Pharmaceutical composition for use in treating subject with hypoxic condition due to respiratory failure or the like

Abstract

To provide a pharmaceutical composition for use in administering oxygen to a subject, a kit, an administration control device, and an administration method.SOLUTION: Provided is a pharmaceutical composition comprising a perfluorocarbon having oxygen dissolved therein, for use in administering oxygen to a subject. Also provided is a pharmaceutical composition comprising a perfluorocarbon for use in lowering the partial pressure of carbon dioxide in the blood of a subject.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition used to treat a subject suffering from hypoxia due to respiratory failure or the like. [Background technology]

[0002] Mechanical ventilation plays an important role in the clinical management of respiratory failure due to severe illnesses such as pneumonia and acute respiratory distress syndrome. Mechanical ventilation is the most commonly used short-term life support technique worldwide. 1,2 Extracorporeal membrane oxygenation (ECMO) is an alternative approach to artificial respiration for patients with severe respiratory failure who cannot tolerate mechanical ventilation, and is generally used as temporary palliative care. 3 However, the recent SARS-CoV-2 pandemic has overwhelmed the clinical need for ventilators and artificial lungs, resulting in a critical shortage of available devices and endangering the lives of patients worldwide. A small study by Yang et al. compared the clinical characteristics and outcomes of different treatments in severely ill SARS-CoV-2 patients and found that five of six patients (83%) who received ECMO died. 4,5 Furthermore, ECMO requires significant human resources and is costly in terms of healthcare costs. Other complications of ECMO include neurological complications such as seizures, ischemic stroke, intracranial hemorrhage, and brain death, with hemorrhage being the most common complication in patients receiving ECMO. 3 Currently, there are no other effective indwelling ventilators, so supportive care for severe respiratory failure must be developed.

[0003] Improving hypoxia is the most important factor for improving respiratory failure. Molecular oxygen is the essential primary substrate for mitochondrial ATP production and numerous intracellular biochemical reactions for the majority of living organisms. 6Notably, several mammalian species, as well as some unique non-mammals, have evolved to adapt and survive in low-oxygen environments. These species require accessory respiratory mechanisms other than lungs or gills. For example, frog subspecies use their skin for breathing, loach (Misgumus anguillicandatus), sea cucumbers, corydoras, and Tetragnatha praedonia use their intestines for breathing, and naked mole rats use fructose-driven glycolysis. 7-10 Interestingly, loaches normally use bronchial breathing in normoxic environments, but in hypoxic environments, they switch to the posterior intestine as an auxiliary breathing site for survival. When living in prolonged hypoxic environments, loaches and other species also alter their antioxidant systems and immune defenses. 11 By modifying transporter and vascularization genes, they transform their intestinal digestive function into intestinal respiration, while enhancing Summary of the Invention

[0004] According to the present invention, there is provided a pharmaceutical composition for use in treating a subject suffering from a hypoxic state due to respiratory failure or the like.

[0005] The present inventors have demonstrated that absorption of oxygen gas from the intestinal tract (preferably the large intestine, more preferably the rectum) with a mucosal detachment can improve a subject's blood oxygen partial pressure. The present inventors have also demonstrated that administration of a perfluorocarbon solution containing dissolved oxygen to the intestinal tract (preferably the large intestine, more preferably the rectum) can improve a subject's blood oxygen partial pressure without the need for mucosal detachment. This method was applied to an animal model of moderate to severe acute respiratory distress syndrome (ARDS), and arterial oxygen saturation and intravenous oxygen partial pressure were successfully improved. The present inventors have further demonstrated that administration of a perfluorocarbon solution to the intestinal tract (preferably the large intestine, more preferably the rectum) can induce a decrease in a subject's blood carbon dioxide partial pressure. Rectal administration of a perfluorocarbon solution containing dissolved oxygen was able to increase the subject's blood oxygen partial pressure and also decrease the blood carbon dioxide partial pressure.

[0006] According to the present invention, the following inventions are provided. (1) A pharmaceutical composition for enteral administration, comprising a perfluorocarbon having dissolved therein oxygen. (2) The pharmaceutical composition according to (1) above for use in treating hypoxemia. (3) The pharmaceutical composition according to (1) or (2) above, which is administered to a subject with respiratory failure. (4) The pharmaceutical composition according to any one of (1) to (3) above, for use in supplying oxygen to the blood of a subject. (5) An administration device for enteral administration, comprising the pharmaceutical composition according to any one of (1) to (4) above. (6) A pharmaceutical composition in gas form for enteral administration, comprising oxygen gas. (7) The pharmaceutical composition according to (6) above, wherein the intestinal tract is a mucosa-removed intestinal tract or an intestinal tract at least partially coated with perfluorocarbon. (8) An administration device for enteral administration, comprising the pharmaceutical composition according to (6) or (7) above. (9) An administration control device for administering a perfluorocarbon having dissolved oxygen, comprising a delivery unit for delivering the perfluorocarbon having dissolved oxygen or oxygen to a tube, and a control unit for controlling the rate of delivery by the delivery unit based on the oxygen saturation in the subject's blood and / or the pressure in the intestinal tract. (10) The administration control device described in (9) above, further comprising a receiving unit that receives information regarding oxygen saturation and / or intestinal pressure from a blood oxygen monitor. (11) A control unit is provided that controls the delivery rate of the delivery unit based on the oxygen saturation level in the subject's blood; (A) based on the information on the oxygen saturation level received by the receiving unit, when the oxygen saturation level falls below (or is below) a predetermined value, the control unit sends a signal to the transmitting unit to increase the rate of transmission; and / or (B) An administration control device as described in claim 9 or 10, wherein, based on information regarding oxygen saturation received by the receiving unit, when the oxygen saturation becomes equal to or greater than a predetermined value (or exceeds a predetermined value), the control unit sends a signal to the sending unit to reduce the sending rate. (12) A control unit is provided that controls the delivery rate of the delivery unit based on the intestinal pressure of the subject; (C) An administration control device described in any of (9) to (11) above, wherein, based on information regarding intestinal pressure received by the receiving unit, when the intestinal pressure becomes less than (or equal to or less than) a predetermined value, the control unit stops sending a signal to the sending unit to increase the delivery rate, or sends a signal to the sending unit to decrease the delivery rate. (13) An administration control device for administering oxygen gas, comprising an air supply unit for supplying the oxygen-dissolved perfluorocarbon or oxygen to a tube, and a control unit for controlling the speed of air supply by the air supply unit based on the oxygen saturation in the subject's blood and / or the pressure in the intestinal tract. (14) The administration control device according to (13) above, further comprising a receiving unit for receiving information regarding oxygen saturation and / or intestinal pressure from a blood oxygen monitor. (15) A control unit is provided to control the speed of the air supply unit based on the oxygen saturation level in the blood of the subject, (A) based on the information on the oxygen saturation level received by the receiving unit, when the oxygen saturation level falls below (or is equal to or lower than) a predetermined value, the control unit sends a signal to the air delivery unit to increase the rate of air delivery, and / or (B) An administration control device described in (13) or (14) above, in which, based on information regarding oxygen saturation received by the receiving unit, when the oxygen saturation becomes equal to or greater than a predetermined value (or exceeds a predetermined value), the control unit sends a signal to the air supply unit to reduce the air supply rate. (16) A control unit is provided which controls the speed of air supply by the air supply unit based on the intestinal pressure of the subject, (C) An administration control device described in any of (13) to (15) above, wherein, based on information regarding intestinal pressure received by the receiving unit, when the intestinal pressure becomes less than (or equal to or less than) a predetermined value, the control unit stops sending a signal to the air supply unit to increase the air supply speed, or sends a signal to the air supply unit to decrease the air supply speed.

[0007] According to the present invention, the following inventions are provided. (1A) A pharmaceutical composition for oral administration, administration via a gastrostomy tube, administration via a nasogastric tube, or administration into the large intestine, comprising a perfluorocarbon having dissolved therein oxygen. (2A) The pharmaceutical composition according to (1A) above for use in treating hypoxemia. (3A) The pharmaceutical composition according to (1A) or (2A) above, which is administered to a subject with respiratory failure. (4A) The pharmaceutical composition according to any one of (1A) to (3A) above, for use in supplying oxygen to the blood of a subject. (5A) An administration device for administration into the large intestine, comprising the pharmaceutical composition according to any one of (1A) to (4A) above. (6A) A pharmaceutical composition in gas form for oral administration, nasogastric tube administration, gastrostomy administration or colonic administration, comprising oxygen gas, The pharmaceutical composition, wherein the large intestine is a demucosed large intestine or a perfluorocarbon-coated large intestine. (7A) A gaseous composition comprising oxygen gas, which is dissolved in a perfluorocarbon prior to administration and is administered orally, via a gastrostomy tube, or intracolonally. (8A) The composition according to any one of claims 1 to 4, which is mixed with oxygen gas before administration and is administered orally, via a nasogastric tube, via a gastrostomy tube, or into the large intestine. (9A) A gaseous composition comprising oxygen gas, for use in colonic administration to a subject having a mucosa-removed or perfluorocarbon-coated colon. (10A) The composition according to any one of (1A) to (4A) and (6A) to (9A) above, for rectal administration. (11A) The composition according to any one of (1A) to (4A) and (6A) to (9A) above, for oral administration, nasogastric tube administration, or gastrostomy tube administration. (12A) The composition according to any one of (1A) to (4A) and (6A) to (11A) above, for use in reducing the partial pressure of carbon dioxide in the blood of a subject. (13A) A kit for preparing a composition for colonic administration, comprising a gaseous composition containing oxygen gas and a composition containing a perfluorocarbon. (14A) A ready-to-use kit according to (13A) above for use in increasing the blood oxygen partial pressure of a subject. (15A) A ready-to-use kit according to (13A) or (14A) above, for use in lowering the partial pressure of carbon dioxide in the blood of a subject. (16A) An administration device for administration into the large intestine, comprising the composition according to any one of (1A) to (4A) and (6A) to (12A) above. (17A) An administration control device for administering oxygen-dissolved perfluorocarbon or oxygen orally, via gastrostomy, nasogastric tube, or into the large intestine, comprising a delivery unit for delivering the oxygen-dissolved perfluorocarbon or oxygen to the tube, and a control unit for controlling the delivery rate by the delivery unit based on the oxygen saturation in the subject's blood and the pressure inside the large intestine. (18A) The administration control device according to (17A) above, further comprising a receiving unit for receiving information on oxygen saturation and intraintestinal pressure of the large intestine from a blood oxygen monitor. (19A) A control unit that controls the delivery rate of the delivery unit based on the oxygen saturation level in the subject's blood, (A) based on the information on the oxygen saturation level received by the receiving unit, when the oxygen saturation level falls below (or is below) a predetermined value, the control unit sends a signal to the transmitting unit to increase the rate of transmission; and / or (B) An administration control device described in (17A) or (18A) above, in which, based on information regarding oxygen saturation received by the receiving unit, when the oxygen saturation becomes equal to or greater than a predetermined value (or exceeds a predetermined value), the control unit sends a signal to the sending unit to reduce the sending rate. (20A) Further comprising a control unit that controls the delivery rate of the delivery unit based on the intestinal pressure of the large intestine of the subject; (C) An administration control device described in any of (17A) to (19A) above, wherein, based on information regarding the intestinal pressure of the large intestine received by the receiving unit, when the intestinal pressure becomes less than (or equal to or less than) a predetermined value or when the intestinal pressure increases during fluid delivery, the control unit stops sending a signal to the delivery unit to increase the delivery rate, or sends a signal to the delivery unit to decrease the delivery rate. (21A) A method for administering oxygen to a subject, comprising: A method comprising administering to the subject orally, via a nasal tube, or intracolonally, a pharmaceutical composition comprising a perfluorocarbon having dissolved oxygen. (22A) The method according to (21A) above, administering the oxygen-dissolved perfluorocarbon to the subject orally, via a nasogastric tube, via a gastrostomy tube, or into the large intestine while controlling the dosage using an administration control device; The administration control device is an administration control device for administering oxygen or a perfluorocarbon having dissolved therein, and includes a delivery unit for delivering the perfluorocarbon having dissolved therein or oxygen to a tube, and a control unit for controlling the delivery rate by the delivery unit based on the oxygen saturation level in the blood of the subject and / or the intraintestinal pressure of the large intestine. method. (23A) The method according to (22A) or (23A) above, wherein the large intestine is the rectum. (24A) The composition according to any one of (1A) to (4A) and (6A) to (12A), The administration control device is used to administer a perfluorocarbon having dissolved oxygen to the subject orally, via a nasal tube, via a gastrostomy tube, or into the large intestine while controlling the dosage, The administration control device is an administration control device for administering oxygen or a perfluorocarbon having dissolved therein, and includes a delivery unit for delivering the perfluorocarbon having dissolved therein or oxygen to a tube, and a control unit for controlling the delivery rate by the delivery unit based on the oxygen saturation level in the blood of the subject and / or the intraintestinal pressure of the large intestine. Pharmaceutical compositions.

[0008] (25A) An administration control device for administering oxygen gas to the large intestine (preferably the rectum), comprising an air supply unit for supplying oxygen to a tube and a control unit for controlling the speed of air supply by the air supply unit based on the oxygen saturation in the subject's blood and / or the intraintestinal pressure of the large intestine (preferably the rectum). (26A) The administration control device according to (25A) above, further comprising a receiving unit for receiving information regarding oxygen saturation and / or intraintestinal pressure of the large intestine (preferably the rectum) from a blood oxygen monitor. (27A) A control unit that controls the speed of air delivery by the air delivery unit based on the oxygen saturation level in the blood of the subject, (A) based on the information on the oxygen saturation level received by the receiving unit, when the oxygen saturation level falls below (or is equal to or lower than) a predetermined value, the control unit sends a signal to the air delivery unit to increase the rate of air delivery, and / or (B) An administration control device described in (25A) or (26A) above, in which, based on information regarding oxygen saturation received by the receiving unit, when the oxygen saturation becomes equal to or greater than a predetermined value (or exceeds a predetermined value), the control unit sends a signal to the air supply unit to reduce the air supply rate. (28A) A control unit that controls the speed of air supply by the air supply unit based on the intestinal pressure of the large intestine (preferably the rectum) of the subject, (C) An administration control device described in any of (25A) to (27A) above, wherein, based on information regarding the intestinal pressure of the large intestine (preferably the rectum) received by the receiving unit, when the intestinal pressure becomes less than (or equal to or less than) a predetermined value, the control unit stops sending a signal to the air supply unit to increase the air supply rate, or sends a signal to the air supply unit to decrease the air supply rate.

