Life Science-Related Patent Information
Title: Patent Gazette (B2)_ Preparations for tissue repair or regeneration
Application Number: 2008549197
Year: 2013
IPC Classification: A61K 33/00,A61K 9/12,A61P 1/02
Patent Information Cache
MANO Yoshihiro Arakawa Shinichi CHIBA Kanao JP 5255451 Patent Gazette (B2) 20130426 2008549197 20071210 Preparations for tissue repair or regeneration National University Corporation Tokyo Medical and Dental University 504179255 REO Research Institute Co., Ltd. 503357735 Masahiro Nanjo 100113376 Seta Ayako 100132942 MANO Yoshihiro Arakawa Shinichi Chiba Kaneo JP 2006334203 20061212 20130807 A61K 33/00 20060101AFI20130718BHJP A61K 9/12 20060101ALI20130718BHJP A61P 1/02 20060101ALI20130718BHJP JPA61K33/00A61K9/12A61P1/02 A61K 33／00 A61K 9／12 A61P 1／02 CA/MEDLINE/EMBASE/BIOSIS(STN) JSTPlus/JMEDPlus/JST7580(JDreamII) WO 2006/051542(WO,A1) WO 05/084786(WO,A1) WO 05/084718(WO,A1) JP-2005-342030(JP,A) JP-62-213752(JP,A) JP-A-07-010762(JP,A) Onaga T. et al,Development of a New Apparatus for Dental Plaque Removal Using Microbubbles,Proceedings of the Fluid Engineering Division of the Japan Society of Mechanical Engineers, October 28, 2006, Vol.84th,808 5 JP2007001375 20071210 WO2008072370 20080619 10 20101104 Fumihiko Kato The present invention relates to tissue repair or regeneration formulations suitable for the treatment or prevention of various diseases and trauma accompanied by tissue changes such as damage and degeneration. Due to various diseases and trauma, tissues undergo abnormal changes such as damage and degeneration. If it is possible to obtain a drug that can promptly repair or regenerate such abnormally altered tissue, it is considered to be very suitable for the treatment or prevention of various diseases and trauma. For example, stomatitis is a general term for inflammation that develops in the oral mucosa, and it can be said that it is an abnormal change in the oral mucosal tissue. When these inflammations become severe, they are accompanied by pain and bleeding, and it becomes a serious problem for the patient, such as difficulty in feeding food, so it is desirable to treat it at an early stage. AAfterta, which is a typical lesion of stomatitis, is a circular to oval shape in the oral mucosa, in an inflammatory phase with a clear boundary of size up to the size of a flat bean, has a flush red on the periphery and a white to yellow pseudomembrane on the surface, and is a lesion with strong pain. Causes include bacterial infections, immune abnormalities, nutritional disorders, gastrointestinal disorders, and the like, but in recent years in particular, mental stress and changes in the environment are also considered to be one of the main causes. It usually heals completely in about a month, but there are cases where it recurs, and if it can be repeated many times, recurrent aphtha (recurrent aphtha; habitulle aphtha), which is actually the most common stomatitis. Aphtha is considered irregularly dominantly hereditary, is common in nervous people, and is the most common of oral mucosal diseases with a prevalence of as high as 10%. There is no difference between men and women, the etiology is unknown, but it is provoked by a slight external stimulus. One aphtha heals without becoming scarred in 10 days to 2 weeks (in rare cases it may last more than 1 month), but there are severe contact pain and irritating pain, the pain lasts at least 4 to 7 days, and when it becomes severe, fever, swelling of the cervical lymph nodes, fatigue, etc. also appear. As a conventional treatment method of afta, as described above, symptomatic treatment that relieves pain until afterta heals naturally is centered. FFor example, anesthetics such as diclonine and lidocaine are prescribed as innuendotes, coatings. In addition, for the purpose of protecting the afterthought and temporarily soothing pain due to the anti-inflammatory action, ointments for stomatitis containing corticosteroids (triamcinolone, betamethasone, etc.) may be prescribed. In addition, when a plurality of after-effects have developed, a satirical agent containing tetracycline or the like may be prescribed. In addition, silver nitrate may be applied directly to the aphtha for the purpose of raising the threshold of the nerve under the ulcer and relieving pain, but in this case there is a problem that it is accompanied by severe pain. In severe cases, dexamethasone mouthwashes containing steroids and prednisolone tablets for oral steroid use are also used. However, as mentioned above, since the causes of afterta are diverse, at present, only symptomatic treatment (pain relief) is mainly performed, and there is no fundamental