CN113244262A - Inhalation powder spray preparation for preventing and treating respiratory infectious diseases - Google Patents

Inhalation powder spray preparation for preventing and treating respiratory infectious diseases Download PDF

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Publication number
CN113244262A
CN113244262A CN202110163243.7A CN202110163243A CN113244262A CN 113244262 A CN113244262 A CN 113244262A CN 202110163243 A CN202110163243 A CN 202110163243A CN 113244262 A CN113244262 A CN 113244262A
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iodine
virus
cydiodine
respiratory tract
inhalation
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Inventor
姜庆伟
梁希
刘珍珍
陈丹
颜琨
甘艳秋
刘华
杨文斌
高永良
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Beijing Tianheng Junwei Pharmaceutical Technology Development Co Ltd
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Beijing Tianheng Junwei Pharmaceutical Technology Development Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/18—Iodine; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A61K31/787—Polymers containing nitrogen containing heterocyclic rings having nitrogen as a ring hetero atom
    • A61K31/79—Polymers of vinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/04—Drugs for disorders of the respiratory system for throat disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention relates to an inhalation powder spray preparation for preventing and treating respiratory infectious diseases. In particular to an inhalation preparation for preventing and treating respiratory infectious diseases, in particular to an inhalation powder spray preparation. The inhalation powder spray formulation comprises iodine molecules as an active substance and/or a pharmaceutically acceptable carrier. The powder is inhaled into respiratory tract or lung by powder mist for preventing and treating respiratory tract and lung infectious diseases, and has the advantages of direct targeting action on infected parts, rapid onset of action, small dosage and small side effect. Can quickly kill various pathogens in respiratory tract, and achieve the purposes of reducing infectivity, relieving the pain of patients, shortening the rehabilitation period, improving the cure rate, reducing complications and reducing the death rate.

Description

Inhalation powder spray preparation for preventing and treating respiratory infectious diseases
The priority of the chinese patent application (title: a dry powder inhalation formulation for the prevention and treatment of respiratory infectious diseases; application No. 2020100825781) filed on month 07, 02, 2020.
Technical Field
The present application relates to the medical field. More particularly, it relates to an inhalation powder spray preparation for preventing and treating respiratory infectious diseases, and its application in treating infectious diseases.
Background
Respiratory infectious diseases are a serious threat to human health. The disease is usually caused by pathogenic microorganisms reaching the body through respiratory tracheas such as nasal cavity, throat and trachea of people, and related infectious diseases are caused. The respiratory infectious diseases have the characteristics of rapid spread and wide spread range. Once spread, the disease is difficult to control, and seriously harms human life and health. Therefore, prevention and control of respiratory infectious diseases must be done.
With the progress and development of society, people are increasingly frequently in contact with nature and wild animals; the communication and the travel among the people are increased year by year, and the new infectious diseases are increased. This indicates that the influenza virus has an increased mutation and recombination rate. The detection of new viruses and the development of vaccines requires constant updating. The monitoring and prevention of new emerging viruses has become the most effective method for controlling new emerging infectious diseases at present.
Iodine (iododine) is a halogen element. The iodine-enriched crystal is gray black or blue black at normal temperature, has flaky or blocky crystals with metallic luster, has obvious iodine odor, is volatile, is easily soluble in organic solvents such as ethanol, ether or carbon disulfide and the like, is slightly soluble in water, and can only be dissolved by 0.33g/L at the temperature of 25 ℃. Potassium iodide has solubilizing effect on iodine and can promote its solubility, and saturated solution of iodine is acidic, irritating to skin, and has poor stability.
Since the first discovery of elemental iodine by the french pharmaceutical master coulter chart warley in 1811, iodine has been used as a disinfectant for over two more centuries. It has selective killing performance to various microbes and is excellent germicide. Iodine preparations are also commonly used drugs in the treatment of oral and throat diseases. However, iodine and its preparation are extremely unstable in physicochemical properties and have strong irritation and odor to the wound surface of oral mucosa, so that its use is limited.
For years, the clinical iodine-containing laryngopathy treating tablet has poor effect because the stability of iodine is difficult to solve by common preparations, and only iodine ions (HN) can be used4I) The medicine is used in a form. Experiments prove that the iodine-containing throat tablet only has extremely weak bactericidal effect. The iodine-glycerol preparation prepared by the prescription in hospital has certain curative effect on certain diseases of oral cavity, and has limitations in use due to high concentration, irritation to damaged mucosa and poor stability.
In order to solve the above-mentioned iodine problems, a great deal of research has been successively conducted in the development and application of iodine preparations. The disinfectant containing iodine includes iodine tincture, iodine glycerol, iodophor, etc. Organic iodine is also widely reported in medicine, such as amino acid iodine and the like, wherein iodophor and amino acid iodine make breakthrough progress, the defects of iodine such as solubility, instability, large irritation to skin mucosa, difficult color fading and the like are overcome, and good bactericidal performance of iodine is reserved.
In the early 80 s, the development and research of cydiodine were first developed in China by a team of high-perpetual researchers of the military medical academy of sciences. beta-Cyclodextrin (beta-Cyclodextrin) is used as a carrier to form a molecular state inclusion compound which is 1:1 inclusion compound of host and guest molecules with iodine, namely cydiodine (named in Chinese pharmacopoeia). Through comprehensive system research on cydiodine, the physical configuration and the crystalline state of iodine are changed, the dispersion degree of iodine is improved, the dissolution rate of iodine is obviously improved, the physical and chemical stability of iodine is improved, the cydiodine has the same high-broad-spectrum sterilization efficacy as the original iodine, the irritation and the anaphylaxis of iodine are reduced, the bad odor and the corrosivity of iodine are overcome, the powder can be combined with various medicaments, and various formulations are developed according to indications.
Elemental iodine molecules are active and more permeable than other disinfectants. The iodine kills various microorganisms mainly by the halogenation and precipitation of iodine. Iodine molecules can rapidly penetrate cell walls, and are combined with hydroxyl, amino, alkyl and sulfydryl on protein amino acid chains to cause protein denaturation and precipitation, and halogenation is carried out, so that the biological activity of the protein is lost. Iodine included by beta cyclodextrin in cydiodine releases iodine molecules under the action of water, and has the same properties and characteristics as iodine. A large number of sterilization experiments prove that the iodine has wide sterilization spectrum, can kill various microorganisms without selectivity and has no drug resistance.
Since cydiodine is a new physical phase, it can be combined with various drugs to make new preparation. The cydiodine is taken as a main active ingredient, and three new medicines are developed in sequence: iodine powder, cydiodine tablet (trade name Huasu tablet) and compound cydiodine buccal tablet (Chinese patent CN 1049099B).
The iodine powder is powder prepared by taking cydiodine as a main drug and combining the cydiodine with zinc oxide, glucose and the like. 0.5% iodine is contained, and when the iodine is spread on the wound surface, iodine molecules are rapidly released under the action of wound surface exudate and water. Can be widely used for preventing or treating various burns, wounds and other wound surfaces and resisting infection. Clinical verification on burns, wounds and the like shows that the curative effect is superior to that of silver sulfadiazine. The iodine powder obtains (89) a new medicine certificate and a production document of a wei-wei medicine certificate X-34.