[0009] (29A) A pharmaceutical composition comprising a perfluorocarbon having dissolved oxygen, for oral administration to a human. (30A) A pharmaceutical composition comprising a perfluorocarbon having dissolved oxygen, for administration via a nasal tube to a human. (31A) A pharmaceutical composition comprising a perfluorocarbon having dissolved oxygen, which is administered to a human via a gastrostomy tube. (32A) A pharmaceutical composition comprising a perfluorocarbon having dissolved oxygen, for colonic administration to a human. (33A) The pharmaceutical composition according to any one of the above (29A) to (32A), wherein the perfluorocarbon has an oxygen saturation of 50% or more, preferably 60% or more, more preferably 70% or more, even more preferably 80% or more, still more preferably 90% or more, and particularly preferably 95% or more. (34A) The pharmaceutical composition according to any one of (29A) to (33A) above, wherein the administration is by an administration device. (35A) The pharmaceutical composition according to any one of the above (29A) to (34A), wherein the perfluorocarbon is a perfluorocarbon maintained under atmospheric conditions. (36A) The pharmaceutical composition according to any one of (29A) to (34A) above, wherein the perfluorocarbon has a dissolving amount of oxygen that is increased compared to that under atmospheric conditions, for example, the composition can be used after further dissolving oxygen. (37A) The pharmaceutical composition according to any one of (29A) to (36A) above, wherein the human has hypoxemia. (38A) The pharmaceutical composition according to any one of (29A) to (37A) above, wherein the human has a blood carbon dioxide partial pressure of more than 45 Torr. (39A) The pharmaceutical composition according to any one of (29A) to (38A) above, wherein the human has respiratory failure. (40A) The pharmaceutical composition according to (39A), wherein the human has pneumonia accompanied by respiratory failure. (41A) The pharmaceutical composition according to any one of (29A) to (39A) above, wherein the human has asthma. (42A) The pharmaceutical composition according to any one of (29A) to (39A) above, wherein the human has chronic obstructive pulmonary disease (COPD). (43A) The pharmaceutical composition according to any one of (29A) to (39A) above, for use in a human suffering from any one of the diseases listed in Table 1.

[0010] According to the present invention, the following inventions are provided. (1B) A pharmaceutical composition for oral administration, nasal tube administration, or rectal administration, comprising a perfluorocarbon having dissolved therein oxygen. (2B) The pharmaceutical composition according to (1B) above for use in treating hypoxemia. (3B) The pharmaceutical composition according to (1B) or (2B) above, which is administered to a subject with respiratory failure. (4B) The pharmaceutical composition according to any one of (1B) to (3B) above, for use in supplying oxygen to the blood of a subject. (5B) An administration device for rectal administration, comprising the pharmaceutical composition according to any one of (1B) to (4B) above. (6B) A pharmaceutical composition in gas form for oral administration, nasal tube administration, or rectal administration, comprising oxygen gas, The pharmaceutical composition, wherein the rectum is a mucosa-deprived rectum or a perfluorocarbon-coated rectum. (7B) A gaseous composition comprising oxygen gas, which is dissolved in a perfluorocarbon prior to administration and is administered orally or rectally. (8B) The composition according to any one of (1B) to (4B) above, which is mixed with oxygen gas before administration and administered orally, via a nasogastric tube, via a gastrostomy tube, or into the large intestine. (9B) A gaseous composition comprising oxygen gas, for use in rectal administration to a subject having a mucosa-removed rectum or a rectum coated with perfluorocarbon. (10B) The composition according to any one of (1B) to (4B) and (6B) to (9B) above, for rectal administration. (11B) The composition according to any one of (1B) to (4B) and (6B) to (9B) above, for oral administration or nasal tube administration. (12B) The composition according to any one of (1B) to (4B) and (6B) to (11B) above, for use in reducing the partial pressure of carbon dioxide in the blood of a subject. (13B) A kit for preparing a composition for rectal administration, comprising a gaseous composition containing oxygen gas and a composition containing a perfluorocarbon. (14B) The ready-to-use kit described in (13B) above for use in increasing the blood oxygen partial pressure of a subject. (15B) A ready-to-use kit according to (13B) or (14B) above, for use in lowering the partial pressure of carbon dioxide in the blood of a subject. (16B) An administration device for rectal administration, comprising the composition according to any one of (1B) to (4B) and (6B) to (12B) above. (17B) An administration control device for administering oxygen-dissolved perfluorocarbon or oxygen orally, via a nasal tube, or intrarectally, the administration control device comprising a delivery unit for delivering the oxygen-dissolved perfluorocarbon or oxygen to the tube, and a control unit for controlling the delivery rate by the delivery unit based on the oxygen saturation in the subject's blood and the pressure in the rectum. (18B) An administration control device according to (17B) above, further comprising a receiving unit for receiving information on oxygen saturation and rectal intestinal pressure from a blood oxygen monitor. (19B) A control unit that controls the delivery rate of the delivery unit based on the oxygen saturation level in the subject's blood, (A) based on the information on the oxygen saturation level received by the receiving unit, when the oxygen saturation level falls below (or is below) a predetermined value, the control unit sends a signal to the transmitting unit to increase the rate of transmission; and / or (B) An administration control device described in (17B) or (18B) above, in which, based on information regarding oxygen saturation received by the receiving unit, when the oxygen saturation becomes equal to or exceeds a predetermined value (or exceeds the predetermined value), the control unit sends a signal to the sending unit to reduce the sending rate. (20B) Further comprising a control unit that controls the rate of delivery by the delivery unit based on the intestinal pressure of the subject's rectum; (C) An administration control device described in any of (17B) to (19B) above, wherein, based on information regarding the intestinal pressure of the rectum received by the receiving unit, when the intestinal pressure becomes less than (or equal to or less than) a predetermined value or when the intestinal pressure increases during liquid delivery, the control unit stops sending a signal to the delivery unit to increase the delivery rate, or sends a signal to the delivery unit to decrease the delivery rate. (21B) A method for administering oxygen to a subject, comprising: A method comprising administering to the subject orally, via a nasal tube, or rectally a pharmaceutical composition comprising a perfluorocarbon having dissolved oxygen. (22B) The method according to (21B) above, administering to the subject orally, via a nasal tube, or rectally a perfluorocarbon containing dissolved oxygen while controlling the dosage using an administration control device; The administration control device is an administration control device for administering oxygen or a perfluorocarbon having dissolved therein, and includes a delivery unit for delivering the perfluorocarbon having dissolved therein or oxygen to a tube, and a control unit for controlling the rate of delivery by the delivery unit based on the oxygen saturation level in the subject's blood and / or the pressure in the rectum of the intestinal tract. method. (23B) The method according to (22B) or (23B) above, wherein the rectum is the rectum. (24B) The composition according to any one of (1B) to (4B) and (6B) to (12B), The administration control device is used to administer to the subject orally, via a nasal tube, or rectally, a perfluorocarbon having dissolved oxygen while controlling the dosage, The administration control device is an administration control device for administering oxygen or a perfluorocarbon having dissolved therein, and includes a delivery unit for delivering the perfluorocarbon having dissolved therein or oxygen to a tube, and a control unit for controlling the rate of delivery by the delivery unit based on the oxygen saturation level in the subject's blood and / or the pressure in the rectum of the intestinal tract. Pharmaceutical compositions.

[0011] (25B) An administration control device for administering oxygen gas to the rectum, comprising an air supply unit for supplying oxygen to a tube and a control unit for controlling the speed of air supply by the air supply unit based on the oxygen saturation in the subject's blood and / or the intraintestinal pressure of the rectum (preferably the rectum). (26B) The administration control device according to (25B) above, further comprising a receiving unit for receiving information regarding oxygen saturation and / or rectal intestinal pressure from a blood oxygen monitor. (27B) A control unit is provided which controls the speed of the air supply unit based on the oxygen saturation level in the blood of the subject, (A) based on the information on the oxygen saturation level received by the receiving unit, when the oxygen saturation level falls below (or is equal to or lower than) a predetermined value, the control unit sends a signal to the air delivery unit to increase the rate of air delivery, and / or (B) An administration control device described in (25B) or (26B) above, in which, based on information regarding oxygen saturation received by the receiving unit, when the oxygen saturation becomes equal to or exceeds a predetermined value (or exceeds the predetermined value), the control unit sends a signal to the air supply unit to reduce the air supply rate. (28B) A control unit is provided which controls the speed of air supply by the air supply unit based on the intestinal pressure of the subject's rectum; (C) An administration control device described in any of (25B) to (27B) above, wherein, based on information regarding the intestinal pressure of the rectum received by the receiving unit, when the intestinal pressure becomes less than (or equal to or less than) a predetermined value, the control unit stops sending a signal to the air supply unit to increase the air supply speed, or sends a signal to the air supply unit to decrease the air supply speed.

[0012] (29B) A pharmaceutical composition comprising a perfluorocarbon having dissolved oxygen, for oral administration to a human. (30B) A pharmaceutical composition comprising a perfluorocarbon having dissolved oxygen, for administration via a nasal tube to a human. (31B) A pharmaceutical composition comprising a perfluorocarbon having dissolved oxygen, for rectal administration to a human. (32B) The pharmaceutical composition according to any one of (29B) to (31B) above, wherein the perfluorocarbon has an oxygen saturation of 50% or more, preferably 60% or more, more preferably 70% or more, even more preferably 80% or more, still more preferably 90% or more, and particularly preferably 95% or more. (33B) The pharmaceutical composition according to any one of (29B) to (32B) above, wherein the administration is by an administration device. (34B) The pharmaceutical composition according to any one of (29B) to (33B) above, wherein the perfluorocarbon is a perfluorocarbon maintained under atmospheric conditions. (35B) The pharmaceutical composition according to any one of (29B) to (33B) above, wherein the perfluorocarbon has an increased amount of dissolved oxygen compared to that under atmospheric conditions, for example, the composition can be used after further dissolving oxygen. (36B) The pharmaceutical composition according to any one of (29B) to (35B) above, wherein the human has hypoxemia. (37B) The pharmaceutical composition according to any one of (29B) to (36B) above, wherein the human has a blood carbon dioxide partial pressure of more than 45 Torr. (38B) The pharmaceutical composition according to any one of (29B) to (37B) above, wherein the human has respiratory failure. (39B) The pharmaceutical composition according to (38B), wherein the human has pneumonia accompanied by respiratory failure. (40B) The pharmaceutical composition according to any one of (29B) to (38B) above, wherein the human has asthma. (41B) The pharmaceutical composition according to any one of (29B) to (38B) above, wherein the human has chronic obstructive pulmonary disease (COPD). (42B) The pharmaceutical composition according to any one of (29B) to (38B) above, for use in a human suffering from any one of the diseases listed in Table 1. [Brief explanation of the drawings]