treatment without problems of pain and side effects. OOn the other hand, in recent years, it has been noted that water containing a large amount of oxygen in a nanobubble state has various bioactive effects on living organisms, such as improving the adaptability of fish and shellfish to environmental changes and rapidly restoring weakened individuals. A nanobubble is a bubble having a diameter of nano size (1 nm or more but less than 1000 nm, for example, less than 100 nm), and a micro size (1 μm or more but less than 1000 μm) bubble It is an air bubble that is even smaller than a microbubble. Nanobubbles are usually generated in the process of shrinking microbubbles with a diameter of about 50 μm or less, but since they are self-pressurized by the action of surface tension, they rapidly dissolve completely and their lifetime is generally short. However, when covered with a shell with a surfactant or subjected to electrostatic repulsive force due to surface charging, it has been reported that even nano-sized bubbles can exist for a certain period of time. AA method for producing an aqueous solution containing oxygen and ozone in a nanobubble state stably for a long period of time has also been established, and in particular, nanobubbles stabilized by the charging effect retain the characteristics as bubbles, and are expected to have various possibilities of application such as direct action on the cellular level of living organisms (see, for example, Patent Document 1). JP-A-2005-245817 The object of the present invention is to solve the various problems described above, excellent in tissue repair or regeneration ability, and suitable for the treatment or prevention of various diseases and trauma with tissue changes such as damage and denaturation. In order to solve the above problems, as a result of diligent examination, the present inventors have obtained the knowledge that nanobubble water containing a gas in a nanobubble state has an excellent healing promoting effect against canker sores, and can be suitably used in the field of medical care, medical experiments, and the like as an excellent tissue repair or regeneration preparation. This is a new finding found by the present inventors that is not conventionally known at all. The present invention is based on the above knowledge by the present inventors, and the means for solving the above problems are as follows. That is, <1> It is a preparation for tissue repair or regeneration, characterized in that it contains a gas in a nanobubble st<2> It is a preparation for repair or regeneration of the tissue according to < 1 >, characterized in that the gas in the nanobubble state is oxygen. <3> It is a liquid preparation for tissue repair or regeneration, characterized by containing oxygen nanobubble water. <4> It is a treatment or prophylactic agent for stomatitis, characterized by containing gases in a nanobubble state. <5> Characterized in that the gas in the nanobubble state is oxygen, it is a treatment or prophylactic agent for stomatitis according to <4 >. <6> is a therapeutic or prophylactic agent for stomatitis, characterized by containing oxygen nanobubble water. <7> It is a method of tissue repair or regeneration characterized by applying an effective amount of a gas in a nanobubble state. <8> Characterized in that the gas in the nanobubble state is oxygen, it is a method of repair or regeneration of the tissue according to <7>. <9> It is a method of tissue repair or regeneration, characterized by applying an effective amount of oxygen nanobubble water. <10> It is a method of treatment or prevention of stomatitis characterized by applying an effective amount of gas in a nanobubble state. <11> Characterized in that the gas in the nanobubble state is oxyge<12> It is a method of treatment or prevention of stomatitis characterized by applying an effective amount of oxygen nanobubble water. <13> The use of gases in nanobubble states to produce preparations for tissue repair or regeneration. <14> It is the use according to < 13> in which the gas in the nanobubble state is oxygen. <15> It is the use of gases in a nanobubble state to produce a treatment or prophylactic agent for stomatitis. According to the present invention, it is possible to solve various conventional problems, excellent in tissue repair or regeneration ability, suitable for the treatment or prevention of various diseases and trauma involving tissue changes such as damage and denaturation, tissue repair or regeneration formulations, tissue repair or regeneration methods can be provided. In addition, when periodontal disease patients were infiltrated with ozone nanobubble water, not