Cydiodine tablet: cydiodine tablet (Huasu tablet) 1.5mg iodine/tablet is a buccal tablet made up by using cydiodine main medicine, menthol and cane sugar through a certain preparation process, and can be used for curing infective diseases of said portion by acting on the oral cavity and throat in the form of iodine molecule. When the tablet is used for buccal administration, active iodine can be rapidly released under the action of saliva to kill various microorganisms. The medicine is proved to have obvious curative effect on treating chronic pharyngitis, a plurality of oral ulcers, chronic periodontitis, gingivitis, candida albicans infectious stomatitis and other diseases, and also has exact curative effect on treating chronic oral disease erosive lichen planus. Compared with other medicines, the cydiodine tablet has broad-spectrum, high-efficiency and quick sterilization effects and does not generate drug resistance; has obvious astringing effect, and can promote the healing of the wound surface of the oral ulcer; has no toxic and side effects. Cydiodine tablet (huasu tablet) obtains (92) sanitary drug certificate character X-203 new drug certificate and production file number.
The compound cydiodine buccal tablet comprises the following components: the medicine takes iodine molecules in cydiodine as disinfectant and bactericide, and combines local anesthetic dyclonine hydrochloride (1.5mg iodine +1.0mg dyclonine/tablet). Based on the splitting and optimizing experimental results of the drug effect, the prescription and the process are determined, and the sucrose auxiliary materials are not contained. The buccal tablet can rapidly release active iodine under the action of oral saliva, sterilize, and control the infection of oral ulcer; the released dyclonine hydrochloride can be absorbed rapidly, and can achieve analgesic effect within 1-5 min. And 8, 7 and 26 in 2019, the notice of clinical trials issued by the State drug administration (TCM). The new drug has already finished the design of the phase I clinical research scheme and is formally reported to the new drug evaluation center, and after the scheme passes, the new drug is currently undergoing phase I clinical research.
In the aspect of clinical application, the iodine powder has reliable anti-infection curative effect after treating burn, has no irritation to the burn wound surface, and does not generate drug-resistant strains; the cydiodine tablet (huasu tablet) has obvious anti-infection effect on the wound surface of the oral ulcer and no stimulation to the wound surface. In addition, the eye drops of cydiodine suspension (0.2mg/ml) have good prevention and treatment effects on viral conjunctivitis (red eye disease) (CN 104055791B).
Chinese patent applications CN101396370A, CN101411691A, CN1640412A, CN1513475A, CN1596924A disclose the use of cydiodine in the treatment of oral and throat diseases. CN1634131A discloses the use of cydiodine as a disinfectant and bactericidal preparation for vaginal mucosa. CN102008398A discloses an effervescent composition containing cydiodine. CN104055792A discloses the use of cydiodine for the treatment of otitis media. CN105412012A discloses a spray for treating chronic pharyngitis with cydiodine. CN107517963A discloses a high-stability powder containing cydiodine, which comprises 1kg of iodine, 3-5kg of hydroxypropyl-alpha-cyclodextrin, 0.2-0.3kg of potassium iodide, 3-5L of 75% ethanol, 0.2-0.4kg of tween 80 and 30-80L of water.
However, there is no report on the use of active iodine molecules for the prevention and treatment of diseases associated with respiratory tract and lung diseases, particularly the use of active iodine molecules for the prevention and treatment of diseases associated with lower respiratory tract and lung infections by inhalation.
Disclosure of Invention
The inventor unexpectedly finds that the medicine containing active iodine molecules can be inhaled or sprayed into respiratory tract or lung, so as to prevent and treat respiratory tract diseases, especially respiratory tract infectious diseases. Furthermore, the powder mist is inhaled into the respiratory tract or the lung and acts on the mucosal tissue of the respiratory tract or the lung, can be used for preventing and treating respiratory tract and lung infectious diseases, and has the advantages of direct target action on the infected part, quick response, small dosage, small side effect and no drug resistance. Can quickly kill various microorganisms in the respiratory tract, including pathogens such as bacteria, viruses, fungi, chlamydia and the like, and achieves the aims of reducing infectivity, relieving the pain of a patient, shortening the rehabilitation period, improving the cure rate, reducing complications and reducing the death rate, thereby completing the application.
First, the present application provides the use of active iodine molecules for the preparation of a medicament for the prevention and treatment of respiratory diseases.
As one embodiment of the use of the present application, the respiratory disease is an infectious disease of the respiratory tract.
As one embodiment of the use of the present application, the infectious diseases of the suction tract include upper respiratory tract infections and lower respiratory tract infections. Upper respiratory tract infection including common cold, acute pharyngitis, acute laryngitis (which is a general term for inflammation of nasal cavity, pharynx or larynx); lower respiratory tract infection includes acute bronchitis, chronic bronchitis, pneumonia, and bronchiectasis.
In some embodiments, the respiratory infectious disease comprises a respiratory infectious disease caused by a pathogen such as a bacterium, a fungus (e.g., a mold), a chlamydia, a mycoplasma, a rickettsia, a virus, or the like.
Viruses that may be used in accordance with one embodiment of the present invention include influenza virus, parainfluenza virus, cytomegalovirus, adenovirus, rhinovirus, coronavirus, coxsackievirus, echovirus, herpes simplex virus, varicella-zoster virus, rubella virus, measles virus.
As an embodiment of the use of the present application, the coronavirus includes SARS, MERS, 2019-nCoV and variants thereof.
In some embodiments, the respiratory infectious disease is a respiratory and pulmonary infectious disease, including bacterial, viral, fungal infections.
As an embodiment of the use of the present application, the above use is for administering a medicament of active iodine molecules to a subject, preferably to the respiratory tract and/or lungs, by means of spraying or inhalation.
As one embodiment of the use of the present application, a medicament containing active iodine molecules is administered to a subject by inhalation to the respiratory tract and lungs. In some specific embodiments, the inhalation mode is a powder mist inhalation mode.
In some embodiments, the active iodine molecules are derived from one or a combination of: cydiodine, povidone iodine and amino acid iodine are preferably used, and have the advantages of low irritation and good stability.
According to some embodiments of the present application, there is provided a pharmaceutical composition for preventing or treating a respiratory disease comprising or consisting of:
-active iodine molecules,
-a pharmaceutically acceptable carrier.
In some embodiments, the mass ratio of the pharmaceutically acceptable carrier to the active iodine molecule is 10: 1 to 1: 10, e.g. 10: 1. 9: 1. 8: 1. 7: 1. 6: 1. 5: 1. 4: 1. 3: 1. 2: 1. 1: 1. 1: 2. 1: 3. 1: 4. 1: 5. 1: 6. 1: 7. 1: 8. 1: 9. 1: 10. or a range between any of the foregoing values; preferably, 3: 1 to 5: 1.
in some embodiments, a unit dose of the dry powder aerosol comprises 0.05mg to 5mg of the active iodine molecule (e.g., without limitation, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.5, 4.6, 4.9, 4.0, 4.5, 4.6, 4.5, 4, 4.5, or any range therebetween).
In some embodiments, the average particle size of the active iodine molecules is 10 μm or less (10, 9, 8, 7, 6, 5 μm or less) D90, preferably 5 μm or less D90.