[0013] [Figure 1A] An adult loach under isoflurane anesthesia, showing a full view and cross-section of the loach intestine. [Figure 1B] A mouse under isoflurane anesthesia, and a whole image and cross-section of the mouse intestine are shown. [Figure 1C] Hematoxylin staining of normal loach hindgut and mouse intestine after intestinal gas ventilation (IGV) is shown. The distance between the intestinal lumen and microvessels is shorter than in the control group. [Figure 1D] Figure 1 shows the results of quantitative RT-PCR analysis of Vegfa and Anxa1 genes from the abraded distal intestine of mice. Data are expressed as multiples of the value from control treatment of the foregut. Values ​​are means ± SE (n = 3). Differences were analyzed by ANOVA and Tukey post hoc test. *p < 0.05 vs. control treatment. [Figure 1E] Immunochemical staining using hypoxyprobe™ is shown for mice without mucosal detachment or IGV. The staining showed that hypoxyprobe™-positive cells were abundant in the intestinal epithelial region under severe hypoxia. In the intestines of mice placed under severe hypoxia with mucosal detachment and intestinal gas ventilation (IGV), weak hypoxyprobe™-positive cells were present in the intestinal epithelial region, demonstrating the therapeutic effect and improvement of the hypoxic region. PI: hindgut. [Figure 2] This figure shows the results of treatment of lethal hypoxemia by intestinal gas ventilation with systemic oxygenation. Panel A shows the survival rates of the control group, intestinal gas ventilation group, and intestinal gas ventilation with mucosal detachment (IGV) group under 8% critical hypoxia. Panel B shows the oxygen partial pressure in the inferior vena cava with intestinal gas ventilation. Panel C shows the oxygen partial pressure in the left ventricle of the heart with intestinal ventilation. [Figure 3]These images show the results of treating lethal hypoxemia without mucosal ablation by intestinal administration of O2-loaded perfluorocarbons. Panel A shows a schematic diagram of the experimental procedure. Panel B shows a schematic diagram of the experimental procedure for tracking and photographing the mouse behavior. Walking distance was statistically increased in the treatment group compared to the control group (control, 0.408 ± 1.02 cm; treatment, 3.34 ± 4.05 cm; P < 0.0001). Panel C shows the improvement of oxygenation in the inferior vena cava by perfluorocarbon therapy. Panel D shows the improvement of left ventricular oxygenation under hypoxic conditions by intestinal gas ventilation (enteral fluid ventilation) using perfluorocarbons. [Figure 4A] Results of hypoxemia treatment using various bowel ventilation protocols are shown. Venous partial pressure of oxygen under bowel ventilation with and without mucosal stripping is shown. The pressure values ​​in the bowel ventilation with moderate mechanical mucosal stripping were significantly higher than those in the bowel ventilation without mucosal stripping group (PvO2 52.0 ± 7.88 mmHg and 38.4 ± 11.3 mmHg, respectively, p = 0.042). [Figure 4B] Shows the distance between the intestinal lumen and the muscular mucosa. [Figure 4C] Quantitative RT-PCR analysis of Spon1 and Glud1 genes from mucosally-denuded distal intestine of mice. Data are expressed as folds of values ​​from control-treated foregut. Values ​​are shown as mean ± SE (n=3). There were no statistical differences between the control group and any of the treatment groups. [Figure 4D] Estimated scores using hypoxyprobe™ are shown. [Figure 4E] This shows the change in oxygen partial pressure over time in a perfluorocarbon (PFC) bubbled with pure oxygen. After 120 minutes, the average oxygen pressure in the perfluorocarbon was 438±19.9 mmHg. [Figure 5] A schematic diagram of an enema with a typical fig-shaped container is shown. [Figure 6] A schematic diagram of an enema with a typical accordion-type container is shown. [Figure 7] 1 shows a schematic diagram of an administration device for administering to an indwelling intestinal tube of the present invention. [Figure 8]1 shows a schematic diagram of an administration device of the present invention that can simultaneously deliver both liquid and air. [Figure 9] Figure 9 shows the results of treating hypoxemia with a bowel ventilation protocol, comparing the effects of research-grade PFC with clinical-grade PFC. [Figure 10] 1 shows the effect of ligating the inferior vena cava or portal vein, with or without ligation, on blood oxygenation following an intestinal ventilation protocol. [Figure 11] 1 shows the results of treating hypoxemia with a bowel ventilation protocol using gelled PFC. [Figure 12A] The lung appearance and histology of a pig model of acute respiratory distress syndrome (ARDS) are shown. [Figure 12B] 1 shows the results of treatment with an enteral ventilation protocol on a porcine model of acute respiratory distress syndrome (ARDS). [Figure 13] 1 shows the results of treatment of hypoxemia with an enteral ventilation protocol using perflubron (PFB) as the PFC. [Figure 14A] This shows that the intestinal tract of mice orally administered bubbled PFC was distended by PFD. [Figure 14B] This shows that PFCs can be recovered from the intestinal tract of mice orally administered with PFCs. [Figure 14C] This shows that oral administration of oxygen-dissolved PFC improved the partial oxygen pressure and reduced the partial carbon dioxide pressure in the left ventricle of mice. Detailed Description of the Invention

[0014] As used herein, a "subject" is a mammal, particularly a primate, such as a human, a quadruped, such as a dog, cat, hamster, guinea pig, horse, cow, sheep, pig, camel, goat, and a bird, such as a bird. The subject is particularly a human.

[0015] As used herein, "perfluorocarbon" refers to a molecule in which all hydrogen atoms of a hydrocarbon have been replaced with fluorine atoms. Perfluorocarbons may include straight-chain alkyl, branched alkyl, and cycloalkyl. Perfluorocarbons may have one or more carbon atoms replaced by an atom selected from the group consisting of O, N, and S. Perfluorocarbons (PFCs) are known for their high oxygen solubility. Perfluorocarbons can be liquids at room temperature. Perfluorocarbons can dissolve approximately 20 times more oxygen gas than water.

[0016] As used herein, "oxygen" refers to O2. Oxygen gas is highly soluble in liquid perfluorocarbons. In the atmosphere, oxygen typically accounts for approximately 21%.

[0017] As used herein, "oxygen therapy" refers to a treatment that provides oxygen to a subject with the goal of ameliorating respiratory failure in the subject.

[0018] As used herein, "respiratory failure" is defined as a condition in which arterial blood gases exhibit abnormal values, preventing the body from performing normal functions. Hypoxemic respiratory failure (hypoxemia) refers to a respiratory dysfunction or an abnormal condition equivalent to an arterial blood oxygen partial pressure (PaO2) of 60 mmHg (approximately 8,000 Pa) or less when breathing room air. Respiratory failure is broadly classified into type I and type II respiratory failure. Type I respiratory failure is respiratory failure with a PaO2 of 45 mmHg (approximately 6,000 Pa) or less, while type II respiratory failure is respiratory failure with a PaO2 of more than 45 mmHg (approximately 6,000 Pa). Pre-respiratory failure refers to a PaO2 of more than 60 mmHg (approximately 8,000 Pa) but less than 70 mmHg (approximately 9,333 Pa). 1 mmHg is equivalent to 1 Torr or 101,325 / 760 Pa. Respiratory failure can be caused, for example, by pneumonia (e.g., viral pneumonia caused by influenza virus, measles virus, coronavirus, and varicella virus, bacterial pneumonia caused by Haemophilus influenzae, Staphylococcus aureus, and Streptococcus pneumonia, and atypical pneumonia caused by microorganisms such as mycoplasma and chlamydia).

[0019] As used herein, "gas" refers to a gas. A gas may be in gaseous form or dissolved in a liquid. However, unless otherwise specified, in this specification, gas refers to a gas in gaseous form.

[0020] As used herein, "oxygen-containing liquid" means a liquid in which O2 is dissolved.

[0021] As used herein, the term "intestinal tract" refers to the small intestine and the large intestine. The large intestine includes the colon and the rectum. As used herein, colonic administration and rectal administration do not exclude administration from outside the body by making a hole in the large intestine or rectum, but may preferably be administration via the anus. Colonic administration or rectal administration may preferably be administration using an administration device such as an enema device. Colonic administration or rectal administration may also be administration via an artificial anus (e.g., via a stoma).

[0022] As used herein, oral administration refers to administration via the mouth. Oral administration is not particularly limited, but can be performed by conventional oral administration. Administration can also be performed via nasal tube administration, for example, via a nasal insertion device (e.g., a nasal tube). In nasal tube administration, a nasal tube can be inserted into the stomach, and the substance to be administered can be administered directly to the stomach.

[0023] According to a first aspect of the present invention, there is provided a pharmaceutical composition for oral administration, nasal tube administration, gastrostomy administration, or intestinal administration (particularly a pharmaceutical composition for colonic administration, more preferably a pharmaceutical composition for rectal administration), comprising a perfluorocarbon having oxygen dissolved therein. In this aspect, the pharmaceutical composition is in liquid form. Hereinafter, in this specification, the description of a pharmaceutical composition for intestinal administration can also be applied to a pharmaceutical composition for oral administration, nasal tube administration, and gastrostomy administration.

[0024] Perfluorocarbons are liquids at room temperature. Perfluorocarbons and other highly fluorinated liquids have a high affinity for gases; for example, they can dissolve oxygen 20 times more than water. PFC liquids are also inert and have low or no toxicity (Riess, (1984) Artificial Organs, 8: 34-56). Mammals can breathe oxygenated perfluorocarbons without long-term side effects and subsequently return to air breathing (Modell et al., (1970) Federation Proc., 29: 1731-1739; Modell et al., (1976) Chest, 69: 79-81). Here, oxygenated perfluorocarbon refers to perfluorocarbons that have dissolved oxygen by bubbling oxygen through the perfluorocarbon liquid. Fluorocarbon molecules used in the present invention can have a variety of structures, including linear or branched chain, or cyclic structures (Riess, (1984) Artificial Organs, 8: 34-56). Preferably, the fluorocarbon has from about 2, 3, 4, or 5 carbon atoms to about 10, 12, or 14 carbon atoms. Fluorocarbons that can be used in the present invention include many, including perfluorocarbons, which may have some degree of unsaturation and may contain bromine or hydrogen atoms, or they may be amine derivatives, although it is preferred that all hydrogens in the fluorocarbons be replaced with fluorine. Fluorocarbons include bis(F-alkyl)ethanes, such as C4F9=CH4CF9 (sometimes designated "F-44E"), i-C3F9=CHC6F 13 ("F-i36E"), and C6F 13 CH=CHC6CF 13 ("F-66E"); cyclic fluorocarbons, e.g., C 10 F 18("F-decalin", "perfluorodecalin" or "FDC"), F-adamantane ("FA"), F-methyladamantane ("FMA"), F-1,3-dimethyladamantane ("FDMA"), F-di- or F-trimethylbicyclo[3,3,1]nonane ("nonane"); perfluorinated amines, such as F-tripropylamine ("FTPA") and F-tri-butylamine ("FTBA"), F-4-methyloctahydroquinolizine ("FMOQ"), Fn-methyldecahydroisoquinoline ("FMIQ"), F Included are n-methyldecahydroquinoline ("FHQ"), Fn-cyclohexylprolidone ("FCHP"), and F-2-butyltetrahydrofuran ("FC-75" or "RM101"), perfluorobutane, perfluoropropane, perfluoropentane, perfluorohexane, perfluoroheptane, or perfluorooctane. Both linear and branched isomers are contemplated. Other suitable fluorocarbons are brominated perfluorocarbons, such as 1-bromo-heptadecafluorooctane (CF 17 Br, "PFOB", perflubron or perflubron), 1-bromopenta-decafluorohexane (CF 13 Br, "PFHB"). Other brominated fluorocarbons are disclosed in U.S. Patent No. 3,975,512 to Long. Fluorocarbons having non-fluorine substituents, such as perfluorooctyl chloride and perfluorooctyl hydrogen, as well as those having different numbers of carbon atoms, e.g., 6-12 carbon atoms, are also contemplated. Other fluorocarbons contemplated according to the present invention include perfluoroalkylated ethers or polyethers, such as (CF3)2CFO(CF2CF2)2OCF(CF3)2, (CF3)2CFO(CF2CF2)3OCF(CF3), (CF3)CFO(CF2CF2)F, (CF3)2CFO(CF2CF2)2F, (CF3) 13 )2O. Additionally, fluorocarbon-hydrocarbon compounds such as those of the general formula C are also included (as long as the compounds are liquid at room temperature). n F 2n+1 C n’ F 2n’+1 , Cn F 2n+1 OC n’ F 2n’+1 , or C n F 2n+1 CF=CHC n’ F 2n’+1 [wherein n and n' are the same or different and range from about 1 to about 10. Such compounds include, for example, C8F 17 C2H5 and C6F 13 CH=CHC6H 13 is included.

[0025] In certain preferred embodiments of the present invention, the perfluorocarbon (PFC) is one or more selected from the group consisting of, for example, perfluorooctane, perfluorobutylperfluorotetrahydrofuran, perfluoro-1-isopropoxyhexane, perfluoro-1,4-diisopropoxybutane, and octadecafluorodecahydronaphthalene. In other or further embodiments, the PFC in the composition is perfluorodecalin (PFD; C 10 F 18 ), perflubron (PFB; C8BrF 17 ), perfluoro-1,3-dimethylcyclohexane, FC-75, perfluorooctane, and perfluoro-octyl bromide. In some embodiments, the PFC is or includes a PFC having a cycloalkyl group, such as perfluorodecalin, perfluoro-1,3-dimethylcyclohexane, or FC-75.

[0026] According to the present invention, a pharmaceutical composition for enteral administration contains an effective amount of a perfluorocarbon having dissolved oxygen, where the effective amount is an amount that, when administered enterally (preferably into the large intestine, more preferably into the rectum), transports oxygen into the blood through the intact intestinal mucosa and increases the oxygen partial pressure in the blood (e.g., in the artery, vein, pulmonary artery, pulmonary vein, or left or right ventricle).

[0027] According to the present invention, perfluorocarbons with dissolved oxygen have an oxygen partial pressure higher than the blood oxygen partial pressure. In human adults, oxygen saturation is approximately 98% at an oxygen partial pressure of 100 mmHg, approximately 95% at an oxygen partial pressure of 80 mmHg, and approximately 90% at an oxygen partial pressure of 60 mmHg. Therefore, perfluorocarbons with dissolved oxygen preferably have an oxygen partial pressure of, for example, 100 mmHg or more, 150 mmHg or more, 200 mmHg or more, or 250 mmHg or more. This is expected to enable intestinal gas ventilation using perfluorocarbons. In a preferred embodiment, oxygen can be artificially dissolved in perfluorocarbons. For example, oxygen dissolution in perfluorocarbons can be achieved by bubbling oxygen gas through a perfluorocarbon solution. For example, oxygen gas can be bubbled until the oxygen concentration in the perfluorocarbon is saturated or reaches 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more of the saturated oxygen concentration. Bubbling may be performed using a device that bubbles oxygen gas through the perfluorocarbon solution. The above-mentioned saturation concentration refers to the concentration at room temperature and atmospheric pressure. For example, according to the present invention, a gaseous composition (pharmaceutical composition) containing oxygen gas can be dissolved in perfluorocarbon before administration, and then administered to the intestines of a subject. For example, according to the present invention, a pharmaceutical composition containing perfluorocarbon may have oxygen dissolved therein, or preferably have oxygen dissolved therein before administration, and then be administered to the intestines (preferably the large intestine, particularly the rectum) of a subject. Alternatively, a pharmaceutical composition containing a perfluorocarbon with an effective amount of oxygen dissolved therein may be provided and administered to the intestines of a subject.

[0028] According to the present invention, for example, a pharmaceutical composition containing a perfluorocarbon may have oxygen dissolved therein, or preferably have oxygen dissolved therein prior to administration, and then be orally administered to a subject. Alternatively, a pharmaceutical composition containing an effective amount of a perfluorocarbon with oxygen dissolved therein may be provided and orally administered to a subject.

[0029] According to the present invention, for example, a pharmaceutical composition containing a perfluorocarbon may have oxygen dissolved therein, or preferably have oxygen dissolved therein before administration, and then be administered to a subject via nasal tube feeding. Alternatively, a pharmaceutical composition containing a perfluorocarbon with an effective amount of dissolved oxygen may be provided and administered to a subject via nasal tube feeding. Nasal tube feeding may be into the stomach.

