Compositions for upper respiratory tract administration and methods of administering the same

Abstract

The present invention discloses a composition for upper respiratory tract administration, which is used for the treatment and protection of fire injuries and contains a cyanide antidote and a metal chelating agent; with the appropriate carrier combination, the composition can be administered to the required individual in the form of a spray, an inhalant or a drop, etc. to prevent or treat the injuries caused by harmful substances at the fire scene.

Description

Technical Field

[0001] The present invention relates to a composition, in particular to a composition for upper respiratory tract administration, which is applied to fire injury protection and treatment. Background Art

[0002] At the fire scene, the thick smoke produced by completely burned and incompletely burned objects, in addition to solid smoke particles, also contains a large amount of thick smoke and toxic gases produced by high-temperature thermal decomposition, which poses a serious health hazard to fire scene workers, disaster victims and nearby residents.

[0003] In recent years, as synthetic building materials and polymer materials are widely used in homes, offices or entertainment venues, the types and quantities of toxic gases at fire scenes have increased significantly, such as acrolein, acrylonitrile, benzene, formaldehyde, sulfur dioxide, hydrogen cyanide, dioxin and polycyclic aromatic hydrocarbons; these toxic products directly or indirectly cause irreversible harm to people's physical lesions, exhaustion, or chronic diseases. Among them, hydrogen cyanide is an immediately highly toxic substance. It has a high affinity for iron ions in cytochrome oxidase. When it enters the human body, it will cause oxygen to be unable to combine with cytochrome oxidase, resulting in the inability of cells in the body to obtain oxygen in time.

[0004] Acquainted Dicobalt Edetate is administered to individuals in the form of an injection, and the cobalt ion and cyanide can form a fairly stable complex in the blood and be excreted from the body through the urine; however, cobalt existing alone in the form of an ion still has unexpected toxicity to the individual.

[0005] According to British patent publication number GB1404324, a method for diagnosing and tracking excessive amounts of hydrogen cyanide in the blood using a hydroxocobalamin solution for long-term hypercyanogenesis is disclosed. The method uses a combination of sodium thiosulfate and hydroxocobalamin and is administered intramuscularly once or multiple times to track the levels of hydrogen cyanide ions (CN) in the blood. - ) and pointed out that repeated administration would make hypercyanidation more serious and was not suitable for chronic treatment.

[0006] According to U.S. Patent Publication No. US5834448, a new dosage form of hydroxocobalamin for treating cyanide poisoning is disclosed, wherein hydroxocobalamin is freeze-dried in an acidic medium so as to be quickly redissolved in a neutral saline solution, which specifically improves the storage stability of freeze-dried hydroxocobalamin. However, it is mainly administered via intravenous injection, and its administration route is limited to a certain extent when exposed to an environment that may cause cyanide poisoning. It cannot be directly administered into the environment or inhaled by an individual in need to achieve a protective or therapeutic effect.

[0007] In addition to the aforementioned toxic gases, the thick smoke at the fire scene also contains other harmful substances such as suspended particles, dust, fibers, and fiberglass. These harmful substances not only pose a threat to the lives of on-site rescue workers but also to disaster assessment personnel after the disaster. When turning over the debris at the disaster site during assessment, it will also cause the sedimented thick smoke substances such as dust, suspended particles, dust, or fibers to fill the air, causing disaster assessment personnel to inhale or come into contact with these harmful substances and endanger their health.

[0008] According to the "Standard Operating Procedures for Fire Investigation and Appraisal," when entering the fire scene for disaster assessment, a gas mask canister must be worn, which can effectively filter most toxic gases such as organic gases, chlorine gas, hydrochloric acid, sulfur dioxide, hydrogen sulfide, and chlorine dioxide. However, in practical applications, the gas mask canister takes a long time to filter toxic gases such as hydrogen chloride, hydrogen cyanide, and acrolein, which limits its protective effect and increases the risk of personnel inhaling toxic gases.

[0009] In addition, currently, for the protection against harmful substances at the fire scene, in addition to the above method of using a gas mask canister, there are also physical isolation means of wearing respiratory protection equipment. However, the thick smoke at the fire scene is a mixture of suspended particles and toxic gases generated by combustion, and its particle size is generally below 10 micrometers. Currently, the physical protection equipment cannot completely filter the suspended particles in the fire scene air, and the solid particles in the thick smoke are more likely to stimulate the upper respiratory tract and cause a large amount of mucus secretion, thus blocking the respiratory tract.