only the bactericidal effect but also the periodontal tissue repair effect was recognized. Furthermore, when infectious dermatitis carp and the like were bred in oxygen nanobubble water, infectious dermatitis was completely cured. From the examples of the present application and these facts, it has been found that both ozone nanobubble water and oxygen nanobubble water have a bactericidal effect and an effect of tisFurthermore, these facts confirm that the effect of nanobubble water does not depend on the properties of a mere gas, but is a peculiar effect by creating a fine bubble called "a gas in a nanobubble state". FIG. 1 is a diagram showing the effect of the tissue repair or regeneration preparation of the present invention on the canker sores that have developed at the apex of the upper left (second molar) of the upper jaw. FIG. 2 is a diagram showing the effect of the tissue repair or regeneration preparation of the present invention on the canker sores that have developed at the tip of the tongue. The tissue repair or regeneration formulation of the present invention is characterized in that it includes a gas in a nanobubble state. < nanobubbles> In the present invention, "nanobubble" refers to bubbles having a bubble diameter (diameter) of nano size (1 nm or more but less than 1000 nm). In the present invention, there is no particular limitation on the "gas in a nanobubble state", and can be appropriately selected according to the purpose, and examples thereof include oxygen, ozone, hydrogen, nitrogen, carbon dioxide, natural gas (for example, methane) and the like. Among these, from the viewpoint of tissue repair or regeneration ability, oxygen is preferable as the "gas in a nanobubble staIn the present invention, two or more types of gases can be used as "gases in a nanobubble state". As a case where two or more types of gas are used, for example, a mixture of nanobubbles composed only of gas A and nanobubbles composed only of gas B may be used, or nanobubbles containing a mixture of gas A and gas B may be used, but are not limited thereto, For example, some nanobubbles include only gas A, some nanobubbles include only gas A, some nanobubbles include only gas B, Some nanobubbles may be a mixture of nanobubbles containing gas A and gas B. The bubble diameter of the nanobubble can be appropriately selected according to the purpose, but among them, 200 nm or less is preferable, and 100 nm or less is particularly preferable. In general, if the bubble diameter is 100 nm or less, it is advantageous from the viewpoint of stability of the nanobubble. The smaller the bubble diameter, the better the stability of long-term storage is generally considered to be. The bubble diameter of the nanobubble can be adjusted to a desired size using, for example, a reverse osmosis membrane or the like, and the bubble diameter of the nanobubble can be evaluated, for example, by measurement using a dynamic light scattering optics or measurement of free radicals. HHowever, when the "gas in the nanobubble state" is ozone, its use is not necessarily suitable because it may damage the reverse osmosis film. However, it is known that even if the reverse osmosis membrane is not permeated, for example, ozone nanobubble water with a diameter of 100 nm or less can be produced with a bubble distribution of 95% or more. The tissue repair or regeneration formulation of the present invention may have at least a part of the bubbles contained therein as the nanobubbles, and in addition to the nanobubbles, bubbles having a larger bubble diameter (for example, bubble diameter (diameter) may be micro size (bubbles having 1 μm or more but less than 1000 μm)). The concentration of the "gas in the nanobubble state" in the tissue repair or regeneration formulation is particularly preferably a saturated concentration. Further, it is particularly preferable that the "gas in the nanobubble state" is stably present in the solution. When the tissue repair or regeneration preparation is a liquid preparation, the solution constituting the solution is preferably an aqueous solution, but there is no particular limitation, and other liquids can be appropriately selected according to the purpose. IIn the present invention, an aqueous solution containing the "gas in a nanobubble state" is referred to as "nanobubble water". In addition, nanobubble water in which the "gas in the nanobubble state" is substantially only oxygen is appropriately referred to as "oxygen nanobubble water", and the nanobubble water in which the "gas in the nanobubble state" is substantially only ozone is appropriately referred to as "ozone nanobubble water". Note that although