[0030] In a preferred embodiment, the perfluorocarbon has an oxygen partial pressure of 250 mmHg or more under atmospheric conditions (oxygen concentration of approximately 21%), and therefore, perfluorocarbons maintained under atmospheric conditions (or having oxygen dissolved therein under atmospheric conditions) can be used in the present invention.

[0031] When the pharmaceutical composition for enteral administration of the present invention (preferably, a pharmaceutical composition for enteral administration, more preferably, a pharmaceutical composition for rectal administration) is administered to the intestinal tract (preferably, the large intestine) of a subject, oxygen dissolved in the perfluorocarbon permeates the intestinal mucosa and is transferred to the blood. This improves the subject's blood oxygen partial pressure. Therefore, the pharmaceutical composition for enteral administration of the present invention (preferably, a pharmaceutical composition for enteral administration, more preferably, a pharmaceutical composition for rectal administration) can be used to treat hypoxemia. The subject to which the pharmaceutical composition is administered may be, for example, a patient with an arterial blood oxygen saturation of 90 or less, 85 or less, 80 or less, 75 or less, 70 or less, 65 or less, or 60 or less. Furthermore, when the pharmaceutical composition for enteral administration of the present invention (preferably, a pharmaceutical composition for enteral administration, more preferably, a pharmaceutical composition for rectal administration) is administered to the intestinal tract (preferably, the large intestine) of a subject, gases (particularly, carbon dioxide) dissolved in the blood are adsorbed by the perfluorocarbon, resulting in a decrease in the carbon dioxide concentration in the blood. Therefore, the pharmaceutical composition of the present invention for intestinal administration (preferably a pharmaceutical composition for colonic administration, more preferably a pharmaceutical composition for rectal administration) can be used to lower blood gas concentrations (particularly blood carbon dioxide concentrations). The target of the pharmaceutical composition is, for example, arterial blood carbon dioxide partial pressure (PaCO 2The patient may have a blood carbon dioxide partial pressure of >45 mmHg. In diseases accompanied by airway obstruction, such as asthma and chronic obstructive pulmonary disease (COPD), carbon dioxide cannot be sufficiently excreted, and blood carbon dioxide partial pressure may increase. Therefore, the pharmaceutical composition of the present invention can be used to treat these diseases (or conditions) accompanied by an increase in blood carbon dioxide partial pressure (e.g., greater than 45 mmHg). In one embodiment, the pharmaceutical composition for enteral administration of the present invention can be administered in a single dose, multiple doses, or continuously. Continuous administration can be performed by withdrawing the administered PFC and administering a new PFC. When used to reduce carbon dioxide partial pressure, the PFC does not need to be further oxygenated.

[0032] Hypoxemia is also induced in subjects with respiratory failure. Therefore, the pharmaceutical composition for enteral administration of the present invention (preferably, a pharmaceutical composition for colonic administration, more preferably, a pharmaceutical composition for rectal administration) can be used to treat respiratory failure in a subject. The pharmaceutical composition for enteral administration of the present invention (preferably, a pharmaceutical composition for colonic administration, more preferably, a pharmaceutical composition for rectal administration) can be used to treat hypoxemia in a subject with respiratory failure. Thus, the pharmaceutical composition for enteral administration of the present invention (preferably, a pharmaceutical composition for colonic administration, more preferably, a pharmaceutical composition for rectal administration) can be used to supply oxygen to the blood of a subject.

[0033] The pharmaceutical composition of the first aspect does not require the intestinal tract of the subject to be administered to be stripped of its mucosa.

[0034] The pharmaceutical composition of the present invention for enteral administration is a liquid formulation. The pharmaceutical composition of the present invention for enteral administration may further comprise a pharmaceutically acceptable excipient.

[0035] In some embodiments, pharmaceutical compositions containing perfluorocarbons with dissolved oxygen can be administered orally to a human. In some embodiments, pharmaceutical compositions containing perfluorocarbons with dissolved oxygen can be administered to a human via nasogastric tube into the human's stomach. In some embodiments, pharmaceutical compositions containing perfluorocarbons with dissolved oxygen can be administered rectally to a human. In some preferred embodiments, administration can increase the partial pressure of oxygen in the human's blood and / or decrease the partial pressure of carbon dioxide in the human's blood.

[0036] In some embodiments, the pharmaceutical composition comprising a perfluorocarbon having dissolved oxygen can be a perfluorocarbon maintained in the atmosphere and can be administered orally to a human. In some embodiments, the pharmaceutical composition comprising a perfluorocarbon having dissolved oxygen can be a perfluorocarbon maintained in the atmosphere and can be administered to a human via a nasogastric tube into the human's stomach. In some embodiments, the pharmaceutical composition comprising a perfluorocarbon having dissolved oxygen can be a perfluorocarbon maintained in the atmosphere and can be administered to a human rectally. In some preferred embodiments, administration can increase the partial oxygen pressure in the human's blood and / or decrease the partial carbon dioxide pressure in the blood.

[0037] In some embodiments, pharmaceutical compositions containing perfluorocarbons with dissolved oxygen are artificially oxygenated. In preferred embodiments, artificial oxygenation can be achieved by bubbling oxygen through a liquid containing the perfluorocarbon. In some embodiments, such pharmaceutical compositions can be administered orally to a human. In some embodiments, such pharmaceutical compositions can be administered to a human via a nasogastric tube into the human's stomach. In some embodiments, such pharmaceutical compositions can be administered rectally to a human. In some preferred embodiments, administration can increase the partial pressure of oxygen in the human's blood and / or decrease the partial pressure of carbon dioxide in the human's blood.

[0038] In some preferred embodiments, the perfluorocarbon may be perfluorodecalin. In some preferred embodiments, the perfluorocarbon may be perflubron.

[0039] The pharmaceutical composition of the present invention for intestinal administration may be loaded into an administration device for intestinal administration (preferably, an administration device for colonic administration, more preferably, an administration device for rectal administration). The administration device for intestinal administration (preferably, an administration device for colonic administration, more preferably, an administration device for rectal administration) may be an enema having a fig-shaped container (see, for example, Figure 5) or an enema having a bellows-shaped container (see, for example, Figure 6).

[0040] As shown in Figure 5, enema device 10 having a fig-shaped container has a nozzle 1 and a fig-shaped container 2. A pharmaceutical composition for intestinal administration of the present invention (preferably a pharmaceutical composition for colonic administration, more preferably a pharmaceutical composition for rectal administration) is stored inside fig-shaped container 2. Enema device 10 having a fig-shaped container may further include a check valve in nozzle 1. When using enema device 10 having a fig-shaped container, a user can squeeze elastic fig-shaped container 2 to push its contents into the intestinal tract.

[0041] As shown in Figure 6, an enema device 20 having a bellows-type container has a nozzle 21 and a bellows-type container 23, and preferably has an anti-reflux valve 22. A pharmaceutical composition for intestinal administration of the present invention (preferably a pharmaceutical composition for administration into the large intestine, more preferably a pharmaceutical composition for administration into the rectum) is stored inside the bellows-type container 23. When using the enema device 20 having a bellows-type container, a user can squeeze the elastic bellows-type container 23 to push the contents into the intestinal tract (preferably into the large intestine, more preferably into the rectum).

[0042] Thus, according to the present invention, the pharmaceutical composition of the present invention can be formulated as an administration device for intestinal administration (preferably, an administration device for colonic administration, more preferably, an administration device for rectal administration). The present invention provides an administration device for intestinal administration (preferably, an administration device for colonic administration, more preferably, an administration device for rectal administration) comprising the pharmaceutical composition of the present invention.

[0043] The pharmaceutical compositions of the present invention can be administered to a subject using an administration device having a tube placed in the intestinal tract (for example, in the large intestine, preferably in the rectum) (for example, an administration device equipped with a nasally inserted tube such as an Elemental Diet Tube (ED tube), gastrointestinal tube, or ileus tube, or an administration device equipped with a transanally inserted tube such as an ileus tube). The pharmaceutical compositions of the present invention may also be administered directly to the stomach through a gastrostomy. Administration through a gastrostomy (transgastrostomy administration) can be performed using a gastrostomy tube or the like. Intracolonic administration or intrarectal administration may also be via an artificial anus (for example, via a stoma).

[0044] In addition, a second aspect of the present invention provides a gaseous pharmaceutical composition for intestinal administration (preferably for colonic administration, more preferably for rectal administration) comprising oxygen gas. The gaseous pharmaceutical composition for intestinal administration (preferably for colonic administration, more preferably for rectal administration) of the present invention does not contain perfluorocarbon. The gaseous pharmaceutical composition for intestinal administration (preferably for colonic administration, more preferably for rectal administration) of the present invention contains oxygen in a concentration and amount sufficient to improve the blood oxygen partial pressure of a subject when administered to the intestinal tract of the subject. The gaseous pharmaceutical composition has a gas composition suitable for the medical use of the present invention.

[0045] The pharmaceutical composition of the present invention according to the second aspect can be preferably administered to a subject having a mucosa-removed intestinal tract (preferably the large intestine, particularly the distal intestine, or the rectum). Here, mucosa-removed means that the mucosa has been removed or peeled from at least a portion of the intestinal tract (i.e., the entire portion or a portion of the portion that comes into contact with the pharmaceutical composition). This allows oxygen to be administered in the form of gas from the intestinal tract without using perfluorocarbons, thereby increasing the subject's blood oxygen partial pressure.

[0046] Mucosa removal can be performed by a doctor as appropriate, taking into consideration the age, weight, height, sex, etc. of the subject.

[0047] The pharmaceutical composition of the present invention according to the second aspect can be preferably administered to a subject whose intestinal tract (preferably the large intestine, more preferably the rectum) has been coated with a PFC. Here, coating the intestinal tract (preferably the large intestine) with a PFC means that at least a portion of the intestinal tract (preferably the large intestine, more preferably the rectum) (i.e., the entire or a portion of the portion that comes into contact with the pharmaceutical composition) is coated with a PFC. By coating the surface of the intestinal tract (preferably the large intestine, more preferably the rectum) with a PFC and then delivering oxygen to the intestinal tract, the oxygen dissolves in the PFC. This is expected to exert an effect similar to that of the pharmaceutical composition of the present invention according to the first aspect, thereby improving the oxygen saturation of the subject. In this aspect, a composition for administration to the large intestine containing a perfluorocarbon can be preferably used, and the intestinal tract of the subject can be coated with the perfluorocarbon.

[0048] The pharmaceutical composition of the present invention according to the second aspect may be used to treat hypoxemia.The pharmaceutical composition of the present invention according to the second aspect may be used to treat hypoxia-ischemia.

[0049] Hypoxemia is also induced in subjects with respiratory failure. Thus, the pharmaceutical composition of the present invention according to the second aspect can be used to treat respiratory failure in a subject. Also, the pharmaceutical composition of the present invention according to the second aspect can be used to treat hypoxemia in a subject with respiratory failure. Thus, the pharmaceutical composition of the present invention according to the second aspect can be for use in oxygenating the blood of a subject.

[0050] The pharmaceutical composition of the present invention according to the second aspect may contain other gases besides oxygen, such as nitrogen, as long as they are not harmful.

[0051] The pharmaceutical composition of the present invention according to the second aspect can be administered to a subject using an administration device having a tube placed in the intestinal tract (preferably the large intestine, more preferably the rectum) (for example, an administration device equipped with a nasally inserted tube such as an Elemental Diet Tube (ED tube), gastrointestinal tube, or ileus tube, or an administration device equipped with a transanally inserted tube such as an ileus tube). The pharmaceutical composition of the present invention may also be administered directly to the stomach through a gastrostomy. Administration through a gastrostomy (transgastrostomy administration) can be carried out using a gastrostomy tube or the like. Intracolonic administration or intrarectal administration may also be via an artificial anus (for example, via a stoma).

[0052] To administer the pharmaceutical composition of the present invention according to the first and / or second aspects, an administration control device 30 having a tube placed in the intestinal tract can be used. As shown in FIG. 7, the administration control device 30 can include a delivery unit 31 for delivering the pharmaceutical composition of the present invention (toward the delivery unit 31) to the tube and a control unit 32 for controlling the delivery rate by the delivery unit 31 based on the oxygen saturation level in the patient's blood. Blood oxygen saturation can be measured using various methods known to those skilled in the art (e.g., a measuring device that irradiates a fingertip with red and infrared light and measures the oxygen saturation level in arterial blood based on the absorption wavelength of the light transmitted through the fingertip can be used). Thus, according to the present invention, there is provided an administration control device for the pharmaceutical composition of the present invention (hereinafter referred to as the "administration control device of the present invention") that includes a delivery unit 31 for delivering the pharmaceutical composition of the present invention to the tube and a control unit 32 for controlling the delivery rate by the delivery unit 31 based on the oxygen saturation level in the patient's blood.