[0010] Furthermore, at the fire scene, in addition to inhaling cyanide being the main cause of immediate harm, the free radicals generated by pyrolysis due to high temperature also exert a considerable oxidative stress on human tissues. When the number of free radicals in the body exceeds the normal range, it will lead to a "free radical chain reaction," which will cause substances such as proteins, carbohydrates, and lipids to be oxidized and generate new free radicals, resulting in a chain effect. The excess free radicals will gradually damage the genetic material of the human body (such as DNA), cause lipid peroxidation, protease deactivation, and abnormal reactions of immune cells such as monocytes or macrophages, triggering inflammatory reactions, etc., which are quite harmful to the short-term or long-term health of an individual.

[0011] Therefore, in order to improve the current situation where it is difficult to achieve comprehensive protection against solid and gaseous harmful substances in fire smoke in the prior art, it is necessary to develop a means that can simultaneously eliminate and neutralize solid and gaseous harmful substances in fire smoke, not only to protect the lives and health of people trapped in the fire and prevent them from being harmed by thick smoke but also to reverse the harm caused by inhaling thick smoke, so as to achieve a therapeutic effect. Summary of the Invention

[0012] In view of the fact that the thick smoke at the fire scene is a comprehensive harm to the lives of the on-site personnel, in order to simultaneously remove and neutralize harmful substances such as solid and gaseous substances in the thick smoke, the present inventor has developed a new type of comprehensive protection and treatment means in addition to the existing means of removing cyanide; therefore, the present invention discloses a composition for upper respiratory tract administration, which is used for the treatment and protection of fire injuries and contains a cyanide antidote and a metal chelator.

[0013] The composition as described above, wherein the cyanide antidote is selected from the group consisting of Hydroxocobalamin, Dicobalt edetate, Cobinamide, Aquohydroxocobinamide, Dinitrocobinamide, Methemoglobin, Sodium nitrite, amyl nitrite, dimethyl aminophenol, Sodium thiosulfate and glutathione.

[0014] The composition as described above, wherein the metal chelator is selected from the group consisting of deferoxamine, deferiprone and deferasirox.

[0015] The composition as described above, which further comprises an expectorant selected from the group consisting of potassium iodide (KI), iodinated glycerol, glyceryl guaiacolate, guaifenesin, Ambroxol, Bromhexine, N-Acetylcysteine and Lysozyme.

[0016] The composition as described above, which further comprises a carrier, and the carrier comprises ionized water, secondary water, ultrapure water or a buffer solution, wherein the buffer solution has a buffer selected from the group consisting of phosphate, 3-(N-morpholino)propanesulfonic acid, bis(2-hydroxyethyl)glycine, tris(hydroxymethyl)aminomethane, tris(hydroxymethyl)methylglycine, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid, 3-(N-morpholino)ethanesulfonic acid, piperazine-N,N'-bis(2-ethanesulfonic acid), cacodylic acid, sodium citrate and 2-(N-morpholino)ethanesulfonic acid.

[0017] The composition as described above is further used for the protection and treatment of potential high-concentration cyanide environment exposure.

[0018] Furthermore, the present invention discloses a method of administration via the respiratory tract to achieve fire injury protection, which is to administer the composition as described above to a desired individual at a certain point in time up to an effective dose to inhibit the injury suffered by the desired individual exposed to toxic gases, wherein the point in time is before the desired individual is exposed to toxic gases or after the desired individual is exposed to toxic gases.

[0019] The method as described above, wherein the toxic gas includes suspended particles, free radicals or cyanide.

[0020] The method as described above, wherein the administration route includes absorption by biological fluid or mucosal absorption.

[0021] The method as described above, wherein the desired individual includes mammals.

[0022] For the existing means of removing cyanide, the main route of administration is still solution injection, such as intramuscular injection or intravenous injection. The time required for the effect to occur is long, and there are concerns about the stability of the dosage form. There are insurmountable obstacles for both the user end and the production end. Moreover, at the fire scene, there are not only risks of cyanide poisoning, but also other harmful factors such as suspended particles and free radicals, which are also difficult to overcome in the prior art.

[0023] Furthermore, environments prone to cyanide poisoning include workplaces of specific occupations, such as electroplating, metallurgy, plastic industries, etc. In addition to acute poisoning, it is necessary to consider that workers are exposed to a potentially cyanide-poisoned environment for a long time. Therefore, the consideration of drug administration is not only to be able to treat in the acute poisoning stage, but also to be able to achieve the effect of preventing poisoning before entering these workplaces, which is not an effect easily achieved by solution injection in the prior art.