the nanobubble water in the present invention contains a gas as an internal gas, its bubble size is extremely fine (for example, less than 100 nm), even by containing a certain number of pieces, the overall amount of dissolved gas is not particularly increased. In this respect, it differs from water in which the amount of dissolved gas is increased. For example, in one aspect of the present invention, the dissolved oxygen concentration of oxygen nanobubble water is maintained at almost the same level as normal water, and existing techniques that are said to have an oxygen content tens or hundreds of times (for example, sometimes circulated under the name of "nanobubble water", such as high-concentration oxygen water. It is different from. Further, when radicals are measured by an electron spin resonance method using DMPO as a spin trapping agent, under the condition that DMPO is added together with hydrochloric acid, in the case of oxygen nanobubble water, which is one embodiment of the present invention, a large peak of a normal hydroxyl radical can be confirmed. OOn the other hand, in the case of highly concentrated oxygenated water, only a weak peak of impurity origin of DMPO is detected. Thus, in terms of dissolved gas concentration and generation of hydroxyl radicals during hydrochloric acid addition, nanobubble water can be distinguished from existing technology. <Other components> The nanobubble water can contain other components as necessary in addition to the "gas in the nanobubble state". There is no particular limitation on the other components, and can be appropriately selected according to the purpose, and examples thereof include iron, manganese, salt, and the like. Further, there are no particular restrictions on the salinity, pH, hardness, and the like of the nanobubble water, and can be appropriately selected according to the purpose. These can be adjusted to a desired degree, for example, in the manufacturing process of nanobubble water described later, and once the nanobubble water is produced. < manufacturing> The method for producing the nanobubble water is not particularly limited, and can be appropriately selected according to the purpose, and for example, Japanese Patent Laid-Open No. 2005-245817, Japanese Patent Laid-Open No. 2005-246294, and Japanese Patent Laid-Open No. 2005-246293 (WO2005/084718, WO2005/084786, resIt can be produced according to the manufacturing method described in WO2005/085141 No. 1) and the like. According to the manufacturing method described in the publication, it is preferable that "a gas in a nanobubble state" stably exists for a long period of several months or more and can produce nanobubble water that does not disappear from the aqueous solution. Further, in the manufacturing process of the nanobubble water, it is preferable to add iron, manganese, salt, or the like to the aqueous solution used. In the manufacturing process of the nanobubble water, the salinity of the aqueous solution used is preferably 0.2 to 3.0% by mass, and more preferably 0.8 to 1.2% by mass. In general, when the salinity is in the range of 0.8 to 1.2% by mass, it is easy to produce a gas nucleus of nanobubbles, and the manufacturing efficiency of nanobubble water will be excellent. The salinity can be measured, for example, using a known salinity measuring instrument. In the manufacturing process of the nanobubble water, the pH, hardness, etc. of the aqueous solution used generally do not have as much influence as the salinity on the production efficiency of the nanobubble, but usually, the pH is preferably 7 to 8, and the hardness is preferably 20 to 30. TThe pH, hardness, and the like can be measured, for example, using a known pH measuring instrument, a known hardness measuring instrument, or the like. More specifically, for example, the nanobubble water can be produced by rapidly crushing microbubbles of 50 μm or less using hard water (groundwater) having a salinity of 1.0% by mass as a raw material. Furthermore, by passing a reverse osmosis membrane of 10 Å twice, nanobubble water having a salinity of 0% by mass can be produced (oxygen nanobubble water having a salinity of 0% by mass is "Naga no Drop" (NAGA Co., Ltd.) approved by the Ministry of Health, Labour and Welfare as drinking water). On the other hand, a stage that does not pass through a reverse osmosis membrane of 10 Å can be used as nanobubble water having a salinity of 1.0% by mass. By changing the mixing ratio of these two nanobubble waters, it is possible to provide nanobubble water having a salinity of 0 to 1.0% by mass. In the case of ozone nanobubble water, the use of a reverse osmosis membrane is not