[0053] The administration control device of the present invention further includes a receiving unit 33 that receives information about oxygen saturation from a blood oxygen monitor. Based on the information about oxygen saturation received by the receiving unit 33, if the oxygen saturation falls below (or is equal to or lower than) a predetermined value, the control unit 32 can send a signal to the sending unit 31 to increase the delivery rate. Based on the information about oxygen saturation received by the receiving unit 33, if the oxygen saturation rises above (or exceeds) a predetermined value, the control unit 32 can send a signal to the sending unit 31 to decrease the delivery rate. Furthermore, in the administration control device of the present invention, the receiving unit 33 may further receive information about intestinal pressure (particularly intestinal pressure in the large intestine) (this does not exclude the case where the receiving unit for information about oxygen saturation and the receiving unit for information about intestinal pressure are separate). If the intestinal pressure exceeds a predetermined value or if the intestinal pressure begins to increase during infusion, the control unit 32 may stop sending a signal to the delivery unit to increase the delivery rate or send a signal to the delivery unit 31 to decrease the delivery rate, based on the intestinal pressure information received by the receiving unit 33. Furthermore, if the intestinal pressure falls below a predetermined value, the control unit 32 may send a signal to the delivery unit 31 to increase the delivery rate. Alternatively, the delivery unit 31 that has received the signal to increase the delivery rate may be configured to increase the delivery rate. Here, the control unit 32 can determine whether to send a signal to increase the delivery rate or a signal to decrease the delivery rate to the delivery unit 31 based on the relationship with the subject's oxygen saturation and / or intestinal pressure. Furthermore, the delivery unit 31 that has received a signal to decrease the delivery rate may be configured to decrease the delivery rate. The receiving unit 33 may be physically connected to the blood oxygen monitor via a cable or the like and receive signals through the cable or may receive signals from the oxygen monitor via radio signals. The pharmaceutical composition of the present invention is ejected from the delivery section 31 through the delivery port 34 from the administration control device. The ejected pharmaceutical composition can be administered into the intestine via an administration device equipped with a tube or an administration device to which the delivery port can be connected. Typically, the administration device is configured separately from the administration control device and can be connected to the administration control device when in use.In this way, the administration control device 30 of the present invention can be operated to maintain the subject's blood oxygen saturation above a certain level and / or the subject's intestinal pressure below a certain level. Note that appropriate blood oxygen saturation and intestinal pressure can be determined appropriately by a physician. Generally, when the intestinal pressure reaches a certain level or increases (or begins to increase), it is not desirable to increase the intestinal administration rate of the drug even if the oxygen saturation is below a specified value. The present invention also provides a method for operating the administration control device of the present invention. The administration device may be equipped with a sensor that measures the intestinal pressure in the large intestine, and the measurement value from the sensor can be transmitted to the receiving unit 33 of the administration control device. In a preferred embodiment, the intestinal tract is the large intestine, more preferably the rectum.

[0054] The predetermined value for oxygen saturation can be, for example, 50% or more, 60% or more, 70% or more, 80% or more, or 90% or more, and can be, for example, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, or 96% or more.

[0055] The administration control device 30 of the present invention may have a storage section 35 capable of storing the pharmaceutical composition of the present invention. The liquid supply section 31 can expel the pharmaceutical stored in the storage section 35 from the administration device via the liquid supply port (or air supply port) 34. The liquid supply port (or air supply port) 34 can be connected to an administration device having a tube placed in the intestinal tract (preferably the large intestine, more preferably the rectum), for example. While the storage section 35 is illustrated within the administration device, it does not necessarily have to be included within the device; it need only be connected to the device. Furthermore, the administration device 30 does not necessarily have to have a storage section 35. For example, a container (e.g., a storage container) cartridge containing the pharmaceutical composition of the present invention may be connected to the administration device as the storage section 35. In this case, when the pharmaceutical in the container (e.g., storage container) cartridge containing the pharmaceutical composition of the present invention is consumed, it is replaced with a container cartridge containing a new pharmaceutical composition. Alternatively, the pharmaceutical may be prepared just before use by mixing oxygen gas with a perfluorocarbon and supplied to the storage section 35.

[0056] A subject may be administered either or both of the pharmaceutical composition of the present invention according to the first aspect and the pharmaceutical composition of the present invention according to the second aspect. In this case, the pharmaceutical composition of the present invention according to the first aspect and the pharmaceutical composition of the present invention according to the second aspect may be administered simultaneously or sequentially. When administered sequentially, the pharmaceutical composition of the present invention according to the first aspect may be administered first, followed by the pharmaceutical composition of the present invention according to the second aspect, or the pharmaceutical composition of the present invention according to the second aspect may be administered first, followed by the pharmaceutical composition of the present invention according to the first aspect. Alternatively, an administration cycle including the administration of the pharmaceutical composition of the present invention according to the first aspect and the pharmaceutical composition of the present invention according to the second aspect may be carried out. In addition, when the pharmaceutical composition of the present invention according to the first aspect is administered first, followed by the pharmaceutical composition of the present invention according to the second aspect, the effect of the pharmaceutical composition of the present invention according to the second aspect can be enhanced by administering the pharmaceutical composition of the present invention according to the second aspect into the intestinal tract (preferably into the large intestine, more preferably into the rectum) while the PFC in the pharmaceutical composition of the present invention according to the first aspect is coating the intestinal lining (preferably the large intestine, more preferably the rectum).

[0057] When both the pharmaceutical composition of the present invention according to the first aspect and the pharmaceutical composition of the present invention according to the second aspect are administered by an administration device via a tube placed in the intestinal tract, an administration device 40 can be used, as shown in FIG. 8, which includes a tube 41, a balloon 42 for fixing the tube in the rectum, a liquid administration port 43, a gas administration port 44, and a collection container 45 for collecting excrement and the like in the rectum. The administration device 40 may have a pressure adjustment port 46 for adjusting the pressure in the intestine. The pressure adjustment port 46 can appropriately control the pressure in the intestine using a valve. An example of such an administration device is a device capable of simultaneously administering a liquid and a gas, such as a Flexiseal. The balloon has a small volume when inserted and can be inflated with air or the like after the tube 41 is inserted.

[0058] Administration device 40 can be used to administer to a subject a pharmaceutical composition according to the first aspect and a pharmaceutical composition according to the second aspect of the invention simultaneously or sequentially.

[0059] Those skilled in the art would be able to appropriately adjust the dosage and administration time of the pharmaceutical composition of the present invention based on the patient's blood oxygen partial pressure and oxygen saturation. In addition, those skilled in the art would also be able to use other methods, such as an artificial respirator and ECMO, which are used to treat respiratory failure.

[0060] In a further aspect of the invention, 1. A method of administering oxygen to a subject, comprising: Methods are provided that include administering to the subject a pharmaceutical composition for enteral administration (e.g., a pharmaceutical composition of the first aspect) that includes a perfluorocarbon having dissolved therein oxygen. In a preferred embodiment, the oxygen is administered to the subject's enteral tract, particularly the large intestine or rectum.

[0061] In a further aspect of the invention, 1. A method of treating hypoxemia in a subject in need thereof, comprising: Methods are provided that include administering to the subject a pharmaceutical composition for enteral administration (e.g., a pharmaceutical composition of the first aspect) that includes a perfluorocarbon having dissolved therein oxygen. In a preferred embodiment, the oxygen is administered to the subject's enteral tract, particularly the large intestine or rectum.

[0062] In this aspect, the subject may have, for example, a disease described in Table 1 below. [Table 1]

[0063] In a further aspect of the invention, 1. A method of treating respiratory failure in a subject in need thereof, comprising: Methods are provided that include administering to the subject a pharmaceutical composition for enteral administration (e.g., a pharmaceutical composition of the first aspect) that includes a perfluorocarbon having dissolved therein oxygen. In a preferred embodiment, the oxygen is administered to the subject's enteral tract, particularly the large intestine or rectum.

[0064] In some embodiments of the present invention, the respiratory failure may be type I respiratory failure. In some embodiments, the respiratory failure may be pneumonia. In some embodiments, the pneumonia may be, for example, pneumonia caused by an infectious disease, such as pneumonia caused by a coronavirus infection (e.g., a viral infection caused by SARS-CoV-2).

[0065] In a further aspect of the invention, 1. A method of lowering blood carbon dioxide partial pressure in a subject, comprising: A method is provided which comprises administering a perfluorocarbon or a perfluorocarbon having dissolved oxygen (e.g., a pharmaceutical composition of the first aspect) to the intestinal tract of a subject whose intestinal mucosa has been removed. In a preferred embodiment, the intestinal tract may be the large intestine or rectum.

[0066] In a further aspect of the invention, 1. A method of administering oxygen to a subject, comprising: Methods are provided that include administering oxygen gas (e.g., a pharmaceutical composition of the second aspect) to the intestinal tract of a subject from which the intestinal mucosa has been removed. In a preferred embodiment, the oxygen is administered to the large intestine or rectum of the subject.

[0067] In a further aspect of the invention, 1. A method of treating hypoxemia in a subject in need thereof, comprising: A method is provided, comprising administering oxygen gas (e.g., a pharmaceutical composition of the second aspect) to the intestinal tract of a subject from which the intestinal mucosa has been removed. In a preferred embodiment, the intestinal tract may be the large intestine or rectum.

[0068] In a further aspect of the invention, 1. A method of treating respiratory failure in a subject in need thereof, comprising: A method is provided, comprising administering oxygen gas (e.g., a pharmaceutical composition of the second aspect) to the intestinal tract of a subject from which the intestinal mucosa has been removed. In a preferred embodiment, the intestinal tract may be the large intestine or rectum.

[0069] In some embodiments of the present invention, the respiratory failure may be type 1 respiratory failure. In some embodiments of the present invention, the method of the present invention, which comprises administering oxygen gas (e.g., the pharmaceutical composition of the second aspect), may further comprise removing the mucosa of the intestinal tract of the subject. In a preferred embodiment, the intestinal tract may be the large intestine or the rectum.

[0070] In a further aspect of the invention, 1. A method of lowering blood carbon dioxide partial pressure in a subject, comprising: A method is provided, comprising administering oxygen gas (e.g., a pharmaceutical composition of the second aspect) to the intestinal tract of a subject whose intestinal mucosa is coated with a perfluorocarbon. In a preferred embodiment, the intestinal tract may be the large intestine or rectum.

[0071] In a further aspect of the invention, 1. A method of administering oxygen to a subject, comprising: Methods are provided that include administering oxygen gas (e.g., a pharmaceutical composition of the second aspect) to the intestinal tract of a subject whose intestinal mucosa is coated with a perfluorocarbon. In a preferred embodiment, the oxygen is administered to the large intestine or rectum of the subject.

[0072] In a further aspect of the invention, 1. A method of treating hypoxemia in a subject in need thereof, comprising: A method is provided, comprising administering oxygen gas (e.g., a pharmaceutical composition of the second aspect) to the intestinal tract of a subject whose intestinal mucosa is coated with a perfluorocarbon. In a preferred embodiment, the intestinal tract may be the large intestine or rectum.

[0073] In a further aspect of the invention, 1. A method of treating respiratory failure in a subject in need thereof, comprising: A method is provided, comprising administering oxygen gas (e.g., a pharmaceutical composition of the second aspect) to the intestinal tract of a subject whose intestinal mucosa is coated with a perfluorocarbon. In a preferred embodiment, the intestinal tract may be the large intestine or rectum.

[0074] In some embodiments of the present invention, the respiratory failure may be type 1 respiratory failure. In some embodiments of the present invention, the method of the present invention, which comprises administering oxygen gas (e.g., a pharmaceutical composition of the second aspect), may further comprise coating the mucosa of the intestinal tract of the subject with a perfluorocarbon. In a preferred embodiment, the intestinal tract may be the large intestine or rectum.

[0075] In a further aspect of the invention, 1. A method of lowering blood carbon dioxide partial pressure in a subject, comprising: A method is provided, comprising administering oxygen gas (e.g., a pharmaceutical composition of the second aspect) to the intestinal tract of a subject whose intestinal mucosa is coated with a perfluorocarbon. In a preferred embodiment, the intestinal tract may be the large intestine or rectum.

[0076] In the above, the coating of the mucous membrane of the intestinal tract may be total or partial. The intestinal tract may particularly be the rectum, and the coating may be total or partial of the mucous membrane of the rectum.

[0077] In a further aspect of the present invention, there can be provided a composition comprising oxygen gas for use in the above method.

[0078] In a further aspect of the present invention, there can be provided a composition comprising a perfluorocarbon for use in the above method.

[0079] In a further aspect of the present invention, there can be provided a composition comprising a perfluorocarbon having oxygen gas dissolved therein for use in the above method.

[0080] In a further aspect of the present invention, there is provided the use of a perfluorocarbon having oxygen dissolved therein in the manufacture of a pharmaceutical composition for enteral administration (preferably for colonic administration, more preferably for rectal administration). The pharmaceutical composition for enteral administration (preferably for colonic administration, more preferably for rectal administration) of the present invention can be used to treat hypoxemia. Furthermore, the pharmaceutical composition for enteral administration (preferably for colonic administration, more preferably for rectal administration) of the present invention can be used to treat respiratory failure in a subject. Furthermore, the pharmaceutical composition for enteral administration (preferably for colonic administration, more preferably for rectal administration) of the present invention can be used to treat hypoxemia in a subject with respiratory failure. Thus, the pharmaceutical composition for enteral administration (preferably for colonic administration, more preferably for rectal administration) of the present invention can be used to supply oxygen to the blood of a subject.

[0081] In a further aspect of the present invention, there is provided a perfluorocarbon having dissolved oxygen for enteral administration (preferably for colonic administration, more preferably for rectal administration). The perfluorocarbon having dissolved oxygen of the present invention can be used to treat hypoxemia. The perfluorocarbon having dissolved oxygen of the present invention can also be used to treat respiratory failure in a subject. The perfluorocarbon having dissolved oxygen of the present invention can also be used to treat hypoxemia in a subject with respiratory failure. Thus, the perfluorocarbon having dissolved oxygen of the present invention can be used to oxygenate the blood of a subject.

[0082] In a further aspect of the present invention, there is provided use of oxygen gas in the manufacture of a gaseous pharmaceutical composition for enteral administration (preferably for colonic administration, more preferably for rectal administration). The gaseous pharmaceutical composition of the present invention for enteral administration (preferably for colonic administration, more preferably for rectal administration) can be used to treat hypoxemia. The gaseous pharmaceutical composition of the present invention for enteral administration (preferably for colonic administration, more preferably for rectal administration) can be used to treat respiratory failure in a subject. The gaseous pharmaceutical composition of the present invention for enteral administration (preferably for colonic administration, more preferably for rectal administration) can be used to treat hypoxemia in a subject with respiratory failure. The gaseous pharmaceutical composition of the present invention for enteral administration (preferably for colonic administration, more preferably for rectal administration) can be used to lower the blood carbon dioxide partial pressure in a subject. Thus, the gaseous pharmaceutical composition of the present invention for enteral administration (preferably for colonic administration, more preferably for rectal administration) can be used to oxygenate the blood of a subject.