[0024] The composition and method for upper respiratory tract administration provided by the present invention can be applied not only to the treatment of acute or chronic cyanide poisoning, but also to the prevention of the occurrence of cyanide poisoning to solve the problems encountered in the conventional treatment of cyanide poisoning. In addition, the addition of metal chelating agents can cut off the chemical reaction chain of free radicals and greatly relieve the oxidative stress of human tissue cells. Further, expectorants can be used in combination to promote mucus excretion, eliminate the irritation and blockage of suspended particles to the upper respiratory tract, and maintain the patency of the respiratory tract.

[0025] In summary, the composition and method for upper respiratory tract administration provided by the present invention overcome the limitations of the existing administration forms, enabling the composition to enter the body quickly and in a low dose for users in general situations, fire scenes, or micro-cyanide environments, achieving the effects of protection and treatment.

[0026] In addition, since the composition for upper respiratory tract administration provided by the present invention is not affected by the on-site environment and individual status during the drug administration stage; when necessary, it is supplied to the individual for inhalation in the form of atomization, and directly enters the blood through the absorption of the individual's lungs or directly forms a protective layer on the surface of the upper respiratory tract and alveoli to achieve the effects of fire injury protection and treatment, while taking into account the first aid for acute poisoning and the prevention of long-term exposure. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1A To present an exemplary barrel tank in a cyanide gas environment;

[0028] Figure 1B To present an exemplary spray administration method. DETAILED DESCRIPTION OF THE INVENTION

[0029] One embodiment of the present invention is to provide a composition for upper respiratory tract administration, which is used for the treatment and protection of fire injuries, and comprises a cyanide antidote and a metal chelating agent; in some embodiments, the composition comprises 5 to 10 parts by weight of the cyanide antidote and 1 to 5 parts by weight of the metal chelating agent.

[0030] In multiple embodiments, the cyanide antidote is selected from the group consisting of Hydroxocobalamin, Dicobalt edetate, Cobinamide, Aquohydroxocobinamide, Dinitrocobinamide, Methemoglobin, Sodium nitrite, Amyl nitrite, dimethyl aminophenol, Sodium thiosulfate, and Glutathione; preferably, the cyanide antidote includes Hydroxocobalamin; specifically, these cyanide antidotes coordinate with cyanide ions to neutralize the toxicity of cyanide ions, avoiding the competition between cyanide ions and oxygen molecules for divalent iron ions (Fe 2+), for example, hydroxocobalamin (vitamin B12a) has a cobalt atom at the center of its chemical structure, which can combine with cyanide ions (CN - ) to form cyanocobalamin, i.e., vitamin B12, which is non-toxic and can be excreted from the body with water; in addition, hydroxocobalamin can also quickly enter the mitochondria to combine with cyanide to restore normal oxidative metabolism of cells.

[0031] In multiple embodiments, the metal chelator is selected from the group consisting of deferoxamine, deferiprone, and deferasirox; preferably, the metal chelator includes deferoxamine; specifically, a large number of free radicals generated by high-temperature pyrolysis at the fire scene, after being inhaled into the human body, react with existing metal ions in the body, such as iron ions or copper ions, through Fenton's Reaction, thus promoting the generation of more free radicals, causing greater oxidative stress on tissues and cells in the body, and further causing free radical damage; in order to eliminate the harm caused by free radicals, the metal chelator contained in the composition, such as deferoxamine, can compete with free radicals for iron ions in the blood, thereby blocking the chain reaction of free radical generation and protecting cells from the influence of oxidative stress.

[0032] Furthermore, in order to enable the composition to effectively remove excessive mucus generated by irritation in the upper respiratory tract when the user inhales harmful substances such as suspended particles, the composition further includes an expectorant, which is selected from the group consisting of potassium iodide (KI), iodinated glycerol, glyceryl guaiacolate, guaifenesin, ambroxol, bromhexine, N-acetylcysteine, and lysozyme; preferably, the expectorant includes N-acetylcysteine; in multiple embodiments, the composition contains 5 to 10 parts by weight of a cyanide antidote, 1 to 5 parts by weight of a metal chelator, and 5 to 10 parts by weight of an expectorant.