In some embodiments, the pharmaceutically acceptable carrier has an average particle size D90 ≦ 200 μm, preferably D90 ≦ 150 μm.
In some embodiments, the pharmaceutically acceptable carrier is lactose.
In some embodiments, the pharmaceutical composition is prepared in the form of a dry powder spray.
In some embodiments, the pharmaceutical composition may be prepared as: single dose capsules, or multiple dose reservoirs.
In some embodiments, the capsule comprises hypromellose.
According to some embodiments, the present application provides the use of the above pharmaceutical composition for the prevention or treatment of respiratory diseases, said use comprising an infection of the respiratory tract or lungs selected from any one or a combination of: bacterial infection, fungal infection, and viral infection.
In the uses described herein, the virally infected virus is selected from any one or combination of: influenza virus, parainfluenza virus, cytomegalovirus, adenovirus, rhinovirus, coronavirus, coxsackievirus, echovirus, herpes simplex virus, varicella-zoster virus, rubella virus, measles virus.
In some embodiments, the coronavirus is selected from any one or a combination of: SARS, MERS, 2019-nCoV, or a variant thereof.
In a particular embodiment, the dry powder inhalation is used for the prevention or treatment of respiratory or pulmonary infections.
In a specific embodiment, the virus causing the infection is a 2019-nCoV novel coronavirus.
The present application also provides a method for preventing or treating a respiratory or pulmonary infection comprising contacting a subject with a prophylactically or therapeutically effective amount of a pharmaceutical composition or active iodine molecule of the present application.
In particular embodiments, the subject's contact time is 10min to 4 hours per administration, such as, but not limited to, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 150, 200, 210, 220, 230, 240 min.
In particular embodiments, the administration period is from 1 to 3 times daily (e.g., 1, 2, 3); or 1 to 30 times per week (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30).
According to some embodiments of the present application, there is provided a method for preparing a dry powder aerosol, comprising:
1) providing an active iodine molecule or a combination thereof selected from the group consisting of: cydiodine, povidone iodine, amino acid iodine; pulverizing to obtain pulverized product with average particle diameter D90 ≤ 10 μm (preferably D90 ≤ 5 μm);
2) providing a pharmaceutically acceptable carrier (preferably lactose) having an average particle size D90 ≦ 200 μm (preferably D90 ≦ 150 μm);
3) mixing the products obtained in the step 1) and the step 2);
4) optionally, packaging, preferably a single dose capsule or a multi-dose reservoir;
step 1) and step 2) can be interchanged in sequence or in parallel.
In a particular embodiment, the milling is carried out using a jet mill.
The lung inhalation preparation is a preparation which is introduced into deep respiratory tract, cavity and mucous membrane by a device to exert systemic or local effect. The main dosage forms in the prior art include metered dose inhalers, dry powder inhalers, and aerosol inhalers. The administration mode is mostly inhalation administration, the inhalation administration can realize effective lung targeted administration, and the required medicine amount is less than oral administration or injection administration.
Detailed Description
Preparation example 1 preparation of cydiodine
Cydiodine can be prepared by the prior art, such as Chinese patent 90106682.6, and also can be prepared by the following process:
1. cydiodine composition: 3.0g of iodine; 2.0g of potassium iodide; 12.5g of beta cyclodextrin; purified water 56.0 g.
2. Preparation process
(1) Potassium iodide was weighed, and 3 times the amount of purified water was added thereto and dissolved by stirring. Adding iodine, water bathing at 50 deg.C, stirring to dissolve, and keeping.
(2) Weighing beta-cyclodextrin, placing into a suitable container, adding 4 times of purified water, and stirring at 80 deg.C to dissolve completely.
(3) And (3) dripping the iodine solution in the step (1) into a beta cyclodextrin water solution, maintaining the water bath temperature at 80 ℃, continuously stirring for 2 hours, taking out the solution, standing for 1 day at room temperature, carrying out vacuum filtration, washing with purified water for 3 times, draining the water, scraping off coffee-colored solids, and drying in an oven at 60 ℃ to obtain the cydiodine.
Preparation example 2
1. Cydiodine inhalation powder.
TABLE 1
Composition of Content (wt.)
Cydiodine (in iodine) 0.05g
Inhalation type lactose 20.0g
2. Preparation process
(1) Pulverizing the prepared cydiodine by a jet mill, and controlling the particle size D90 to be less than 5 μm.
(2) Weighing cydiodine and lactose, mixing, and encapsulating or filling with multi-dose storage type inhalation device.
Preparation example 3
1. Cydiodine inhalation powder.
TABLE 2
Composition of Content (wt.)
Cydiodine (in iodine) 1.0g
Inhalation type lactose 20.0g
2. Preparation process
(1) Pulverizing the prepared cydiodine by a jet mill, and controlling the particle size D90 to be less than 5 μm.
(2) Weighing cydiodine and lactose, mixing, and encapsulating or filling with multi-dose storage type inhalation device.
Preparation example 4
1. Cydiodine inhalation powder.
TABLE 3
Composition of Content (wt.)
Cydiodine (in iodine) 5.0g
Inhalation type lactose 5.0g
2. Preparation process
(1) Pulverizing the prepared cydiodine by a jet mill, and controlling the particle size D90 to be less than 5 μm.
(2) Weighing cydiodine and lactose, mixing, and encapsulating or filling with multi-dose storage type inhalation device.
Preparation example 5
1. Povidone iodine inhalation powder spray.
TABLE 4
Composition of Content (wt.)
Povidone iodine (in iodine) 1.0g
Inhalation type lactose 20.0g
2. Preparation process
(1) And (3) crushing the prepared povidone iodine by using a jet mill, and controlling the particle size D90 to be less than 5 mu m.
(2) Weighing povidone iodine and lactose, mixing, and making into capsule or multiple dose storage type inhalation device.
Preparation example 6
1. Povidone iodine inhalation powder spray.
TABLE 5
Composition of Content (wt.)
Povidone iodine (in iodine) 1.0g
Inhalation type lactose 15.0g
2. Preparation process
(1) And (3) crushing the prepared povidone iodine by using a jet mill, and controlling the particle size D90 to be less than 5 mu m.
(2) Weighing povidone iodine and lactose, mixing, and making into capsule or multiple dose storage type inhalation device.
Preparation example 7
1. Cydiodine inhalation powder.
TABLE 6
Composition of Content (wt.)
Cydiodine (in iodine) 1.0g
Inhalation type lactose 19.0g
2. Preparation process
(1) Pulverizing the prepared cydiodine by a jet mill, and controlling the particle size D90 to be less than 5 μm.
(2) Weighing cydiodine and lactose, mixing, and encapsulating or filling with multi-dose storage type inhalation device.
Test example ACI (Andersen Cascade Impactor) dose of fine particles at each stage
The inhaled preparation determines that particles can reach respiratory tract parts with aerodynamic particle size, generally, particles with aerodynamic particle size less than 5 μm can be deposited in deep parts of respiratory tract and lung, but most of particles with aerodynamic particle size less than 0.5 μm are exhaled after being inhaled, and effective inhalation cannot be obtained.