[0083] In a further aspect of the present invention, oxygen gas for enteral administration (preferably for colonic administration, more preferably for rectal administration) is provided. The oxygen gas of the present invention can be used to treat hypoxemia. The oxygen gas of the present invention can also be used to treat respiratory failure in a subject. The oxygen gas of the present invention can also be used to treat hypoxemia in a subject with respiratory failure. Thus, the oxygen gas of the present invention can be used to supply oxygen to the blood of a subject.

[0084] The pharmaceutical compositions of the first and second aspects of the present invention can be administered to a subject so as to maintain the subject's blood oxygen partial pressure at 60 mmHg or higher. The pharmaceutical compositions of the first and second aspects of the present invention can be administered to a subject once or multiple times daily. The pharmaceutical compositions of the first and second aspects of the present invention can be used in conjunction with artificial ventilation using a ventilator and an artificial lung (e.g., extracorporeal membrane oxygenation). [Example]

[0085] [method] animal C57BL / 6J mice were purchased from SLC (Shizuoka, Japan). These mice were housed in a pathogen-free environment with a 12-h light-dark cycle and free access to water and food. All animal care and experiments were conducted in accordance with institutional and national guidelines (Ministry of Education, Culture, Sports, Science and Technology) and were approved by the Kyoto University Animal Care Committee (approval number: Med Kyo 19583).

[0086] Ventilation of intestinal gas We designed an intestinal gas ventilation (IGV) system to deliver pure oxygen directly to the colon. Six different intestinal abrasion methods were initially evaluated (see Table 1). Mice were randomly assigned to eight groups (Table 1): Group 1, Sham (n = 3); Group 2, Non-Abrasion (n = 3); Group 3, Oral Administration of 2% Dextran Sodium Sulfate (DSS) for 5 days (n = 5); Group 4, Intestinal Administration of 2% DSS for 5 days (n = 5); Group 5, Oral Administration of 2% DSS for 5 days followed by a single infusion of basic fibroblast growth factor (bFGF) per intestine (n = 6); Group 6, Mild Mechanical Mucosal Abrasion (n = 10); Group 7, Moderate Mechanical Mucosal Abrasion (n = 10); and Group 8, Severe Mechanical Mucosal Abrasion (n = 5). For Groups 1 to 8, skin incisions were performed under anesthesia with ketamine (80–100 mg / kg) and xylazine (10 mg / kg), and blood samples were collected. Pure oxygen was administered to the intestine over a 4 cm area per colon, and the amount of oxygen in the inferior vena cava was estimated for Groups 2 to 8. Venous gas analysis was also performed for Group 1, and for Group 5, venous gas analysis was performed 3 days after bFGF injection. For the mechanical group, intestinal mucosa was scraped under anesthesia (see Table 1), and mechanical brushing using an interdental brush was induced along the length of the intestine for a specified time. For Groups 9 to 11, artificial ventilation (500 μl / breath, 100–120 breaths / min, 2 cmH2O puff) was performed. Mice were randomly assigned to three groups. Patients were randomly assigned to three groups: Group 9, sham group (n=10); Group 10, non-abrasive intestinal gas ventilation group (non-abrasive IGV group, n=7); and Group 11, mucosal abrasive intestinal gas ventilation group (moderate abrasive IGV group, n=11).

[0087] [Table 2]

[0088] Intestinal gas ventilation (intestinal fluid ventilation) Liquid Perfluorocarbons (PFCs) 12-16We developed an intestinal gas ventilation (ILV) system using a sham mouse model. Mice were randomly assigned to two groups: a sham group (group 9, n = 10) and an intestinal gas ventilation group (group 12, n = 12). For ILV, pure oxygen was bubbled through PFC (octadecafluorodecahydronaphthalene, Wako Pure Chemical Industries, Osaka, Japan) for 45 minutes to dissolve oxygen. One mL of PFC was administered via the intestinal tract, and the oxygen tension in the inferior vena cava at the right renal vein level was analyzed 120 minutes later.

[0089] Recovery of respiratory failure with IGV and ILV For the IGV experiment, animals were randomly assigned to two groups (Table 1). Group 13, the non-ventilated group (Sham group, n = 4); Group 14, the ventilated group with mucosal abrasion (moderate abrasion, IGV group, n = 4). Under anesthesia, the skin and trachea were incised, and mechanical ventilation was performed as described above. For Group 14, pure oxygen was administered into the intestinal lumen. In addition, hypoxia (FiO20.10) was administered to the mouse airway 10 minutes after mechanical ventilation, and the oxygen partial pressure in the left ventricle of the heart was estimated 10 minutes after hypoxia administration. Survival experiments were performed under FiO20.08 conditions, as FiO20.10 is a sublethal dose. Animals were randomly assigned to three groups (Table 1). Patients were randomly assigned to three groups: Group 15, a sham group (n = 3); Group 16, an intestinal gas ventilation group (non-mucosal stripping IGV, n = 3); and Group 17, a mucosal stripping intestinal gas ventilation group (moderate mucosal stripping IGV, n = 4). Survival rates were compared among Groups 15, 16, and 17. For the ILV experiment, mice were randomly assigned to two groups: a sham group (Group 13, n = 4) and an ILV group (Group 18, n = 4; Group 19, n = 4). PFC was administered via the intestinal tract as described above, and the oxygen tension in the left ventricle of the heart under hypoxic inhalation was analyzed 60 and 120 minutes later (FiO2 0.10, inhalation time: 10 minutes).

[0090] behavior analysis We analyzed the behavioral improvement of hypoxic mice treated with ILV. The mobility of each mouse was monitored by a set of two parameters from the fitted ellipse (centroid position (x, y)). Using these parameters, the walking distance of mice in the control and treatment groups (n = 3) was calculated every 20 seconds. The walking behavior of each mouse was observed for a total of 5 minutes. In the treatment group, hypoxia (FiO2 0.10) was administered 120 minutes after the intestinal injection using O2-labeled perfluorocarbon (Figure 4A).

[0091] Hematoxylin and eosin staining Adult loaches, Misgurnus anguillicaudatus (average body length approximately 15 cm), were purchased from Meito Suien Co., Ltd. (Aichi Prefecture). The intestines of C57BL / 6J mice and adult loaches were analyzed. The mouse intestines were divided into three groups: a non-intestinal respiration group (group 1, sham group), an intestinal respiration group (group 2, non-mucosally stripped IGV group), and a mucosally stripped intestinal respiration group (group 7, mucosally stripped IGV group). Histopathological analysis of the loach hindgut, for which intestinal respiration has been reported, was performed.

[0092] Histological quantification Slides prepared from mounted, formalin-fixed, paraffin-embedded tissues were stained with hematoxylin and eosin. Under a high-power microscope (400x, light microscope), 20 random fields were selected and blindly scored for each parameter. For slides from samples in Group 7, the distance between the intestinal lumen and the muscular mucosa was estimated at five random locations. Each slide was scored by three independent raters, including an experienced pathologist and surgeon.

[0093] Hypoxyprobe TM Immunochemical staining with Immunochemical analysis of intestinal regions undergoing intestinal respiration was performed using Hypoxyprobe TM -1 kit (HP2-100, Hypoxyprobe, Burlington, MA) according to the manufacturer's instructions.17 Briefly, the Hypoxyprobe TM A 60 mg / kg body weight dose of PI-1 solution was injected into the peritoneum of mice. Intestinal sections were fixed in 10% neutral-buffered formalin, subjected to antigen retrieval (blocking solution, 90°C for 20 minutes), washed with PBST (PBS + 0.1% Triton X-100), and exposed to FITC-conjugated anti-pimonidazole mouse monoclonal primary antibody for 60 minutes at room temperature. After further PBST washes, a peroxidase-conjugated anti-FITC rabbit secondary antibody was applied and visualized under a BX 43 light microscope (Olympus Corporation, Tokyo, Japan). The signal intensity of 10 mucosal epithelial cells adjacent to each intestinal ciliary segment was scored as negative (0 points), weakly positive (1 point), or strongly positive (2 points). A total of five fields were evaluated, and a total score was calculated. Three raters, including an experienced pathologist and surgeon, independently scored each slide.

[0094] RT-qPCR analysis To evaluate molecular changes associated with moderate and severe mechanical intestinal mucosal stripping, mice were sacrificed at 0 min, 20 min, 6 h, and 24 h after intestinal mucosal stripping (n = 12 per mechanical stripping). Intestinal tissues were collected, and RNA was immediately stored for later use (QIAGEN, Hilden, Germany). Total RNA from the tissues was extracted using the FastGene RNA Basic Kit (Nihon Genetics Co., Ltd., Tokyo). First-stranded cDNA was synthesized using ReverTra Ace qPCR Master Mix with gDNA Remover (Toyobo, Osaka, Japan). Quantitative PCR was performed on a QuantStudio 3 real-time PCR system (ThermoFisher Scientific, Tokyo, Japan) using THUNDERBIRD SYBR qPCR Mix (Toyobo, Osaka, Japan). Standard curves were generated for each gene for relative quantification, and the expression levels of each gene were normalized to the Rn28s gene. The specific primers used were as follows: Vegfa-F (SEQ ID NO: 1) 5'-AGGCTGCTGTAACGATGAAG-3' and Vegfa-R (SEQ ID NO: 2) 5′-TCTCCTATGTGCTGGCTTTG-3′; Anxa1-F (SEQ ID NO: 3) 5'-CCAGCACTCCAGCTTTCTTT-3' and Anxa1-R (SEQ ID NO: 4) 5'- TCCGAACGGGAGACCATAAT-3'; Spon1-F (SEQ ID NO: 5) 5'- AGAGAACCAGGAGGGAGATAAG-3' and Spon1-R (SEQ ID NO: 6) 5'- GCCACAGGACAGTTACTCATAAA-3'; Glud1-F (SEQ ID NO: 7) 5'- TACCGTTTGGAGGTGCTAAAG-3' and Glud1-R (SEQ ID NO: 8) 5'- CCATAGTGAACCTCCGTGTAAT-3'

[0095] Statistical analysis of results Statistical analysis was performed using JMP-Pro 14 software (Cary, NC, USA). Survival rates were estimated using the Kaplan-Meier method, and differences between groups were tested using the log-rank test. Differences in intravascular oxygen tension between the sham group, non-mucosal abrasive gas ventilation group, and mucosal abrasive gas ventilation group were analyzed using the Wilcoxon signed-rank test. A p value of less than 0.05 was considered statistically significant. All data are presented as mean ± standard deviation (SD).

[0096] [result] Intestinal gas ventilation (IGV) alleviates local hypoxic injury. Histopathological staining analysis revealed that the loach hindgut has abundant capillaries and red blood cells, which are thought to be important for intestinal respiratory capacity. 18We hypothesized that breathing would improve if the intestinal lumen was closer to the capillaries, and we selected several mouse models to test this hypothesis. To enable more efficient intraluminal access to the submucosal vessels, we applied various chemical and mechanical mucosal stripping protocols to remove the epithelium surrounding the distal intestine (Table 1, groups 1–8, Figure 1A and 1B). Of these, the moderate mechanical mucosal stripping protocol was the most efficient in enabling oxygen exchange with the intestinal lumen, increasing the dissolved oxygen concentration by 13.6 ± 5.66 mmHg compared to the non-mucosal stripped condition (Figure 4A). The distance between the intestinal lumen and the muscular mucosa in the mucosally stripped IGV group was significantly shorter than in the sham group (mucosally stripped IGV: 151.7 ± 13.7 µm, sham: 196 ± 17.8 µm, p = 0.012, Figure 4B). Importantly, the mortality rate was 0% in all groups: the sham group, the non-denuded group, the 2% DSS oral administration group, and the moderate mechanical demucosal group, demonstrating that these methods are nonlethal. In the other groups, the mortality rate was 16-20% due to colitis or intestinal bleeding as a result of intestinal demucosalization. These histopathological findings demonstrate a similarity between the hindgut of the loach in Group 7 mice and the demucosalized distal intestine (i.e., the rectum) (Figure 1C).

[0097] In M. anguillicaudatus, the intestinal air-breathing function begins to develop around 10 days after hatching. Recent RNA-seq analysis of the hindgut of M. anguillicaudatus at different developmental stages revealed the presence of gene signatures closely related to the acquisition of intestinal respiratory function, including upregulation of vascularization (VEGFA, SPON1B), mucosal inflammation (ANXA1), and downregulation of oxidative phosphorylation (GDH). 18We investigated whether mechanical mucosal stripping of the intestinal lumen induces similar gene expression changes in the mouse distal intestine, focusing on its mouse homologs, Vegfa, Spon1, Anxa1, and Glud1. Quantitative RT-PCR analysis showed that Vegfa and Anxa1 were significantly increased 6 and 24 hours after moderate or severe mucosal stripping, particularly in the anterior region of the dissected distal intestine, whereas Spon1 and Glud1 showed only minor changes compared to the control (non-mucosal stripped) (Figure 1D and Figure 4C). 18 .

[0098] To further evaluate the physiological changes in local tissues due to hypoxia, we performed a hypoxia-treated (FiO20.10) mouse (with or without IGV) test using Hypoxyprobe. TM Immunochemical staining of the intestine was performed using the IFN-1 kit. In the absence of IGV and hypoxia, positively stained cells (hypoxic cells) in sham mice were limited to the mucosal epithelium. However, after hypoxia, the number of strongly positive cells increased and was distributed throughout the mucosa, submucosa, and connective tissue (Figure 1E). In contrast, the number of hypoxic cells found in the hypoxic areas was much lower in the non-mucosally stripped IGV and mucosally stripped IGV groups (Figure 1E). The pathological scores of the non-mucosally stripped IGV and mucosally stripped IGV groups were significantly lower than those of the non-IGV group under hypoxia (mucosally stripped IGV vs. non-mucosally stripped IGV; p = 0.0001, non-mucosally stripped IGV vs. sham; p < 0.0001), demonstrating that intestinal gas ventilation significantly alleviates local hypoxic injury (Figure 1E and Figure 4D).