[0033] Specifically, expectorants work by breaking disulfide bonds to reduce the viscosity of sputum, thereby promoting the excretion of sputum. Take acetylcysteine as an example. It has a thiol group (-SH). Since the sulfur atom has a relatively large hybrid orbital composed of 3s / 3p, while hydrogen has a smaller 1s orbital for bonding, the sulfur-hydrogen bond is relatively weak and is easily oxidized, exposing the lone pair of electrons on the sulfur atom. The lone pair of electrons then reduces and breaks the disulfide bond, reducing the viscosity of sputum. Another example is bromhexine. It stimulates the mucus secretion in the bronchi and further dissolves the mucus, reducing its viscosity, and can activate the ciliated epithelium to achieve the effect of mucus excretion. Another example is ambroxol, which is an active metabolite of bromhexine. It also has the characteristics of promoting mucus excretion and dissolving secretions, accelerating the excretion of mucus in the respiratory tract and reducing mucus retention, enhancing sputum excretion and improving the respiratory condition. Similarly, for example, lysozyme, as a natural antibacterial enzyme, exists in human secretions such as tears and saliva. Through the side chains of glutamic acid (Glu35) at the 35th position and aspartic acid (Asp52) at the 52nd position in the lysozyme protein sequence, it cleaves the carbon-oxygen bond of the substrate, further decomposing the mucus and promoting the excretion of sputum. In addition to the mechanism of decomposing mucus, some expectorants achieve the effect of rapidly excreting sputum by stimulating the surface cells of the upper respiratory tract, such as respiratory epithelium cells in the lungs. Another example is glyceryl guaiacolate, which directly stimulates the bronchial secretory cells and stimulates the individual's own reflex to dilute the sputum.

[0034] In this embodiment, the composition further includes a carrier to enable the composition to carry the active ingredient into the human body in various different dosage forms. The dosage forms can be sprays, inhalants, drops, etc., and are not limited thereto. In addition, the inhalant can be a metered-dose inhalant, a nebulizer or a dry powder inhalant, etc. The carrier can be any solvent or solution that has an appropriate solubility for the active ingredient, without any particular limitation. In multiple embodiments, the carrier includes ionized water, secondary water, ultrapure water or a buffer solution. Among them, the buffer solution contains a buffer selected from the group consisting of phosphate, 3-(N-morpholino)propanesulfonic acid, N,N-bis(2-hydroxyethyl)glycine, tris(hydroxymethyl)aminomethane, tris(hydroxymethyl)methylglycine, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid, 3-(N-morpholino)ethanesulfonic acid, piperazine-N,N'-bis(2-ethanesulfonic acid), cacodylic acid, sodium citrate and 2-morpholinoethanesulfonic acid.

[0035] In multiple embodiments, the composition comprises 5 to 10 parts by weight of a cyanide antidote, 1 to 5 parts by weight of a metal chelating agent, 5 to 10 parts by weight of an expectorant, and 60 to 200 parts by weight of a carrier.

[0036] In addition to being used on people at the fire scene, volatile cyanides are also harmful to on-site workers in various occupational workplaces; taking hydrogen cyanide as an example, it is easily volatilized and dissolved in water in an environment above 28 degrees Celsius. Hydrogen cyanide can be released into the air by cyanogenic glycosides, and cyanogenic glycosides are natural components of some economic crops, such as bitter almonds, sorghum, cassava, emperor beans, stone fruits, or bamboo shoots, etc.; taking cassava as an example, its roots contain linamarase, which can decompose cyanogenic glycosides and release cyanohydrin. Cyanohydrin dissociates to produce hydrogen cyanide in a low-acidity environment, ultimately leading to an increase in the cyanide concentration in the cassava processing environment. Therefore, the upper respiratory tract administration composition provided by the present invention can also play a positive role in the protection and treatment of exposure to potentially high-concentration cyanide environments as described above, so as to reduce the occupational injuries caused to workers in these work environments. The potentially high-concentration cyanide environments include, in addition to the processing of cyanogenic glycoside-containing crops, such as cassava processing, sorghum processing, or stone fruit processing, but are not limited to, photographic operations, electroplating operations, hydrogen sulfide manufacturing operations, fumigant operations, pharmaceutical manufacturing operations, papermaking operations, dyeing operations, rodenticide operations, insecticide operations, blast furnace gas manufacturing operations, cyanide manufacturing operations, nitric acid manufacturing operations, rubber and plastic operations, synthetic fiber operations, leather operations, pesticide industries, gold and silver processing operations, metal surface hardening operations, fiber printing Prussian blue operations, metallurgical operations, bone extraction of phosphoric acid operations, organic nitrogen compound operations, soda manufacturing operations, gold inlay operations, illuminating gas manufacturing operations, or nitrocellulose combustion operations.