The pharmaceutical composition obtained in preparation example 3 was evaluated for aerodynamic particle size of a powder inhalation preparation (specifically, a dry powder inhalation preparation) by ACI according to the method specified in chinese pharmacopoeia 2015 edition 4, having a particle size distribution in the range of 0.7 μm to 4.8 μm in the level 2-6, which is effective for deposition into the deep part of the respiratory tract and the lung, and the amount of deposition in the level 2-6 was about 0.16mg by this method.
Effect example 1 treatment of influenza Virus (H)3N2) Killing effect of
First, equipment
1. Test virus strains: influenza virus (H)3N2)。
2.9 to 11 day old white shell chick embryos, SPF grade.
3. A sample to be tested: cydiodine dry powder inhalation formulation (preparation 3) at a concentration of 5% w/w in terms of active iodine.
4. Neutralizer components and concentrations: 5g/L sodium thiosulfate.
5. Standard hard water (342 mg/L hardness).
6. Sterile normal saline.
7.96 well hemagglutination titer assay plates.
8. 1ml of sterile injector, biological safety cabinet, egg candler, paraffin, sterile equipment and the like in an incubator (humidification).
Second, method
1. The detection basis is as follows: disinfection Specification (2002 edition) items 2.1.1.10.5 and 2.1.1.10.7.
2. Virus suspension: selecting a material with the blood coagulation titer being more than or equal to 1: 640 of influenza vaccine strain (H)3N2) Suspending the solution at a constant temperature of 20 ℃ for later use.
3. And (3) identification test of a neutralizer: diluting the sample with standard hard water to obtain test solution with effective iodine content of 120mg/L and action time of 5.0min, diluting with normal saline, and inoculating 0.2ml sample solution to 4 chick embryo allantoic cavities. The test temperature was constant at 37 ℃. The experiment was repeated 3 times.
4. Virus inactivation test: diluting the sample with standard hard water to obtain test solution with effective iodine content of 120mg/L and action time of 10.0min, 15.0min and 20min, diluting with normal saline solution, and inoculating sample solution 0.2ml to 4 chick embryo allantoic cavities. The test temperature was constant at 37 ℃. The experiment was repeated 3 times.
Three, result in
1. Neutralizer identification test
The results of identifying the neutralizing agent for the test solution with an available iodine content of 120mg/L after 3 repeated tests are shown in Table 7.
TABLE 7 neutralizing agent identification results
Figure BDA0002936373800000091
2. Inactivation effect of influenza virus
After 3 times of repeated tests, the test solution of cydiodine (the effective iodine concentration is 120mg/L) is used for 15min under the constant temperature condition that the test temperature is 37 ℃, and the average inactivation logarithm value of the influenza virus is more than or equal to 4.00 (see table 8).
TABLE 8 for influenza virus (H)3N2) Inactivating effect
Figure BDA0002936373800000092
Remarking: deactivation rate is 10[ control group]-10[ test group]]/10[ control group]×100％。
Fourth, conclusion
1. After 3 times of repeated tests, the used neutralizing agent solution containing 5g/L of sodium thiosulfate can be used as a test solution with the effective iodine content of 120mg/L, and the neutralizing agent solution and the neutralization product solution have no influence on the growth of influenza virus H3N2 and chick embryos basically.
2. After 3 times of repeated tests, under the constant temperature condition of the test temperature of 37 ℃, the test solution with the effective iodine content of 120mg/L is applied to act for 15.0min, and the average inactivation logarithm value of the influenza virus H3N2 is more than or equal to 4.00 (the average inactivation rate is more than or equal to 99.99%).
Effect example 2 Effect on killing human coronavirus 229E
First, equipment
1. Test virus strains: human Coronavirus 229E (Human Coronavir 229E, VR-740).
2. Host cell: MRC-5 cells (CCL-171).
3. A sample to be tested: cydiodine dry powder inhalation formulation (preparation 3) at a concentration of 5% w/w in terms of available iodine.
4. Neutralizer components and concentrations: 5g/L sodium thiosulfate.
5. Cell culture bottles and 96-well culture plates.
6. Standard hard water (342 mg/L hardness).
7. Cell maintenance medium, cell complete medium and fetal bovine serum.
8. A thermostat, a carbon dioxide incubator, a biological safety cabinet, an adjustable pipettor and sterile equipment.
Second, method
1. The detection basis is as follows: disinfection Specification 2002 edition 2.1.1.10.5 and 2.1.1.10.7.
2. Virus suspensionPreparing liquid: the titer of the test sample is 106To 107TCID500, lml HCoV-229E virus suspension, and keeping the temperature constant at 20 ℃ for later use.
3. And (3) identification test of a neutralizer: the test sample is diluted into test solution by standard hard water, the effective iodine content is 120mg/L, the action time is 5.0min, and the test temperature is constant at 37 ℃. The trial was repeated 3 times.
4. Virus inactivation test: the test sample is diluted into test solution with standard hard water, the effective iodine content is 120mg/L, the action time is l0.0min, 15.0min and 20.0min, and the test temperature is constant at 37 ℃. The experiment was repeated 3 times.
Three, result in
1. Neutralizer identification test
After 3 times of repeated tests, the identification result of the test solution neutralizer with the effective iodine content of 120mg/L under the constant temperature test condition at 37 ℃ is shown in Table 9.
TABLE 9 neutralizing agent identification results
Figure BDA0002936373800000101
2. Inactivation effect on coronavirus
After 3 times of repeated tests, under the condition of constant temperature test at 37 ℃, the test solution containing 120mg/L of effective active iodine is applied for 15.0min, and the average inactivation logarithm value of the coronavirus is more than or equal to 4.00 (see table 10).
TABLE 10 inactivation of human coronavirus 229E strain
Figure BDA0002936373800000102
Note: negative control cells grew well without cytopathic effects.
Remarking: deactivation rate is 10[ control group]-10[ test group]]/10[ control group]×100％。
Fourth, conclusion
1. After 3 times of repeated tests, the used sodium thiosulfate neutralizing agent solution containing 5g/L can effectively neutralize the residual action of the test solution with the effective iodine content of 120mg/L on the human coronavirus 229E strain, and the neutralizing agent and a neutralized product have no influence on the growth of the human coronavirus 229E strain and cells.
2. After 3 repeated tests, under the condition of a constant temperature test at 37 ℃, the test solution with the effective iodine content of 120mg/L is applied to act for 15.0min, and the average inactivation log value of the human coronavirus 229E strain is more than or equal to 4.00 (the average inactivation rate is more than or equal to 99.99%).
Effect example 3 Effect on killing adenovirus type 5
First, introduction
According to the characteristics of the application of cydiodine, a cydiodine dry powder inhalation preparation (preparation example 3) is prepared for a representative respiratory virus: study of the inactivation efficiency of adenovirus type 5 (ATCCVR-5).
The experimental method is mainly based on the Disinfection technical Specification 2002 edition.
The study content mainly includes the following 4 sections.
(l) Cydiodine dry powder inhalation formulation (25 ℃, 120 μ g/ml), neutralization agent identification test for adenovirus inactivation.
(2) The inactivation effect of the cydiodine dry powder inhalation preparation (25 ℃, 120 mu g/ml) on adenovirus is tested under the condition of 37 ℃ and acting for different times (2.5min, 5.0min, 10.0min, 15.0min and 30.0 min).