preferable because there is a risk that the apparatus may melt and break if it is passed through the reverse osmosis membrane. TThe nanobubble water obtained as described above may be used, for example, as it is, as a preparation for repair or regeneration of the tissue, or may be used as a preparation for repair or regeneration of the tissue by combining it with other components. For example, by adding an existing drug or the like that can be used for the purpose of tissue repair or regeneration to the nanobubble water, or by using the nanobubble water for the preparation of an existing drug that can be used for the purpose of tissue repair or regeneration, tissue repair or regeneration ability It is expected that it can be further improved. Furthermore, the nanobubble water can be used in combination with an existing drug or the like that can be used for tissue repair or regeneration purposes. Therefore, such tissue repair or regeneration formulations using the nanobubble water in part are also included within the scope of tissue repair or regeneration formulations of the present invention. < tissue> There is no particular limitation on the "tissue" to which the tissue repair or regeneration preparation of the present invention is applied, and can be appropriately selected according to the purpose, for example, epithelial tissue, connective tissue, muscle tissue, nerve tissue, and the lAs used herein, the "tissue" is a concept that includes "cells" constituting the tissue and "organs" composed of the tissue. Examples of the "cell" include epidermal cells, pancreatic parenchymal cells, pancreatic duct cells, hepatocytes, blood cells, cardiomyocytes, skeletal muscle cells, osteoblasts, skeletal myoblast cells, nerve cells, vascular endothelial cells, pigment cells, smooth muscle cells, adipocytes, bone cells, chondrocytes, and the like. Examples of the "organ" include skin, blood vessels, cornea, kidney, heart, liver, umbilical cord, intestine, nerve, lung, placenta, pancreas, brain, limb periphery, retina, and the like. The tissue may be derived from any organism and can be appropriately selected according to the purpose, but among them, it can be derived from a mammal, and can be particularly derived from humans. The tissue may be a tissue existing in the body, or may be a tissue existing outside the body (for example, a culture tissue, etc.). <Repair, Regeneration> In the present invention, "repair" and "regeneration" of tissue both mean to physically and / or functionally return a tissue that has undergone a change such as damage or degeneration to its original normal st<Application> There is no particular limitation on the method of using the tissue repair or regeneration preparation of the present invention, and can be appropriately selected according to the purpose, for example, it can be used by contacting the tissue that has undergone a change in damage or denaturation due to disease or trauma by any method. In the tissue repair or regeneration method of the present invention, the application method of "gas in a nanobubble state" is not particularly limited, and can be appropriately selected according to the purpose, for example, the tissue that has been damaged or denatured due to disease or trauma It can be applied by contacting an effective amount of nanobubble water in any way. There is no particular limitation on the storage method of the tissue repair or regeneration preparation, and can be appropriately selected according to the purpose. When ozone is used as the "gas in a nanobubble state", it is preferable to perform dark refrigerated storage avoiding ultraviolet rays from the viewpoint of preventing deterioration. Since the tissue repair or regeneration preparation is excellent in tissue repair or regeneration ability, for example, the treatment or prevention of various diseases and injuries accompanied by tissue changes such as damage and degeneration (eg, treatment or prevention of stomatitis and the like) It can be suitably uIn the method for treating or preventing stomatitis of the present invention, there is no particular limitation on the method of applying "gas in a nanobubble state", it can be appropriately selected according to the purpose, for example, by contacting the affected area with an effective amount of nanobubble water in any way, it can be applied. The canker sores are not particularly limited, and examples thereof include canker sores, catarrhal stomatitis, viral stomatitis (herpetic stomatitis), candidiac stomatitis, canker sores due to allergies, and the like. Examples of the present invention will be described below, but the present invention is not limited in any