[0037] Furthermore, to improve the solubility of the active ingredients in the carrier, the composition may further include an acid-base regulator to adjust the composition to be weakly alkaline. Preferably, the composition can be adjusted to have a pH value between 7 and 9, and more preferably a pH value between 7.5 and 8.5. For example, the acid-base regulator can be citric acid, acetic acid, phosphoric acid, carbonic acid, hydrochloric acid, tartaric acid, maleic acid, or sodium hydroxide, but is not limited thereto.

[0038] Another embodiment of the present invention is a method of administering drugs through the respiratory tract to achieve fire injury protection. It is to administer the composition as described above to the required individual at an effective dose at a certain point in time to inhibit the injury suffered by the required individual exposed to toxic gases. Among them, the certain point in time is before the required individual is exposed to toxic gases or after the required individual is exposed to toxic gases.

[0039] In this embodiment, the composition is mainly administered to the personnel at the fire scene or the workers who are exposed to the potential hydrogen poisoning environment for a long time; among them, the toxic gas at the fire scene is a mixture of a solid suspension and a gas, and among them, the gas contains harmful substances such as free radicals or cyanides.

[0040] In this embodiment, the administration route includes absorption by biological fluid or mucosal absorption; in a preferred embodiment, the administration method includes atomizing the composition with a nebulizer and enabling the required individual to inhale through the mouth, nose and other routes, and directly absorbing the composition through the surface cells in the upper respiratory tract, or the composition enters the biological fluid on the tissue surface, such as tissue fluid, mucus, etc., to form a protective layer, and then the effective components are absorbed by the cells; in these embodiments, the composition that enters the surface biological fluid or stays on the mucosal surface layer will form a protective layer so that after the required individual inhales the harmful substances in the thick smoke, a neutralization effect can be achieved on the surface layer, and the part that enters the blood circulation can further neutralize the harmful substances in the blood circulation, such as cyanide ions, so as to achieve the effects of protection and treatment; in some other embodiments, when the composition includes the expectorant, the expectorant can promote the excretion of mucus out of the body by reducing the mucus viscosity, stimulating the pulmonary respiratory epithelial cells, etc., so as to remove the inhaled suspended particles.

[0041] In this embodiment, the required individual includes mammals, and the mammals can include humans, monkeys, mice, rats, rabbits, dogs, cats, cows, horses, pigs, sheep, etc.; it should be noted that the so-called effective dose can be calculated based on various benchmarks such as the body size, body weight, body surface area, lung lobe volume, alveolar area of various mammals. Taking the atomized dosage form as an example, the required dose can be calculated based on the lung volume of the dosing object. For example, the average lung lobe volume of a mouse is about 1 milliliter. In order to cover the alveoli and the surface of the upper respiratory tract with a sufficient amount of cyanide antidote, C57BL / 6 mice need to repeatedly inhale the composition with a dose ranging from 25 to 125 milligrams per liter (mg·L -1 ) for 1 to 2 minutes to obtain the protective or therapeutic effect. The aforementioned dose range is set considering individual differences; on the other hand, taking adult humans as an example, at least 10 to 30 milligrams of cyanide antidote need to enter the body. Adult humans need to repeatedly inhale the composition with a dose ranging from 50 to 300 milligrams per liter (mg·L -1 ) for 1 to 2 minutes to protect the upper respiratory tract from the harm of harmful substances such as cyanide and free radicals.

[0042] In terms of the timing of implementing the above-mentioned administration, taking the personnel at the fire scene as an example, if the composition is inhaled to reach an effective dose 3 to 5 minutes before entering the fire scene, it can be expected that the cyanide antidote and metal chelator will form a protective layer on the tissue surface of the upper respiratory tract, the mucosal layer, the alveolar tissue surface and other areas, and achieve protective effects such as neutralizing cyanide and blocking the generation of free radicals within the next 1 to 2 hours, thereby reducing the risk of acute poisoning or irreversible respiratory damage caused by smoke inhalation to personnel at the fire scene; similarly, workers in other potential cyanide poisoning environments can also inhale the composition as mentioned above to reach an effective dose before entering the work site, or inhale the composition within 1 to 2 hours after leaving the work site to achieve the effect of reversing cyanide poisoning.