(3) The inactivation effect of the cydiodine dry powder inhalation preparation (25 ℃, 120 mu g/ml) on adenovirus is tested under the condition of 20 ℃ and different acting times (2.5min, 5.0min, 10.0min, 15.0min and 30.0 min).
(4) When cydiodine dry powder is inhaled into the preparation (25 ℃, 60 mu g/ml), the inactivation effect of the cydiodine dry powder on adenovirus is tested under the condition of 37 ℃ for different times (2.5min, 5.0min, 10.0min, 15.0min and 30.0 min).
Secondly, study on adenovirus inactivation effect
(I) apparatus
1. Test virus strains: adenovirus type 5.
2. Host cell: a549 cells.
3. Sample name and major components and contents: cydiodine dry powder inhalation formulation (preparation example 3), available iodine content 5% w/w.
4. Neutralizer components and concentrations: 5g/L sodium thiosulfate.
5. Cell culture bottles and 96-well culture plates.
6. Standard hard water (342 mg/L hardness).
7. Cell maintenance medium, cell complete medium and fetal bovine serum.
8. A thermostat, a carbon dioxide incubator, a biological safety cabinet, an adjustable pipettor and sterile equipment.
(II) method
1. The detection basis is as follows: disinfection Specification 2002 edition 2.1.1.10.5 and 2.1.1.10.7.
2. Preparation of virus suspension: the titer of the test sample is 106To 107TCID500.1ml of Adv5 virus suspension, and keeping the temperature constant at 20 ℃ for later use.
3. Preparation of a test solution: a proper amount of cydiodine dry powder inhalation preparation is weighed and dissolved in 100ml of sterile distilled water to prepare test solution with the effective iodine content of 120 mu g/ml.
4. And (3) identification test of a neutralizer: the cydiodine dry powder inhalation preparation is selected from water solution (25 ℃, 120 mu g/ml), the action time is 2.5min, and the test temperature is constant at 37 ℃. The experiment was repeated 3 times.
5. Virus inactivation test:
(1) test groups: adding 0.8ml of test solution with the concentration to be measured into a sterile test tube, acting in a thermostat at 25 ℃/30 ℃ for 5min, adding 0.2ml of virus suspension, immediately mixing uniformly and timing. Taking out 0.11ml immediately after 2.5min, 5min, 10min, 15min and 30min, adding into a test tube containing 0.9ml of neutralizer solution, mixing, neutralizing for 10min, diluting with cell maintenance culture medium, sucking sample liquid, inoculating onto monolayer cell culture plate, and inoculating into 4 wells per titer.
(2) Positive control group: sterile deionized water is used for replacing test solution, virus suspension is added according to the specified steps of the test group for test and culture, and whether the virus grows well or not is observed.
(3) Negative control group: complete medium without virus was used as a negative control, and whether the medium used was contaminated or not and whether the cells grew well or not was observed. The experiment was repeated 3 times.
6. Calculation of the results:
the average log inactivation value was calculated as follows: mean virus infection Titer (TCID) of positive (virus) control group50Or pfu) is N0Mean viral infectious Titer (TCID) in test (Disinfection) groups50Or pfu) is Nx.
Mean log N of inactivation0-log Nx
Deactivation rate is 10[ control group]-10[ test group]]/10[ control group]×100％。
(III) results
1. Neutralizer identification test
After 3 repeated tests, the result of identifying the neutralizer of the test solution using the cydiodine dry powder inhalation preparation (effective iodine concentration of 120 mug/ml) under the constant temperature test condition at 37 ℃ is shown in Table 11.
TABLE 11 neutralizing agent identification test results
Figure BDA0002936373800000121
2. Virus inactivation assay
2.1. After 3 repeated experiments, the test solution of cydiodine dry powder inhalation preparation (effective iodine concentration 120 mug/ml) is applied for a certain time under the constant temperature test condition of 37 ℃, and the inactivation log value of adenovirus type 5 is as follows (see table 12).
TABLE 12 inactivation effect of test solutions (120. mu.g/ml) on adenovirus type 5 (37 ℃ C. constant temperature test conditions)
Figure BDA0002936373800000131
2.2. After 3 repeated experiments, the test solution of cydiodine dry powder inhalation preparation (effective iodine concentration 120 mug/ml) is applied for a certain time under the condition of a constant temperature test at 20 ℃, and the inactivation log value of adenovirus type 5 is as follows (see table 13).
TABLE 13 inactivation effect of test solutions (120. mu.g/ml) on adenovirus type 5 (20 ℃ C. constant temperature test conditions)
Figure BDA0002936373800000132
2.3. After 3 repeated experiments, the test solution of cydiodine (with effective iodine concentration of 60 mug/ml) is applied for a certain time under the constant temperature test condition of 37 ℃, and the inactivation log value of adenovirus type 5 is as follows (see table 14).
TABLE 14 inactivation effect of test solutions (60. mu.g/ml) on adenovirus type 5 (37 ℃ C. constant temperature test conditions)
Figure BDA0002936373800000133
Third, conclusion
1. After 3 times of repeated tests, the test solution (with the effective iodine concentration of 120 mu g/ml) containing 5g/L of sodium thiosulfate neutralizer solution can effectively neutralize the residual action of the test solution of the cydiodine dry powder inhalation preparation on adenovirus type 5, and the neutralizer and the neutralized product have no influence on the growth of adenovirus type 5 and cells.
2. After 3 repeated experiments, the test solution (the effective iodine concentration is 120 mug/ml) of the cydiodine dry powder inhalation preparation is applied for 30.0min under the constant temperature test condition of 37 ℃, and the average inactivation logarithm value of adenovirus type 5 is 2.49 (the average inactivation rate is 99.68%).
3. After 3 repeated experiments, the test solution (the effective iodine concentration is 120 mug/ml) of the cydiodine dry powder inhalation preparation is applied for 30.0min under the condition of a constant temperature test at 20 ℃, and the average inactivation logarithm value of the adenovirus type 5 is 1.59 (the average inactivation rate is 97.43%).
4. After 3 repeated experiments, the test solution (with effective iodine concentration of 60 mug/ml) of the cydiodine dry powder inhalation preparation is applied for 30.0min under the constant temperature test condition of 37 ℃, and the average inactivation logarithm value of adenovirus type 5 is 0.99 (the average inactivation rate is 89.77%).
5. Negative control cells grew well without cytopathic effects.
Effect example 4 Effect study on killing of bacterial propagules (Disinfection Standard Strain)
1 materials and subgroups
1.1 Experimental sample: cydiodine dry powder inhalation formulation (preparation 3) at a concentration of 5% w/w in terms of active iodine.
1.2 neutralizing agent: 0.01M sodium thiosulfate (national group, chemical purity).
1.3, enrichment of bacteria liquid: thioglycollate medium.
1.4 viable count plate: one day prior to the experiment, a sufficient number of TSA plates were prepared and placed upside down in a safety cabinet at room temperature.
1.5 dilution: 0.85% -0.90% of normal saline.
1.6 blank sample: the test sample and the cydiodine dry powder inhalation preparation do not contain cydiodine, and the other components are the same as the test sample and the cydiodine dry powder inhalation preparation.
