature-sensitive gel material comprises at least one of poloxamer 407, poloxamer 188, poly N-isopropylacrylamide, polyoxyethylene-polylactic-co-glycolic acid, methylcellulose, and xylan.
4. A nasal povidone-iodine gel formulation according to claim 1 or 3, wherein the temperature-sensitive gel material comprises any one of poloxamer 407, poloxamer 188, poly-N-isopropylacrylamide, polyoxyethylene-polylactic acid-glycolic acid copolymer, methylcellulose and xylan, wherein the content of poloxamer 407 is 10-40%, the content of poloxamer 188 is 5-30%, the content of poly-N-isopropylacrylamide is 20-40%, the content of polyoxyethylene-polylactic acid-glycolic acid copolymer is 15-40%, the content of methylcellulose is 1-10%, and the content of xylan is 0.1-3% based on the mass percentage of the nasal povidone-iodine gel formulation.
5. The nasal povidone-iodine gel formulation of claim 1, wherein the ion-sensitive gel material comprises at least one of deacetylated gellan gum, sodium alginate, xanthan gum, welan gum, and carrageenan.
6. The povidone-iodine gel preparation for nose according to claim 1 or 5, wherein the ion-sensitive gel material comprises any one of deacetylated gellan gum, sodium alginate, xanthan gum, welan gum and carrageenan, wherein the content of the deacetylated gellan gum is 0.04-3%, the content of the carrageenan is 0.2-9%, the content of the welan gum is 0.1-8%, the content of the xanthan gum is 0.1-8%, and the content of the sodium alginate is 0.2-10% based on the mass percentage of the povidone-iodine gel preparation for nose.
7. The nasal povidone-iodine gel formulation of claim 1, wherein the pH-sensitive gel material comprises at least one of cellulose acetate phthalate, carbomer, and chitosan.
8. The povidone-iodine gel preparation for nose according to claim 1 or 7, wherein the pH-sensitive gel material comprises any one of cellulose acetate phthalate, carbomer and chitosan, and the content of cellulose acetate phthalate is 10-40%, the content of carbomer is 0.1-2.0% and the content of chitosan is 0.1-10% based on the mass percentage of the povidone-iodine gel preparation for nose.
9. The nasal povidone-iodine gel formulation of claim 1, wherein the in-situ gel material is a mixed gel material comprising any one of poloxamer 407, a combination of poloxamer 188 and deacetylated gellan gum, a combination of chitosan and sodium alginate, a combination of poloxamer 407 and chitosan, and a combination of poloxamer 407 and cellulose acetate phthalate.
10. The nasal povidone-iodine gel formulation of claim 1, wherein the excipients include at least one of an osmotic pressure regulator, a gel regulator, a pH regulator, and a humectant.
11. The nasal povidone-iodine gel formulation of claim 10, wherein the osmotic pressure regulator comprises at least one of mannitol, sorbitol, glycerin, sodium citrate, potassium chloride, propylene glycol and sodium chloride, and the osmotic pressure regulator is 0.5-5% based on the mass percentage of the nasal povidone-iodine gel formulation.
12. The nasal povidone-iodine gel formulation of claim 10, wherein the humectant is at least one of polyethylene glycol 400, glycerin, propylene glycol, and polysorbates.
13. The nasal povidone-iodine gel preparation according to claim 12, wherein the humectant is any one of polyethylene glycol 400, glycerin, propylene glycol and polysorbates, the glycerin content is 3-30%, the polyethylene glycol 400 content is 5-30%, the propylene glycol content is 5-30%, and the polysorbates content is 0.1-8% based on the mass percentage of the nasal povidone-iodine gel preparation.
14. The nasal povidone-iodine gel formulation of claim 10, wherein the pH adjuster is at least one of citric acid, sodium hydroxide, triethanolamine, potassium hydroxide, hydrochloric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, and dipotassium hydrogen phosphate.
15. A method for preparing a povidone-iodine gel preparation for nose, which is characterized by comprising the following steps:
s0: providing povidone iodine, an in-situ gel material, auxiliary materials and water, wherein the in-situ gel material comprises at least one of a temperature-sensitive gel material, an ion-sensitive gel material and a pH-sensitive gel material, the auxiliary materials comprise at least one of an osmotic pressure regulator, a gel regulator, a pH regulator and a humectant, the povidone iodine content is 0.01-1% by mass of the povidone iodine gel preparation for nose, the in-situ gel material content is 0.04-40% by mass of the auxiliary materials, the auxiliary materials content is 0.01-50% by mass of the water;
S1: adding the auxiliary materials into water, and stirring until the auxiliary materials are completely dissolved to obtain a first solution;
s2: adding the in-situ gel material into the first solution, and uniformly stirring to obtain a second solution;
s3: and adding the povidone iodine into the second solution, uniformly stirring in a dark place, and sequentially carrying out ageing treatment and radiation sterilization treatment to obtain the povidone iodine gel preparation.
16. Use of a nasal povidone-iodine gel formulation according to any one of claims 1-14 for killing pathogenic microorganisms.
17. The use of a nasal povidone-iodine gel formulation according to claim 16 wherein the nasal povidone-iodine gel formulation is introduced into the nasal cavity by any one of nasal spray, application and nebulization to kill pathogenic microorganisms.
18. The use of a nasal povidone-iodine gel formulation of claim 17 wherein the nasal povidone-iodine gel formulation enters the nasal cavity after being nebulized by a nebulizer to form a gel within the nasal cavity for killing pathogenic microorganisms.
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