[0043] In some specific examples, the desired individual is exposed to a cyanide environment of 50 to 500 ppm at a concentration of 25 to 125 mg / L (mg·L -1 ) dose to protect the upper respiratory tract and improve the survival rate after exposure; in other examples, the required individual is administered 25 to 125 mg / L (mg·L) before being exposed to a 180 to 460 ppm cyanide environment. -1 ) to achieve the effect of protecting the upper respiratory tract and improving the survival rate after exposure; in these examples, the upper respiratory tract composition is in the form of atomization for inhalation by the desired individual, the inhalation time is 1 to 2 minutes, and the desired individual is exposed to the cyanide environment for 1 to 45 minutes.

[0044] Several embodiments and experimental examples are listed below to more specifically illustrate the implementation methods and technical effects of the present invention, but the present invention should not be limited thereto.

[0045] Mouse survival rate test

[0046] Take a 25-liter barrel and burn the tech foam in it to generate cyanide gas. Then use a syringe to extract 50 ml of cyanide gas from the barrel and inject it into a 1250 ml empty bottle to dilute the cyanide gas. Use a detector to detect the actual concentration of cyanide in the barrel.

[0047] When the cyanide content in the bucket reaches 189.8±5.8ppm, 30 C57BL / 6 mice are placed in the bucket one after another, and then 2 liters of 95% oxygen are injected to meet the basic oxygen consumption requirements of C57BL / 6 mice; please refer to Figure 1A, which is a specific example of implementing the cyanide exposure tank in subsequent experimental examples; referring to Table 1 again, which shows the conditions of this survival rate test and the preliminary test results, and obtaining the lethal dose of cyanide for C57BL / 6 mice. In an environment with a cyanide content of 189.8 ± 5.8 ppm, after C57BL / 6 mice inhaled cyanide for 30 minutes, 45 minutes, and 60 minutes, the mice were removed from the tank after the mortality rate reached 20%, and the subsequent observed survival rates were 62.5%, 37.5%, and 0.0% respectively.

[0048] On the other hand, the survival rate of ICR mice was tested; when the cyanide content in the tank reached 302.8 ± 10.7 ppm, 41 ICR mice were successively placed into the tank, and then 2 liters of 95% oxygen was injected to meet the basic oxygen consumption requirements of ICR mice; please continue to refer to Table 1, and the lower fields show the conditions of the survival rate test and the preliminary test results, and obtain the lethal dose of cyanide for ICR mice. In an environment with a cyanide content of 302.8 ± 10.7 ppm, after ICR mice inhaled cyanide for 5 minutes, 7.5 minutes, and 10 minutes, the ICR mice were removed from the tank after the mortality rate reached 20%, and the subsequent observed survival rates were 46.7%, 37.5%, and 0.0% respectively.

[0049] Table 1

[0050]

[0051] Example 1

[0052] A composition for upper respiratory tract administration was prepared by mixing 1 ml of sterile water, 25 mg of hydroxocobalamin, and 1 mg of deferoxamine.

[0053] Example 2

[0054] A composition for upper respiratory tract administration was prepared by mixing 1 ml of sterile water, 125 mg of hydroxocobalamin, and 5 mg of deferoxamine.

[0055] Comparative Example 1

[0056] An aqueous solution of hydroxocobalamin was prepared by mixing 1 ml of sterile water and 25 mg of hydroxocobalamin.

[0057] Comparative Example 2

[0058] An aqueous solution of deferoxamine was prepared by mixing 1 ml of sterile water and 5 mg of deferoxamine.

[0059] Experimental Example 1

[0060] In Experimental Example 1, the survival of the control group and the experimental group of C57BL / 6 mice was compared after exposure to an environment with a cyanide content of 184 to 189.8 ppm for 24 to 39 minutes, and the improvement effects of the survival rates of mice treated with sterile water, Example 1, Example 2, and Comparative Example 1 were calculated respectively.

[0061] Before exposure, the mice were placed in a 1-liter bucket, and 1 ml of sterile water, Example 1, Example 2, Comparative Example 1, and Comparative Example 2 were atomized with an atomizer for the mice to inhale. Please refer to Figure 1B , which is a specific example of a mouse inhaling an aerosol; among them, the mice in the control group only inhaled atomized sterile water, while the mice in the experimental group inhaled atomized Example 1, Example 2, Comparative Example 1, and Comparative Example 2 respectively; after each mouse inhaled for 1 to 2 minutes, the mice were exposed to a cyanide-containing bucket for 45 minutes, and the mice were removed from the bucket after the mortality rate reached 20%, and observed continuously for 24 hours. The experimental results are recorded in Table 2.