2 method of experiment
2.1 preparation of bacterial suspension: selecting frozen strain, activating strain according to standard requirement, selecting 3 rd generation lawn, inoculating into 5ml thioglycollate culture tube, incubating for about 18 hr, diluting with normal saline, and preparing into bacterial suspension with concentration of 108cfu/ml-107cfu/ml。
2.2, preparing a liquid medicine: taking a proper amount of cydiodine dry powder inhalation preparation, dissolving in sterile distilled water to prepare 50mg/L liquid medicine, and then respectively diluting into tubes with different concentrations of 25mg/L, 10mg/L and the like, wherein each tube contains 10 ml; a blank sample was taken in the same manner and dissolved in sterile distilled water at 10ml per tube.
2.3 Sterilization test: adding 1ml of the bacterial suspension into test tubes containing 10ml of each medicament respectively, mixing uniformly, and carrying out water bath at 37 ℃. The drug-containing test solution is sampled when acting 2', 4', 6', 8' and 10', the blank sample is sampled when acting 10', 0.5ml of each sample is quickly placed in a test tube of 4.5ml of 0.01M sodium thiosulfate for neutralization for a plurality of minutes, and then diluted by a plurality of tubes by 10 times of physiological saline in an incremental and subtractive way.
2.4 viable count: the number of viable bacteria was counted by dropping 20. mu.l of Schroe's medium on plates 5 drops per plate, by the "drop counting" method, operating on Schroe's Guangdong wave method (< modern disinfections > P96).
2.5 calculation of kill rate:
Figure BDA0002936373800000151
3 results of the experiment
Quantitative sterilization tests are respectively carried out on 3 bacterial propagules comprising staphylococcus aureus (ATCC6538), escherichia coli (8099) and pseudomonas aeruginosa (ATCC15442), the quantitative sterilization tests are repeated for 3 times, and the average killing rate is calculated, which is as follows:
3.1 average kill rate of Staphylococcus aureus
Table 15 average kill (%) for staphylococcus aureus (ATCC6538) (n ═ 3)
Figure BDA0002936373800000152
3.2 average kill rate of Escherichia coli
Table 16. average killing rate (%) of escherichia coli (8099) (n ═ 3)
Figure BDA0002936373800000153
3.3 average killing rate of Pseudomonas aeruginosa
TABLE 17 average kill (%) for Pseudomonas aeruginosa (n ═ 3)
Figure BDA0002936373800000154
Effect example 5 Effect on killing of aerobic bacteria
1 materials and subgroups
1.1 Experimental sample: cydiodine dry powder inhalation formulation (preparation 3) at a concentration of 5% w/w in terms of available iodine.
1.2 neutralizing agent: 0.01M sodium thiosulfate (national group, chemical purity).
1.3, enrichment of bacteria liquid: Todd-Hewitt Broth (oxoid, CM 0189).
1.4 viable count plate: blood agar plates (PBOOI, Luqiao, Beijing).
1.5 dilution: 0.85% -0.90% of normal saline.
1.6 blank sample: the test sample and the cydiodine dry powder inhalation preparation do not contain cydiodine, and the other components are the same as the test sample and the cydiodine dry powder inhalation preparation.
2 method of experiment
2.1 preparation of bacterial suspension: freezing and storing strain of beta hemolytic streptococcus (CMCC 32210), activating strain according to standard requirement, taking 3 rd generation lawn, inoculating into 3ml Todd-Hewitt broth, incubating at 37 deg.C for about 18-24h, diluting with normal saline, and preparing into bacterial suspension with concentration of 108-107 cfu/ml.
2.2, preparing a liquid medicine: the same as in effect example 4.
2.3 Sterilization test: adding 1ml of the bacterial suspension into a test tube containing 10ml of each medicament, uniformly mixing, and carrying out water bath at 37 ℃. Adding 1ml of the bacterial suspension into test tubes containing 10ml of each medicament respectively, mixing uniformly, and carrying out water bath at 37 ℃. The drug-containing test solution is sampled when acting 2', 4', 6', 8' and 10', the blank sample is sampled when acting 10', 0.5ml of each sample is quickly placed in a test tube containing 4.5ml of 0.01M sodium thiosulfate for neutralization for a plurality of minutes, and then diluted by a plurality of tubes by 10 times of physiological saline in an incremental and subtractive way.
2.4 viable count: the number of viable bacteria was counted by tapping 20. mu.l of Schroe's medium with a syringe (5 drops per plate) according to Schroe's method of broad-wave (< modern disinfectometry > P96).
2.5 calculation of kill rate:
Figure BDA0002936373800000161
3. results of the experiment
Quantitative bactericidal test is carried out on the oxygen demand of beta hemolytic streptococcus (CMCC 32210), the test is repeated for 3 times, and the average killing rate is calculated, and the method specifically comprises the following steps:
table 18 average killing rate (%) of b hemolytic streptococcus (CMCC33210) (n ═ 3)
Figure BDA0002936373800000162
Effect example 6 study on the killing Effect of anaerobic bacteria
1 materials and subgroups
1.1 Experimental sample: cydiodine dry powder inhalation formulation (preparation 3) at a concentration of 5% w/w in terms of available iodine.
1.2 neutralizing agent: 0.01M sodium thiosulfate (national group, chemical purity).
1.3, enrichment of bacteria liquid: anaerobic liquid medium (CM 1513, Luqiao, Beijing).
1.4 viable count plate: anaerobic agar (Beijing Luqiao, CM1514) + 5% sheep blood (Beijing Luqiao, P-62).
1.5 dilution: 0.85% -0.90% of normal saline.
1.6 liquid paraffin: steam sterilizing at 121 deg.C for 15min, and isolating air for anaerobic bacteria culture.
1.7 anaerobic culture equipment: MGC 2.5L sealed anaerobic culture box (Mitsubishi gas as the same reference) MGC 7.0L sealed anaerobic culture box (Mitsubishi gas) MGC anaerobic gas bag (Mitsubishi gas in Japan) MGC anaerobic indicator (Mitsubishi gas in Japan).
1.8 blank sample: the test sample and the cydiodine dry powder inhalation preparation do not contain cydiodine, and the other components are the same as the test sample and the cydiodine dry powder inhalation preparation.
2 method of experiment
2.1 preparation of bacterial suspension: taking each freeze-dried anaerobic bacterium spawn tube, activating the spawn according to the standard requirement, taking the 3 rd generation lawn, inoculating the lawn into a 5ml anaerobic liquid culture tube which is boiled in boiling water for 10min and rapidly cooled, covering a layer of sterile paraffin oil to isolate oxygen, and incubating for about 18-24h at 37 ℃.
2.2, preparing a liquid medicine: the same as in effect example 4.
2.3 Sterilization test: adding 1ml of the bacterial suspension into a test tube containing 10ml of each medicament, uniformly mixing, and carrying out water bath at 37 ℃. Adding 1ml of the bacterial suspension into test tubes containing 10ml of each medicament respectively, mixing uniformly, and carrying out water bath at 37 ℃. The drug-containing test solution is sampled when acting 2', 4', 6', 8' and 10', the blank sample is sampled when acting 10', 0.5ml of each sample is quickly placed in a test tube containing 4.5ml of 0.01M sodium thiosulfate for neutralization for a plurality of minutes, and then diluted by a plurality of tubes by 10 times of physiological saline in an incremental and subtractive way.