[0099] Whole-body oxygenation with intestinal gas ventilation Next, we tested whether IGV has a systemic oxygenation effect. First, we evaluated the survival benefit of IGV against lethal hypoxia (FiO2 0.08; Table 1, Groups 15–17). By 3000 seconds (50 minutes) after hypoxia inhalation, the survival rates of the control and non-mucosally stripped groups were 0%. Surprisingly, the survival rate of the mucosally stripped IGV group at 50 minutes was 75%, which was statistically significant compared with the control group (mucosally stripped IGV, 3 / 4; non-mucosally stripped IGV, 0 / 3; sham group, 0 / 3; P<0.001, Kaplan-Meier method and log-rank test, Figure 2A).

[0100] The oxygen partial pressure in the inferior vena cava was statistically higher in the mucosally stripped IGV group than in the sham group (p = 0.004). Furthermore, the oxygen partial pressures in the sham, non-mucosally stripped IGV, and mucosally stripped IGV groups were 31.6 ± 7.44, 32.9 ± 10.6, and 40.3 ± 9.57 mmHg, respectively (FiO2 = 0.21, Figure 2B, Groups 9–11). Similarly, the oxygen partial arterial pressure in the cardiac left ventricle during hypoxia was statistically higher in the mucosally stripped IGV group than in the sham group (p = 0.030). The oxygen pressure levels in the sham and mucosally stripped IGV groups were 40.0 ± 2.94 mmHg and 63.3 ± 6.94 mmHg, respectively (FiO2 = 0.10, Figure 2C, Groups 13–14). These findings demonstrate that intestinal gas ventilation is effective in mitigating potentially fatal hypoxia following mucosal stripping of the distal intestinal mucosa.

[0101] Therapeutic effect of intestinal gas ventilation Oxygenated perfluorocarbon (PFC) liquids have been developed to improve oxygenation, also known as liquid ventilation (LV). Due to their biocompatibility in humans, intrapulmonary application of PFCs in liquid or aerosol form has already been used clinically to reduce lung injury in cases of severe respiratory failure. PFC particle size is tissue-penetrating (having a diameter of less than a few micrometers). 19Given this, we investigated the use of PFC as an inert carrier of oxygen via intestinal delivery method, as this offers numerous advantages over mechanical mucosal abrasion-based approaches of the distal intestine.

[0102] The PFC was first prepared with O2 (1 L / min O2 bubbling for 45 min; Figure 3A). The PFC fluid was then instilled into the intestinal tract (i.e., rectum) of mice (groups 12, 18, and 19), hereafter referred to as the intestinal gas ventilation (ILV) group, at a total volume of 1 mL per mouse. After 45 min of O2 bubbling, the mean oxygen tension in the PFC was 438 ± 19.9 mmHg (n = 3, Figure 4E). The effects on treated mice were assessed by a mobility assay. In summary, the walking distance of each mouse was calculated and statistically increased in the O2-PFC infusion therapy group (ILV group administered PFC containing O2) after hypoxia inhalation compared to the control group (FiO2 0.10, control group: 0.408 ± 1.02 cm per 20 seconds; FiO2 0.10, treatment group: 3.34 ± 4.05 cm, p < 0.0001, Figure 3B).

[0103] In a replication experiment, male Lewis rats weighing 250-350g were divided into three groups: a control group, an I-EVA group (using Wako's research-grade perfluorodecalin (PFD)), and an I-EVA group (using F2C's clinical-grade perfluorodecalin). Perfluorodecalin bubbled with pure oxygen gas was administered intrarectally to the rats at 20ml / kg, and arterial blood samples were taken under anesthesia with 21% oxygen inhalation 15 and 120 minutes later to measure oxygen partial pressure.

[0104] Next, 20-30g C57BL6J mice were divided into two groups: a control group (administered saline) and an I-EVA group (oxygenated perfluorodecalin from F2C). Control mice were anesthetized with intraperitoneal administration of ketamine (80-100mg / kg) and xylazine (10mg / kg), then inhaled under 15% hypoxia. Once SpO2 reached the 70% range, oxygenated perfluorodecalin was administered intrarectally at 40ml / kg. The effects of respiratory failure were assessed using an SpO2 monitor. After the experiment, the enterally administered perfluorodecalin was collected, and the carbon dioxide concentration was measured and compared with the preoperative carbon dioxide concentration of the perfluorodecalin.

[0105] The results are shown in Figure 9. As shown in Figure 9, the oxygenated PFC group showed an improvement in blood oxygen partial pressure compared to the saline group at both 15 and 120 minutes after administration. Also, as shown in Figure 9, the oxygenated PFC group showed a significant decrease in blood carbon dioxide partial pressure at 120 minutes after administration compared to the saline group. This suggests that PFC not only has the ability to dissolve oxygen and replenish it in the blood, but also to adsorb carbon dioxide in the blood, thereby lowering the blood carbon dioxide concentration.

[0106] Next, to examine the blood vessels involved in enteral respiration, we performed vascular clamping of the inferior vena cava (IVC) or portal vein (PV). Specifically, male C57BL6J mice weighing 20–30 g were divided into three groups: a control group, a portal vein clamped group, and a vena cava clamped group. Each group was further divided into room air (21% oxygen) and hypoxia (10% oxygen) groups. Under anesthesia, mice inhaling 21% oxygen were given 40 ml / kg of Wako perfluorodecalin bubbled with pure oxygen intrarectally. 10 min later, blood samples were taken from the vena cava to measure oxygen partial pressure. Under anesthesia, mice inhaling 10% oxygen were given 40 ml / kg of perfluorodecalin bubbled with pure oxygen intrarectally. 20 min later, and 10 min later, blood samples were taken from the vena cava to measure oxygen partial pressure. The results are shown in Figure 10. As shown in Figure 10, intracaval oxygen tension decreased with both PV and IVC ligation, suggesting that more than one blood vessel is involved.

[0107] Furthermore, to facilitate the handling of PFC, we attempted to gel oxygenated PFC. We used Wako's perfluorodecalin as the PFC and mixed it with Spring Powder WO from Akatazen Co., Ltd. (headquarters: Osaka City) to attempt gelation of perfluorodecalin. Perfluorodecalin was dissolved in a 1:1 ratio (1 ml:1 ml) of stock solution and saline, or a 1:3 ml:3 ratio (1 ml:3 ml) of stock solution and then mixed with Spring Powder WO. The 1:1 mixture (0.1 g of Spring Powder WO) was found to have an appropriate viscosity for rectal administration. The components of Spring Powder WO are sucrose fatty acid ester (65%, emulsifier), carrageenan (14%, gelling agent), carombean gum (9.1%, gelling agent), xanthan gum (7.7%, gelling agent), potassium chloride (2.63%, auxiliary agent), and food ingredients (1.57%, food ingredients). Blood samples were collected from the vena cava 4 and 6 hours after administration, and the oxygen partial pressure was measured. The results are shown in Figure 11. As shown in Figure 11, enteral administration of gelled PFC improved the venous oxygen partial pressure. Also, as shown in Figure 11, enteral administration of gelled PFC reduced the intravenous carbon dioxide partial pressure. This indicates that PFC can be gelled as needed.

[0108] Furthermore, we established a pig model of acute respiratory distress syndrome (ARDS) and investigated the improvement of oxygen tension by rectal administration of oxygenated PFC. First, we established the ARDS model using microminipigs and female pigs. 40 ml / kg of saline was administered directly into the airways. Examination of the pig's lungs revealed lung damage in the area enclosed by the dotted line, as shown in Figure 12A, which covered most of the lung. Histological examination of the lung tissue revealed alveolar wall damage, including hyaline membrane formation, intraalveolar proteinaceous remnants, and septal thickening. Furthermore, the PaO2 / FiO2 ratio was below 100. Based on these symptoms, the pigs were considered to have developed moderate to severe ARDS.

[0109] Therefore, the ARDS pigs thus prepared were subjected to a midline abdominal incision, and a drain for administering perfluorodecalin was placed 40 cm from the anus. TM Dennis TM A coronal tube was placed in the ARDS model pig. 20 ml / kg of oxygenated perfluorodecalin (F2C) was repeatedly administered. Arterial oxygen saturation, arterial oxygen partial pressure, and venous oxygen partial pressure were measured. The presence or absence of adverse events was evaluated histopathologically in the intestines, spleen, liver, etc. of the pigs after the experiment. The results are shown in Figure 12B.

[0110] As shown in Figure 12B, arterial oxygen saturation (SpO2) improved by 20-25% after administration. Furthermore, oxygen partial pressure improved by approximately 300 mHg. This demonstrates the effectiveness of intrarectal administration of oxygenated PFC in pigs with lung damage and resulting respiratory failure. The pigs did not develop significant acidosis. Furthermore, intrarectal administration of oxygenated PFC to pigs hypoxic under hypoventilation conditions improved oxygen saturation, improved blood oxygen partial pressure, and reduced carbon dioxide partial pressure.

[0111] We conducted an experiment in which oxygenated perflubron was administered to mice with respiratory failure. OriGen Biomedical's PFB (Perflubron, product name Liquivent) was oxygenated by oxygen bubbling. Male C57BL6J mice weighing 20–30 g were divided into two groups: a control group (saline-administered group) and an I-EVA group (oxygenated perflubron administered). Mice in the control group were anesthetized with intraperitoneal administration of ketamine (80–100 mg / kg) and xylazine (10 mg / kg) and then inhaled under 15% hypoxia. When SpO2 reached the 70% range, perflubron was administered intrarectally at 40 ml / kg. The effects on respiratory failure were assessed using an SpO2 monitor. The results are shown in Figure 13.

[0112] As shown in Figure 13, mice initiating hypoxia inhalation showed a significant decrease in SPO2 immediately after inhalation, but this decrease was significantly restored by intrarectal administration of oxygenated PFB (Panel A, Figure 13). Measurement of the oxygen tension in PFB before oxygen bubbling, after oxygen bubbling, and after rectal administration revealed that PFB increased the oxygen tension (Panels B and C, Figure 13). This indicates that PFB has the ability to preferentially oxygenate. Furthermore, PFB decreased the oxygen tension after rectal administration (Panels B and C, Figure 13). This indicates that PFB released oxygen in the intestine after administration, and at least a portion of it was delivered to the bloodstream. Measurement of the carbon dioxide tension in PFB before oxygen bubbling, after oxygen bubbling, and after rectal administration revealed an increase in the carbon dioxide tension after rectal administration (Panels B and C, Figure 13). This indicates that PFB adsorbed carbon dioxide contained in the blood in the rectum. Thus, PFB has the ability to supply oxygen to the blood and expel carbon dioxide from the blood when administered rectally.

[0113] Blood PDF concentrations following perfluorodecalin (PFD) administration were measured by GC / MS / MS at 0.5, 2, and 24 hours after administration (n=6). The results were below the detection limit (1 μg / mL) at 0.5, 2, and 24 hours after administration. Systemic toxicity was also investigated after six doses of PDF. Serum analysis yielded the results shown in Table 2 below.

[0114] [Table 3]

[0115] As shown in Table 2, no particular toxicity was detected due to rectal administration of PFD.

[0116] Under hypoxic conditions, the oxygen tension in the inferior vena cava was significantly higher in the ILV group than in the control group (120 min, p = 0.037), with a pressure difference of 9.40 ± 3.65 mmHg between the two groups (Figure 3C). Furthermore, the oxygen tension in the left ventricle under hypoxic conditions was also significantly higher in the ILV group than in the control group 60 min after ILV (Figure 3D), with a more pronounced pressure difference (23.8 ± 3.11 mmHg) between the two groups at 120 min (p = 0.020).

[0117] Next, we compared the intraventricular oxygen tension of the heart in this model after PFC treatment with that in a mucosally stripped hypoxic model. The results showed that the intraventricular oxygen tension of the heart under hypoxic conditions was comparable between the IGV and ILV groups (IGV group: PaO2 63.3 ± 6.95 mmHg, ILV group: PaO2 63.8 ± 5.59 mmHg, p = 0.80). These data suggest that in the hypoxic mouse model, enteral administration of O2-containing PFCs is sufficient to restore oxygen levels, and that intestinal (distal intestinal) mucosal stripping is not necessary.

[0118] Mice were orally administered oxygen-bubbled PFD to examine the effects on blood oxygen and carbon dioxide partial pressures. A group of mice (n = 3) orally administered saline served as a negative control. In the group of mice (n = 3) orally administered oxygen-bubbled PFD (bubbling PDF), a volume of oxygen-containing PFD (250 μL / mouse) was administered via a tube into the stomach. Observation of the intestinal tract revealed a clear liquid, but the stomach contained only solid matter and air (Figure 14A). In contrast, the negative control group had less intestinal content than the group administered Bagling PFD (Figure 14A). An attempt was made to retrieve the contents by inserting a syringe into the intestinal tract (Figure 14B). In the group administered Bagling PFD, a clear liquid resembling PFD was recovered into the syringe (Figure 14B). In contrast, no such liquid was recovered in the negative control group; nothing was recovered in the syringe. These results indicated that orally administered PDF passed through the stomach and reached the intestine. Furthermore, PDF that reached the intestine did not reflux back into the stomach. One hour after administration, the tracheotomy was performed and the animals were ventilated with room air under mechanical ventilation. A cardiac blood sample was taken via thoracic opening, and the partial oxygen and carbon dioxide pressures in the collected blood were measured using iSTAT. The results are shown in Figure 14C. As shown in Figure 14C, the oral administration of Bagling PFD tended to increase blood oxygen pressure and decrease blood carbon dioxide pressure compared to the control group. This indicates that oxygen-dissolving PFCs can increase blood oxygen pressure and decrease carbon dioxide pressure, whether administered rectally or orally.