[0062] As can be seen from Table 2, for C57BL / 6 mice that inhaled atomized Example 1 or Example 2, compared with the control group, their survival rates increased by 22.0% and 80.0% respectively, while for the mice that inhaled Comparative Example 1 or Comparative Example 2, their survival rates did not show any significant improvement compared with the control group.

[0063] Table 2

[0064]

[0065] Experimental Example 2

[0066] In Experimental Example 2, the survival of the control group and the experimental group of ICR mice was compared after exposure to an environment with a cyanide content of 273 to 320 ppm for 4.5 to 6 minutes, and the improvement effects of the survival rates of mice treated with sterile water, Example 1, Comparative Example 1, and Comparative Example 2 were calculated respectively.

[0067] Before exposure, the mice in the control group only inhaled atomized sterile water, while the mice in the experimental group inhaled atomized Example 1, Comparative Example 1, and Comparative Example 2 respectively. The inhalation method is the same as that in Experimental Example 1 and will not be elaborated here; after each inhaled for 1 to 2 minutes, the mice were exposed to a cyanide-containing bucket for 5 minutes, and the mice were removed from the bucket after the mortality rate reached 20%, and observed continuously for 24 hours. The experimental results are recorded in Table 3.

[0068] As can be seen from Table 3, for ICR mice that inhaled Example 1, compared with the control group, their survival rate increased by 50.0%. For ICR mice that inhaled Comparative Example 1, their survival rate only increased by 20.0% compared with the control group, while for ICR mice that inhaled Comparative Example 2, their survival rate decreased by 10.0% compared with the control group.

[0069] Table 3

[0070]

[0071]

[0072] Experimental Example 3

[0073] In Experimental Example 3, the survival of ICR mice of Example 1 after exposure to a cyanide-containing environment by intravenous injection (IV) was observed; before exposure, the control group mice were injected only with sterile water, while the experimental group mice were injected with 0.1 ml of the composition of Example 1. Subsequently, the mice were exposed to a cyanide-containing tank for 4.5 minutes. The mice were removed from the tank after the mortality rate reached 20%, and were continuously observed for 24 hours. The experimental results were recorded in Table 4; as can be seen from Table 4, the survival rate of the ICR mice of Example 1 by intravenous injection was only increased by 20% compared with the control group, which was much lower than the efficacy achieved in Experimental Example 2.

[0074] Table 4

[0075]

[0076] Experimental Example 4

[0077] In Experimental Example 4, the survival of ICR mice of Example 1 after exposure to a cyanide-containing environment by intramuscular injection (IM) was observed; before exposure, the control group mice were injected only with sterile water, while the experimental group mice were injected with 1 ml of the composition of Example 1 diluted 5-fold. Subsequently, the mice were exposed to a cyanide-containing tank for 6 minutes. The mice were removed from the tank after the mortality rate reached 20%, and were continuously observed for 24 hours. The experimental results were recorded in Table 5; as can be seen from Table 5, the survival rate of the ICR mice of Example 1 by intramuscular injection was not significantly increased compared with the control group, and the efficacy obtained in Experimental Example 2 could not be achieved either.

[0078] Table 5

[0079]

[0080] Experimental Example 5

[0081] In Experimental Example 5, the survival of the control group and the experimental group of ICR mice after exposure to an environment with a cyanide content of 460 ppm for 1 to 2 minutes was compared, and the improvement effects of the survival rates of the mice treated with sterile water and Example 1 were calculated respectively.

[0082] Before exposure, the mice in the control group only inhaled atomized sterile water, while the mice in the experimental group inhaled atomized Example 1. The inhalation method was the same as that in Experimental Example 1 and will not be elaborated here. After each group inhaled for 1 to 2 minutes, the mice were exposed to a cyanide-containing bucket for 5 minutes. After observing that the mortality rate of the mice reached 20%, the mice were removed from the bucket and continuously observed for 24 hours. The experimental results are recorded in Table 6.

[0083] As can be seen from Table 6, regardless of whether the ICR mice inhaled sterile water or Example 1, none of the mice survived 24 hours after being removed from the bucket.