way to these examples. (Example 1: Evaluation of tissue repair or regeneration effect of oxygen nanobubble water) Oxygen nanobubble water, which is one embodiment of the tissue repair or regeneration formulation of the present invention, was prepared with reference to the manufacturing method described in JP-A-2005-246294 (corresponding to WO2005/084786). Specifically, first, based on the usual manufacturing method as described above, oxygen nanobubble water having a salinity of 1.0% by mass was produced, and then a reverse osmosis membrane of 10 Å was passed twice to obtain oxygen nanobubble water having a salinity of 0% by mass, and refrigerated until use. AAt the time of use, it was divided into unused plastic or glass containers, and in principle refrigerated until it was actually used (in general, even if it is stored at room temperature, there will be little substantial difference in the effect of use). The repair or regeneration effect of the obtained oxygen nanobubble water tissue was clinically studied using a patient suffering from aphtha stomatitis (Aphtha) as a subject. < method> The subject patient is a 36-year-old woman with no special notice on her general condition. In the case of the patient, when canker sores develop, the size usually reaches about 1 cm in diameter, and it is always said that it takes about 2 weeks to heal. First, the patient was subjected to canker sores that developed at the apex of the upper left left (second molar) of the patient, and the healing promoting effect of the oxygen nanobubble water was studied. The onset of the aphthous stomatitis was set to -1 day, and from 0 days and nights, 20 ml of the stock solution of the oxygen nanobubble water was included for 20 seconds, and the size (diameter, mm) and pain change of the canker sore were observed. In addition, the healing promoting effect of the oxygen nanobubble water was also studied for the canker sores that developed at the apex of the tongue of the patient. The onset of the aphthous stomatitis was set to 0 days, and from 0 days and nights, 20 ml of the stock solution of the oxygen nanobubble water was included twice a day for 20 seconds, and the size (diameter, mm) and pain change of the canker sore were obser< results> The results are shown in Tables 1 to 2 and FIGS. 1 to 2. Tables 1 and 1 show results for canker sores that have developed at the apex of the upper left side of the maxillary upper 7 (second molar), and Tables 2 and 2 show results for canker sores that have developed at the apex of the tongue. In Tables 1 to 2, the pain evaluation criteria are as follows. [Pain Criteria] +: Obvious pain. +/-: There is more discomfort than awareness of pain. -: Subjective symptoms disappear. From the above results, it was shown that the inclusion of the oxygen nanobubble water heals in a very short period of time than usual by the aphthous stomatitis. The aphthous stomatitis can be said to be an abnormal tissue change of the oral mucosal tissue, but it can be seen that the tissue change was quickly normalized by the inclusion of the oxygen nanobubble water. Therefore, from these results, it was shown that the nanobubble water has an excellent tissue repair or regeneration action. Also noteworthy is that the pain of aphthous stomatitis was attenuated only 2 days (3-4 infusions) after the onset of intake (it is common for it to last for 1 week). In this embodiment, there was no irritation to the affected area by the oxygen nanobubble water used as a satisfyant. From these, nanobubble water is painless, very promising as a radical treatment or prophylactic agent for canker sores, and utilizes its excellent tissue repair or regeneration ability, It is considered that it is possible to widely apply it to the treatment or prevention of various diseases and trauma with tissue changes such as damage and degeneration. Tissue repair or regenerative formulations of the present invention can be suitably used to treat or prevent various diseases and trauma (eg, stomatitis) with tissue changes such as damage and denaturation. Treatment or prophylactic agent for stomatitis, characterized by containing oxygen in a nanobubble state. Characterized by containing oxygen nanobubble water, stomatitis treatment or prophylactic agent. A method of treatment or prevention of canker sores in organisms other than humans, characterized by the application of an effective amount of oxygen in a nanobubble state. Treatment or prevention of stomatitis in organisms other than humans, characterized by applying an effective amount of oxygen nanobubble water. The use of oxygen in nanobubble states to produce canker sores treatment or prophylactic ag