2.4 viable count: the number of viable bacteria was counted by tapping 20. mu.l of Schroe's medium with a syringe (5 drops per plate) according to Schroe's method of broad-wave (< modern disinfectometry > P96).
2.5 calculation of kill rate:
Figure BDA0002936373800000171
3. results of the experiment
Quantitative bactericidal tests are carried out on three anaerobic bacteria such as fusobacterium necrophorum (ATCC25286), anaerobic streptococcus digestus (ATCC27337) and porphyromonas saccharolytica (ATCC 25260), and the tests are repeated for 3 times respectively, and the average killing rate is calculated as follows:
3.1 average killing rate of Fusobacterium necrophorum
TABLE 19 average killing rate (%) of Fusobacterium necrophorum (ATCC25286) (n-3)
Figure BDA0002936373800000181
3.2 average kill Rate of anaerobic digestion Streptococci
TABLE 20 average kill (%) of anaerobically digested Streptococcus (ATCC27337) (n ═ 3)
Figure BDA0002936373800000182
3.3 average killing rate of non-saccharolytic Porphyromonas
TABLE 21 average killing rate (%) of non-saccharoporphyromonas saccharolytica (n ═ 3)
Figure BDA0002936373800000183
Effect example 7 Effect study on bacterial spore killing
1 materials and subgroups
1.1 Experimental sample: cydiodine dry powder inhalation formulation (preparation 3) at a concentration of 5% w/w in terms of available iodine.
1.2 neutralizing agent: 0.01M sodium thiosulfate (national group, chemical purity).
1.3, enrichment of bacteria liquid: thioglycollate medium (Beijing Luqiao).
1.4 viable count plate: one day prior to the experiment, a sufficient number of TSA plates were prepared and placed upside down in a safety cabinet at room temperature.
1.5 dilution: 0.85% -0.90% of normal saline.
1.6 blank sample: the test sample and the cydiodine dry powder inhalation preparation do not contain cydiodine, and the other components are the same as the test sample and the cydiodine dry powder inhalation preparation.
2 method of experiment
2.1 preparation of bacterial suspension: collecting Bacillus anthracis (8008) spore liquid, diluting with normal saline, and making into bacterial suspension with concentration of 108cfu/ml-107cfu/ml。
2.2, preparing a liquid medicine: the same as in effect example 4.
2.3 Sterilization test: adding 1ml of the bacterial suspension into a test tube containing 10ml of each medicament, uniformly mixing, and carrying out water bath at 37 ℃. Adding 1ml of the bacterial suspension into test tubes containing 10ml of each medicament respectively, mixing uniformly, and carrying out water bath at 37 ℃. The drug-containing test solution is sampled when acting 2', 4', 6', 8' and 10', the blank sample is sampled when acting 10', 0.5ml of each sample is quickly placed in a test tube containing 4.5ml of 0.01M sodium thiosulfate for neutralization for a plurality of minutes, and then diluted by a plurality of tubes by 10 times of physiological saline in an incremental and subtractive way.
2.4 viable count: the number of viable bacteria was counted by tapping 20. mu.l of Schroe's medium with a syringe (5 drops per plate) according to Schroe's method of broad-wave (< modern disinfectometry > P96).
2.5 calculation of kill rate:
Figure BDA0002936373800000191
3. results of the experiment
Quantitative sterilization test is carried out on bacillus anthracis spore (8008), the test is repeated for 3 times, and the average killing rate is calculated as follows:
TABLE 22 average killing rate (%) of Bacillus anthracis (n ═ 3)
Figure BDA0002936373800000192
Effect example 8 investigation of antifungal Effect
1 materials and subgroups
1.1 Experimental sample: cydiodine dry powder inhalation formulation (preparation 3) (5% w/w in terms of available iodine content).
1.2 neutralizing agent: 0.01M sodium thiosulfate (national group, chemical purity).
1.3, enrichment of bacteria liquid: sandcastle broth.
1.4 viable count plate: safburg agar.
1.5 dilution: sterile purified water.
1.6 liquid paraffin: steam sterilizing at 121 deg.C for 15min, and isolating air for anaerobic bacteria culture.
1.7 anaerobic culture equipment: MGC 2.5L sealed anaerobic culture box (Mitsubishi gas as the same reference) MGC 7.0L sealed anaerobic culture box (Mitsubishi gas) MGC anaerobic gas bag (Mitsubishi gas in Japan) MGC anaerobic indicator (Mitsubishi gas in Japan).
2 method of experiment
2.1 preparation of bacterial suspension: taking each freeze-dried fungus strain tube, activating strains according to the standard requirements, taking 3 rd generation lawn, inoculating the lawn in the sandcastle broth, and incubating at 28 ℃ for about 18-24 hours; diluting with pure water to obtain bacterial suspension with concentration of 108cfu/ml-107cfu/ml。
2.2, preparing a liquid medicine: cydiodine dry powder inhalation preparation (5% w/w based on active iodine content) is dissolved in 30ml of sterile distilled water respectively to prepare liquid medicine with the concentration of 50mg/L, 100mg/L, 200mg/L, 400mg/L and 800mg/L respectively based on active iodine.
2.3 determination of minimum inhibitory concentration: the test was carried out in a 20 ℃ water bath using the broth dilution method. 2.5ml of the above liquid medicine with different gradient concentrations was added to a double concentration Sabouraud's broth containing 2.5 ml. Then adding 0.1ml of bacterial suspension with the bacterial content of about 108cfu/ml, and uniformly mixing to obtain an experimental group sample; meanwhile, a positive control and a negative control are set. The cells were incubated at 37 ℃ for 24 hours and the results were observed.
When the positive control had bacteria growth (turbidity) and the negative control had no bacteria growth (transparency), the effective iodine concentration of the test suspension was 5X 105cfu/ml-5×106At cfu/ml, the concentration of disinfectant contained at the lowest dilution at which the experimental group grew aseptically was taken as the MIC value of the corresponding test bacterium, and all experiments were repeated 3 times.
3. Results of the experiment
The minimum inhibitory concentration tests of candida albicans (ATCC 10231) and aspergillus niger (ATCC 16404) were performed, each repeated 3 times, and the average minimum inhibitory concentration was calculated as follows:
3.1 the minimum inhibitory concentration of candida albicans is (n is 3): 350 mg/L.
3.2 the minimum inhibitory concentration of aspergillus niger is (n is 3): 400 mg/L.
Effect example 9 local irritation study by inhalation
The purpose is as follows:
according to the technical guidelines for drug irritation, allergy and hemolysis, SD rats were observed to continuously inhale the dry cydiodine powder inhalation formulation (preparation example 3), and the local irritation response of the test substance to the respiratory system was observed, and the inhalation irritation of the test substance was determined by histopathological examination.