[0084] Table 6

[0085]

[0086] As can be seen from the aforementioned Experimental Examples 1 to 4, the upper respiratory tract administration composition provided by the present invention, after being atomized and inhaled by mice, has achieved an improvement in the survival rate of mice exposed to a cyanide environment. Moreover, compared with only administering a cyanide antidote, the compound of a cyanide antidote and a metal chelating agent has effectively improved the survival rate of mice. In addition, only administering a metal chelating agent not only fails to improve the survival rate of mice, but also causes a decrease in the survival rate of mice after exposure to a cyanide environment, which obviously has a negative impact on the protective effect of mice in a cyanide environment. The above experiments illustrate that the upper respiratory tract administration composition provided by the present invention not only achieves a protective and therapeutic effect with a cyanide antidote, but also further significantly improves the protective and therapeutic effects of mice exposed to a cyanide environment in a compound dosage form combined with a metal chelating agent.

[0087] The composition for upper respiratory tract administration and its administration method provided by the present invention overcome the limitation of solution injection in the prior art and only need to be supplied for individual inhalation by atomization. It can not only quickly enter the individual's blood circulation, but also enable the individual to use it in general situations, fire scenes or environments with trace amounts of cyanide. Moreover, it can achieve the protection of the individual from the smoke damage at the fire scene under relatively low-dose conditions. In addition to neutralizing cyanide to prevent the user from acute hypoxia, it can also block the chain reaction after free radicals enter the human body, reduce the pressure of human peroxidation, preserve the integrity of lung tissue and the upper respiratory tract, and form a protective layer on the surface of the upper respiratory tract or alveoli to prevent harmful substances in the smoke from invading the human body. In other words, the composition provided by the present invention can be inhaled by the user in advance to protect the upper respiratory tract before exposure to a fire scene or a potential cyanide poisoning environment. After exposure to the aforementioned harmful environment, the composition provided by the present invention can quickly enter the body to achieve cyanide neutralization and the blocking of the free radical production chain, and can also promote the mucosa to expel the suspended particles contained in the smoke out of the body, taking into account the positive effects such as first aid for acute poisoning and pre-exposure prevention.

[0088] However, the above are only the preferred embodiments of the present invention and cannot be used to limit the patent protection scope of the present invention. Therefore, all simple equivalent changes and modifications made according to the claims and the content of the specification of the present invention application still fall within the patent protection scope of the present invention.

Claims

1. A composition for upper respiratory tract administration, which is used for the protection against toxic gas injuries in a fire scenario, characterized in that, It is an inhalant, comprising a cyanide antidote and a metal chelator. Among them, the cyanide antidote includes hydroxocobalamin, and the metal chelator includes deferoxamine. The inhalant includes a metered-dose inhaler, a nebulizer inhaler or a dry powder inhaler.

2. The composition according to claim 1, characterized in that, The cyanide antidote further includes cobaltic edetate, formamide, hydroxyacetamide hydrate, dinitromethanamide, methemoglobin, sodium nitrite, amyl nitrite, dimethylaminophenol, sodium thiosulfate, glutathione or any combination thereof.

3. The composition according to claim 1, characterized in that, The metal chelator further includes deferiprone, deferiphen or any combination thereof.

4. The composition according to claim 1, characterized in that, It further includes an expectorant selected from the group consisting of potassium iodide, iodinated glycerol, guaifenesin glycerol ether, guaifenesin, ambroxol, bromhexine, acetylcysteine and lysozyme.

5. The composition according to claim 1, characterized in that, It further includes a carrier, which includes ionized water, secondary water, ultrapure water or a buffer solution. Among them, the buffer solution has a buffer selected from the group consisting of phosphate, tris (hydroxymethyl) methylaminopropanesulfonic acid, diglycolylglycine, tris (hydroxymethyl) aminomethane, tris (hydroxymethyl) methylglycine, 4-(2-hydroxyethyl) piperazine-1-ethanesulfonic acid, N-tris (hydroxymethyl) methyl-2-aminoethanesulfonic acid, 3-(N-morpholino) ethanesulfonic acid, piperazine-N,N'-bis (2-ethanesulfonic acid), cacodylic acid, sodium citrate and 2-morpholinoethanesulfonic acid.

6. The composition according to claim 1, characterized in that, It is further used for the protection and treatment of potential high-concentration cyanide environment exposure.

7. Use of a composition according to any one of claims 1 to 6 in the preparation of a medicament for protecting an individual against fire injuries, characterized in that, It is administered through the upper respiratory tract. The fire injury is the injury suffered by the required individual exposed to toxic gases, and the toxic gases include cyanide.

8. The use according to claim 7, characterized in that, The toxic gases include suspended particles, free radicals or cyanide.

9. The use according to claim 7, characterized in that, The administration route of the drug includes absorption by biological fluid or mucosal absorption.

10. The use according to claim 7, characterized in that, The required individual includes mammals.

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