[0119] [Consideration] We demonstrated a proof-of-principle approach in which intestinal ventilation improved type I respiratory failure in mice. Type I respiratory failure is the most common form of respiratory failure and is characterized by an arterial oxygen partial pressure of less than 60 mmHg and normal or low carbon dioxide partial pressure due to gas exchange dysfunction. Hypoxic inhalation leads to hyperventilation and a decrease in carbon dioxide partial pressure. The respiratory system depends on three factors: 1. oxygen concentration or partial pressure, 2. oxygen dissolution rate through the large alveolar surface containing lipid-soluble surfactant, and 3. efficient oxygen transport to the blood vessels through the thin interstitial tissue. Our experimental system adapts the intestinal respiratory mechanism via both IGVs and ILVs to increase oxygen partial pressure and systemic oxygen transport, thereby improving respiratory failure. We also demonstrated that intestinal ventilation reduced blood carbon dioxide partial pressure, providing a therapeutic strategy for type II respiratory failure with elevated blood carbon dioxide partial pressure. Thus, according to the present invention, the PFC can be utilized as a gas exchange platform that can both supply oxygen to the blood and absorb carbon dioxide from it.

[0120] Enteric respiration is seen in loaches, corydoras, and sea cucumbers. 7,20 This has been reported in the literature, but has not been studied in mammalian systems. Histopathological findings show that the mucosal epithelium of the loach hindgut is thin and rich in blood vessels. Furthermore, there is a significant increase in genes related to angiogenesis in the loach hindgut. 11,18,20-24 Similarly, mechanical mucosal detachment in our mouse model allowed for both epithelial thinning and the induction of angiogenic factors seen in the acute phase. These physiological features and molecular signatures are likely key factors in the efficient oxygenation observed in our model system.

[0121] When PFCs are administered directly to the blood vessels or airways, they can cause side effects such as increased blood pressure and organ damage. 13,14,16,25However, to develop a more clinically relevant intestinal ventilation system that does not require mechanical mucosal abrasion, we employed a liquid-based oxygen carrier, PFC. When PFC was introduced into a highly vascularized intestinal region (e.g., the rectum, which has a rectal venous plexus), it quickly penetrated the tissue and migrated to the capillaries. As expected, the ratio of arterial oxygen partial pressure between the control and treatment groups was approximately 1.6 (40.0 ± 2.94 mmHg and 63.8 ± 5.59 mmHg, respectively), improving type I respiratory failure. This increase in ratio is sufficient to treat patients with severe respiratory failure in humans. Assuming that the total body fluid volume of humans is 1,000 times that of mice, more than 1–2 liters of liquid PFC per day should be required to improve severe respiratory failure, such as in the acute respiratory distress syndrome group. For example, PFC supplemented with oxygen in a glycerin enema could be administered in divided doses every 6–8 hours into the intestinal tract (particularly into the colon or rectum). PFCs absorb oxygen from the atmosphere and retain dissolved oxygen even under atmospheric conditions. Therefore, PFCs maintained under atmospheric conditions may be administered rectally. PFCs may also be administered after increasing the dissolved oxygen content by oxygen bubbling. A hybrid administration method combining IGV and ILV may also be an effective oxygenation method. Specifically, by administering liquid PFC followed by oxygen gas, it is possible to repeatedly increase the oxygen saturation of PFCs retained in the intestinal tract (especially the large intestine or rectum). Repeated administration of these methods is expected to continuously improve oxygen delivery from PFCs to the blood. Furthermore, the possibility of oxygen delivery and gastric carbon dioxide excretion through oral administration of oxygen-containing PFCs has been demonstrated. This opens the door to more convenient oxygen delivery.

[0122] References 1. Tobin M, Manthous C. Mechanical Ventilation. Am J Respir Crit Care Med 2017; 196: P3-P4.2. Pham T, Brochard LJ, Slutsky AS. Mechanical Ventilation: State of the Art. Mayo Clin Proc 2017; 92: 1382-400. 3. Patel B, Chatterjee S, Davignon S, Herlihy JP. Extracorporeal membrane oxygenation as rescue therapy for severe hypoxemic respiratory failure. J Thorac Dis 2019; 11: S1688-S97. 4. Henry BM. COVID-19, ECMO, and lymphopenia: a word of caution. Lancet Respir Med 2020; 8: e24. 5. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020. 6. Nakazawa MS, Keith B, Simon MC. Oxygen availability and metabolic adaptations. Nat Rev Cancer 2016; 16: 663-73. 7. Plaul SE, Barbeito CG, Diaz AO. Histochemical differences along the intestine of Corydoras paleatus (Siluriformes: Callichthyidae). Rev Biol Trop 2016; 64: 327-40. 8. Bickford D, Iskandar D, Barlian A. A lungless frog discovered on Borneo. Curr Biol 2008; 18: R374-5. 9. Woods HA, Lane SJ, Shishido C, Tobalske BW, Arango CP, Moran AL. Respiratory gut peristalsis by sea spiders. Curr Biol 2017; 27: R638-R9. 10. Park TJ, Reznick J, Peterson BL, et al. Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat. Science 2017; 356: 307-11. 11. Huo D, Sun L, Ru X, et al. Impact of hypoxia stress on the physiological responses of sea cucumber Apostichopus japonicus: respiration, digestion, immunity and oxidative damage. PeerJ 2018; 6 :e4651. 12. Caridi-Scheible ME, Blum JM. Use of Perfluorodecalin for Bronchoalveolar Lavage in Case of Severe Pulmonary Hemorrhage and Extracorporeal Membrane Oxygenation: A Case Report and Review of the Literature. A A Case Rep 2016; 7: 215-8. 13. Ferrari RS, Thomaz L, Simoneti LEL, Ulbrich JM, Andrade CF. Effect of vaporized perfluorocarbon on oxidative stress during the cold ischemia phase of lung graft preservation. J Bras Pneumol 2019; 45: e20170288. 14. Forgiarini Junior LA, Holand AR, Forgiarini LF, et al. Endobronchial perfluorocarbon reduces inflammatory activity before and after lung transplantation in an animal experimental model. Mediators Inflamm 2013; 2013: 193484. 15. Riess JG. Understanding the fundamentals of perfluorocarbons and perfluorocarbon emulsions relevant to in vivo oxygen delivery. Artif Cells Blood Substit Immobil Biotechnol 2005; 33: 47-63. 16. Yu Q, Liu K, Su L, Xia X, Xu X. Perfluorocarbon liquid: its application in vitreoretinal surgery and related ocular inflammation. Biomed Res Int 2014; 2014: 250323. 17. Aguilera KY, Brekken RA. Hypoxia Studies with Pimonidazole in vivo. Bio Protoc 2014; 4. 18. Luo W, Cao X, Xu X, Huang S, Liu C, Tomljanovic T. Developmental transcriptome analysis and identification of genes involved in formation of intestinal air-breathing function of Dojo loach, Misgurnus anguillicaudatus. Sci Rep 2016; 6: 31845. 19. Kuznetsova IN. Stability of perfluorocarbon emulsions and their compatibility with blood serum. Artif Cells Blood Substit Immobil Biotechnol 1998; 26: 181-9. 20. Huo D, Sun L, Li X, et al. Differential Expression of miRNAs in the Respiratory Tree of the Sea Cucumber Apostichopus japonicus Under Hypoxia Stress. G3 (Bethesda) 2017; 7: 3681-92. 21. Huang S, Cao X, Tian X. Transcriptomic Analysis of Compromise Between Air-Breathing and Nutrient Uptake of Posterior Intestine in Loach (Misgurnus anguillicaudatus), an Air-Breathing Fish. Mar Biotechnol (NY) 2016; 18: 521-33. 22. Fish JE, Cantu Gutierrez M, Dang LT, et al. Dynamic regulation of VEGF-inducible genes by an ERK / ERG / p300 transcriptional network. Development 2017; 144: 2428-44. 23. Wang Y, Nakayama M, Pitulescu ME, et al. Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis. Nature 2010; 465: 483-6. 24. Wilson JM, Moreira-Silva J, Delgado IL, et al. Mechanisms of transepithelial ammonia excretion and luminal alkalinization in the gut of an intestinal air-breathing fish, Misgurnus anguilliacaudatus. J Exp Biol 2013; 216: 623-32. 25. Chambers DC, Cherikh WS, Goldfarb SB, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-fifth adult lung and heart-lung transplant report-2018; Focus theme: Multiorgan Transplantation. J Heart Lung Transplant 2018; 37: 1169-83.

Claims

1. A pharmaceutical composition for oral administration, nasogastric tube administration, gastrostomy administration, or colonic administration, comprising a perfluorocarbon having dissolved oxygen.

2. 10. The pharmaceutical composition of claim 1 for use in treating hypoxemia.

3. 3. The pharmaceutical composition of claim 1 or 2, administered to a subject with respiratory failure.

4. A pharmaceutical composition according to any one of claims 1 to 3 for use in oxygenating the blood of a subject.

5. An administration device for colonic administration, comprising the pharmaceutical composition according to any one of claims 1 to 4.

6. A pharmaceutical composition in gas form for oral administration, nasogastric tube administration, gastrostomy administration, or colonic administration, comprising oxygen gas, The pharmaceutical composition, wherein the large intestine is a demucosed large intestine or a perfluorocarbon-coated large intestine.

7. A composition comprising oxygen gas in gaseous form, which is dissolved in a perfluorocarbon prior to administration and is administered orally, via a nasogastric tube, via a gastrostomy tube, or into the colon.

8. The composition according to any one of claims 1 to 4, which is mixed with oxygen gas before administration and is administered orally, via a nasogastric tube, via a gastrostomy tube, or into the large intestine.

9. A gaseous composition comprising oxygen gas, for use in colonic administration to a subject having a mucosal-deprived or perfluorocarbon-coated colon.

10. The composition according to any one of claims 1 to 4 and 6 to 9, for rectal administration.

11. The composition according to any one of claims 1 to 4 and 6 to 9, which is for oral administration, nasogastric tube administration, or gastrostomy administration.

12. The composition according to any one of claims 1 to 4 and 6 to 11, for use in lowering the partial pressure of carbon dioxide in the blood of a subject.

13. A kit for preparing a composition for administration to the large intestine, the kit comprising a gaseous composition containing oxygen gas and a composition containing a perfluorocarbon.

14. 14. The preparation kit of claim 13 for use in increasing blood oxygen tension in a subject.

15. 15. The preparation kit according to claim 13 or 14, for use in lowering the partial pressure of carbon dioxide in the blood of a subject.

16. An administration device for colonic administration, comprising the composition according to any one of claims 1 to 4 and 6 to 12.

17. An administration control device for administering oxygen or a perfluorocarbon having dissolved oxygen or oxygen orally, via a nasal tube, via a gastrostomy tube, or into the large intestine, the administration control device comprising: a delivery unit for delivering the perfluorocarbon or oxygen having dissolved oxygen to a tube; and a control unit for controlling the delivery rate by the delivery unit based on the oxygen saturation in the subject's blood and the intraintestinal pressure of the large intestine.

18. The administration control device of claim 17, further comprising a receiving unit that receives information regarding oxygen saturation and intraintestinal pressure of the large intestine from a blood oxygen monitor.

19. a control unit that controls a delivery rate by the delivery unit based on the oxygen saturation level in the blood of the subject; (A) based on the information on the oxygen saturation level received by the receiving unit, when the oxygen saturation level falls below (or is equal to or lower than) a predetermined value, the control unit sends a signal to the sending unit to increase the sending rate; and / or (B) An administration control device as described in claim 17 or 18, wherein, based on information regarding oxygen saturation received by the receiving unit, when the oxygen saturation becomes equal to or greater than a predetermined value (or exceeds a predetermined value), the control unit sends a signal to the sending unit to reduce the sending rate.

20. a control unit that controls a rate of delivery by the delivery unit based on an intestinal pressure of the large intestine of the subject; (C) An administration control device described in any one of claims 17 to 19, wherein, based on information regarding the intestinal pressure of the large intestine received by the receiving unit, when the intestinal pressure becomes less than (or equal to or less than) a predetermined value or when the intestinal pressure increases during fluid delivery, the control unit stops sending a signal to the delivery unit to increase the delivery rate, or sends a signal to the delivery unit to decrease the delivery rate.

21. 1. A method of administering oxygen to a subject, comprising: A method comprising administering to the subject orally, via a nasogastric tube, via a gastrostomy tube, or intracolonally, a pharmaceutical composition comprising a perfluorocarbon having dissolved oxygen.

22. 22. The method of claim 21, administering the oxygen-dissolved perfluorocarbon to the subject orally, via a nasogastric tube, via a gastrostomy tube, or into the large intestine while controlling the dosage using an administration control device; The administration control device is an administration control device for administering oxygen or a perfluorocarbon having dissolved therein, and includes a delivery unit for delivering the perfluorocarbon having dissolved therein or oxygen to a tube, and a control unit for controlling the delivery rate by the delivery unit based on the oxygen saturation level in the blood of the subject and / or the intraintestinal pressure of the large intestine. method.

23. 24. The method of claim 22 or 23, wherein the large intestine is the rectum.

24. The composition according to any one of claims 1 to 4 and 6 to 12, The administration control device is used to administer a perfluorocarbon having dissolved oxygen to the subject orally, via a nasal tube, via a gastrostomy tube, or into the large intestine while controlling the dosage, The administration control device is an administration control device for administering oxygen or a perfluorocarbon having dissolved therein, and includes a delivery unit for delivering the perfluorocarbon having dissolved therein or oxygen to a tube, and a control unit for controlling the delivery rate by the delivery unit based on the oxygen saturation level in the blood of the subject and / or the intraintestinal pressure of the large intestine. Pharmaceutical compositions.

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