The method comprises the following steps:
SD rats are used in the test, 3 dose groups are set in the test, wherein the dose groups are 5mg/L, 2.5mg/L and 0.5mg/L respectively, a blank control group is 1 group, 4 groups are totally used, 10 animals are used in each sex group, and 80 animals are totally used in each sex group. The test samples were generated by a generator and mixed with clean air, inhaled into a nasal exposure device for administration, and the animals were continuously administered for 7 days with continuous exposure for 4h each day. The gas concentration and exposure environmental parameters of the test sample are monitored during the administration process. Surviving animals were subjected to body weight determination on the day of administration (D0) and D6, respectively. Animals were subjected to clinical observation once a day after dosing was completed. Respectively taking 5 males and females in each group for general dissection 4h and 24h after last administration, observing whether congestion, red swelling and other phenomena of mucous membranes of tissues and organs and parts of respiratory tract (nasal cavity, larynx, trachea, bronchus and lung) of oral cavity, pharynx and esophagus exist, and carrying out further pathological examination on the tissues and organs and tissues of oral cavity mucous membranes, pharynx, larynx, nasal cavity, esophagus, trachea and lung (including bronchus) which are found to be abnormal.
As a result:
the gas concentration of the test sample remains relatively stable during exposure, and the temperature, humidity, oxygen and carbon dioxide contents of the exposure environment do not exceed the target ranges. All animals were observed to be uninnormal and to grow normally during the test period, with no apparent weight loss.
At the end of the observation period, 4h, 24h after the last dose, gross anatomical examination of the animals: the mucous membranes of local respiratory tract (nasal cavity, larynx, trachea, bronchus and lung) oral cavity, pharynx and esophagus have no congestion, red swelling and other phenomena, and abnormal tissue changes are not seen in body surface and natural cavity examination (ear cavity, perianal cavity, chest cavity, nasal cavity, urethral orifice, pelvic cavity, oral cavity, abdominal cavity, cranial cavity and body surface) and animal organ examination (heart, liver, lung, kidney, spleen, adrenal gland, thymus, digestive tract, gastrointestinal tract and the like). Histopathological examination showed no pathological changes in the lungs, bronchi, trachea, esophagus, throat, oral cavity and nasal cavity.
And (4) conclusion:
under the test condition, SD rats continuously inhale the cydiodine dry powder inhalation preparation for 7 days, inhale for 4 hours every day, and the inhalation concentrations are respectively 5mg/L, 2.5mg/L and 0.5mg/L, and no obvious tissue and pathology changes are seen, which indicates that the inhalation preparation has no irritation to the respiratory system.
Compared with the scheme of preventing and treating respiratory tract and lung infectious diseases in the prior art, the invention has the advantages that:
1. the traditional Chinese medicine composition is inhaled into respiratory tract or lung, is used for preventing and treating respiratory tract and lung infectious diseases, has the advantages of direct targeting action on infected parts, quick response, small dosage, small side effect and no drug resistance.
2. Can quickly kill various microorganisms in respiratory tract, including pathogens such as bacteria, viruses, fungi, chlamydia and the like, and achieves the purposes of reducing infectivity, relieving the pain of patients, shortening the rehabilitation period, improving the cure rate, reducing complications and reducing the death rate.

Claims (9)

1. Use of active iodine molecules in the preparation of a dry powder for the prevention or treatment of respiratory diseases;
preferably, the respiratory disease is a respiratory infectious disease;
the respiratory infectious diseases are selected from: upper respiratory tract infection, lower respiratory tract infection;
the upper respiratory tract infection is selected from: common cold, acute pharyngitis, acute laryngitis;
the lower respiratory tract infection is selected from: acute bronchitis, chronic bronchitis, pneumonia, bronchiectasis.
2. The use according to claim 1, wherein the infectious disease of the respiratory tract is an infectious disease of the respiratory tract caused by a pathogen selected from the group consisting of: bacteria, fungi, chlamydia, mycoplasma, rickettsia, viruses;
preferably, the virus is selected from: influenza virus, parainfluenza virus, cytomegalovirus, adenovirus, rhinovirus, coronavirus, coxsackievirus, echovirus, herpes simplex virus, varicella-zoster virus, rubella virus, measles virus;
more preferably, the coronavirus is selected from the group consisting of: SARS, MERS, 2019-nCoV.
3. The use of claim 1, wherein the dry aerosol is suitable for administration of the active iodine molecule to a subject by spraying or inhalation;
preferably, the dry powder inhalation is suitable for administering the active iodine molecule to the respiratory tract and/or lungs of a subject by inhalation;
more preferably, the dry aerosol is suitable for administration of the active iodine molecule to the respiratory tract and/or lungs of a subject by means of dry aerosol inhalation.
4. Use according to any one of claims 1 to 3, the active iodine molecules being derived from one or a combination of: cydiodine, povidone iodine, amino acid iodine.
5. A pharmaceutical composition for preventing or treating a respiratory disease, comprising:
-active iodine molecules, and
-a pharmaceutically acceptable carrier, wherein the carrier is a pharmaceutically acceptable carrier,
wherein the content of the first and second substances,
the mass ratio of the pharmaceutically acceptable carrier to the active iodine molecules is 10: 1 to 1: 10, preferably 3: 1 to 5: 1;
preferably, the pharmaceutically acceptable carrier is lactose;
preferably, the pharmaceutically acceptable carrier has a particle size D90 ≦ 200 μm, more preferably D90 ≦ 150 μm;
preferably, the active iodine molecules are derived from one or a combination of: cydiodine, povidone iodine, amino acid iodine, preferably cydiodine.
6. The pharmaceutical composition according to claim 5, which is a powder aerosol and has an average particle size distribution of active iodine molecules of D90 ≤ 10 μm, preferably D90 ≤ 5 μm.
7. The pharmaceutical composition according to claim 5 or 6, prepared as a single dose capsule, or as a multi-dose reservoir;
preferably, the capsule comprises hypromellose;
preferably, the single dose comprises 0.05mg to 5mg of active iodine molecule.
8. Use of a pharmaceutical composition according to any one of claims 5 to 7 for the preparation of a medicament for the prevention or treatment of infectious diseases of the respiratory tract, wherein:
the respiratory infectious disease is a respiratory infectious disease caused by a pathogen selected from the group consisting of: bacteria, fungi, chlamydia, mycoplasma, rickettsia, viruses;
preferably, the virus is selected from: influenza virus, parainfluenza virus, cytomegalovirus, adenovirus, rhinovirus, coronavirus, coxsackievirus, echovirus, herpes simplex virus, varicella zoster virus, rubella virus, measles virus;
more preferably, the coronavirus is selected from the group consisting of: SARS, MERS, 2019-nCoV.
9. A preparation method of a powder spray comprises the following steps:
1) providing an active iodine molecule or a combination thereof selected from the group consisting of: cydiodine, povidone iodine, amino acid iodine; pulverizing to make average particle diameter D90 not more than 10 μm;
2) providing a pharmaceutically acceptable carrier; preferably, the pharmaceutically acceptable carrier is lactose; the average particle size D90 of the pharmaceutically acceptable carrier is not less than 200 mu m, and more preferably, D90 is not less than 150 mu m;
3) mixing the products obtained in the step 1) and the step 2);
4) optionally, packaging the mixture obtained in step 3); preferably in single dose capsules or multi-dose reservoirs;
step 1) and step 2) can be interchanged in sequence or in parallel;
preferably, the pulverization is carried out by a jet milling method;
preferably, the capsule comprises hypromellose;
preferably, the single dose comprises 0.05mg to 5mg of active iodine molecule.
CN202110163243.7A 2020-02-07 2021-02-05 Inhalation powder spray preparation for preventing and treating respiratory infectious diseases Pending CN113244262A (en)

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