Treatment of sepsis and septic shock

Abstract

The present invention relates to a composition comprising a mixture of empty liposomes wherein the mixture of empty liposomes comprises: (a) a first empty liposome comprising cholesterol wherein the amount of cholesterol is at least 30% (weight / weight); and (b) a second empty liposome comprising sphingomyelin, for use in the treatment of sepsis, severe sepsis, septic shock or long-term and severe hypotension, preferably persistent hypotension, in an animal, preferably a human, for use in the treatment of hyperlipidemia in an animal, preferably a human. The present invention relates to a pharmaceutical composition for treating toxic shock syndrome in animals, preferably humans, or to the treatment of toxic shock syndrome in animals, preferably humans, or to the treatment of hypotension in acute lung injury, preferably said persistent hypotension, or to the treatment of toxic shock syndrome in animals, preferably humans, preferably septicaemia, severe septicaemia, acute respiratory distress syndrome, or to the treatment of hypotension in acute lung injury, preferably said persistent hypotension.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202511192851.5 (22) Application Date 2019.04.18 (30) Priority Data 18168436.6 2018.04.20 EP (62) Divisional Application Data 201980025257.3 2019.04.18 (71) Applicant Compass GmbH Address Éparange, Switzerland (72) Inventor S. Azeredo da Silvia Lajaunias F. Lajaunias (74) Patent Agency King & Wood Mallesons, Beijing 11256 Patent Attorneys Chen Wenping Mao Yunbei (51) Int.Cl. A61K 31 / 575 (2006.01) A61K 9 / 127 (2025.01) A61K 47 / 28 (2006.01) A61K 47 / 24 (2006.01) A61K 31 / 688 (2006.01) A61P 31 / 00 (2006.01) (54) Invention Title Treatment of Sepsis and Septic Shock (57) Abstract This invention relates to a composition comprising a mixture of empty liposomes, wherein the mixture of empty liposomes comprises: (a) a first empty liposome comprising cholesterol, wherein the amount of cholesterol is at least 30% (w / w); and (b) a second empty liposome comprising sphingomyelin, the composition being used to treat animals, Preferably, the composition is for treating sepsis, severe sepsis, septic shock, or prolonged and severe hypotension in humans, preferably persistent hypotension, for treating animals, preferably hypotension in septic shock, sepsis, severe sepsis, acute respiratory distress syndrome, or acute lung injury in humans, preferably the persistent hypotension, or for treating animals, preferably toxic shock syndrome in humans. Claims 2 pages, Description 22 pages, Drawings 1 page CN 121102236 A 2025.12.12 CN 1 21 10 22 36 A 1. A composition comprising a mixture of empty liposomes, preferably composed of the mixture of said empty liposomes, wherein said mixture of empty liposomes comprises, preferably, the following: (a) a first empty liposome comprising cholesterol, wherein the amount of cholesterol is at least 30% (w / w); and (b) a second empty liposome comprising sphingomyelin, wherein preferably the second empty liposome (b) comprises said sphingomyelin as the sole lipid component; the composition is for treating sepsis in animals, preferably humans. 2. The composition for use according to claim 1, wherein the composition is used to treat septic shock in the animal, preferably the human.3. The composition for use according to claim 1, wherein the composition is used to treat hypotension, preferably persistent hypotension, in animals suffering from septicemia, preferably in humans. 4. The composition for use according to claim 2, wherein the composition is used to treat hypotension, preferably persistent hypotension, in animals suffering from septic shock. 5. The composition for use according to any of the preceding claims, wherein the amount of cholesterol in the empty liposome (a) is 45% to 55% (w / w), and wherein the second empty liposome (b) is composed of sphingomyelin. 6. The composition for use according to any of the preceding claims, wherein the first empty liposome (a) is composed of cholesterol and sphingomyelin, and wherein the amount of cholesterol in the empty liposome (a) is about 50% (w / w), and wherein the mixture of empty liposomes comprises at least 40%, preferably at least 45% (w / w) of the first empty liposome (a) and the second empty liposome (b). 7. The composition for use according to any one of the preceding claims, wherein the first empty liposome (a) comprises a 1:1 (weight / weight-w / w) mixture of the first empty liposome and the second liposome, wherein the first empty liposome consists of cholesterol and sphingomyelin in a 1:1 weight ratio (1:1 w / w; molar ratio 35:65), and the second empty liposome consists only of sphingomyelin, wherein the first empty liposome (a) comprises the cholesterol and the sphingomyelin as the sole lipid component, and the second empty liposome (b) comprises the sphingomyelin as the sole lipid component. 8. The composition for use according to any one of claims 3 to 7, wherein the hypotension, preferably the persistent hypotension, is associated with a mean arterial pressure <70 mmHg. 9. The composition for use according to claim 8, wherein the hypotension, preferably the persistent hypotension, is pretreated with a vasopressor for at least 2 hours. 10. The composition for use according to any one of the preceding claims, wherein the treatment is adjunctive to antibiotic therapy. 11. The composition for use according to claim 10, wherein the antibiotic therapy is intravenous (IV) or oral antibiotic therapy. 12. The composition for use according to any one of the preceding claims, wherein the animal is a human patient, and wherein the human patient has pneumonia, wherein preferably the pneumonia is selected from community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP). 13. The composition for use according to claim 12, wherein the pneumonia is severe pneumonia, preferably severe community-acquired pneumonia (sCAP) or severe community-acquired pneumococcal pneumonia (sCAPP).14. The composition for use according to claim 12 or 13, wherein the pneumonia or the severe pneumonia is caused by: Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis, Legionella pneumophila, Haemophilus influenzae, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, Bordetella pertussis, Serratia marcescens, Oligotrophoblastus budding, Moraxella catarrhalis, or Mycobacterium tuberculosis, wherein preferably the pneumonia or the severe pneumonia is caused by Streptococcus pneumoniae. 15. The composition for use according to any of the preceding claims, wherein the composition is in the form of a solution for intravenous administration. 16. The composition for use according to any one of the preceding claims, wherein the composition is administered to the animal, preferably to the human, in at least two doses: a first dose and a second dose, and wherein the interval between the first dose and the second dose is 6 hours to 96 hours, preferably 12 hours to 72 hours, more preferably 24 hours to 48 hours, and even more preferably 24 hours or 48 hours. 17. The composition for use according to any one of the preceding claims, wherein the sepsis, septic shock, or the hypotension, preferably persistent hypotension, requires hospitalization, preferably in a hospital intensive care unit (ICU). 18. The composition for use according to claim 17, wherein the treatment reduces the length of hospital stay compared to the length of hospital stay without such treatment. 19. The composition for use according to claim 17 or claim 18, wherein the reduction in hospital stay due to the treatment is at least one day, preferably two days, more preferably three days, even more preferably four days, even more preferably five days, even more preferably six days, even more preferably seven days, even more preferably eight days, and even more preferably nine days. 20. The composition for use according to any one of the preceding claims, wherein the recovery time for the sepsis, septic shock, or hypotension, preferably persistent hypotension, is shorter compared to the absence of such treatment. 21. The composition for use according to claim 20, wherein the shorter recovery time is at least one day less, preferably two days less, or more preferably at least three days less, even more preferably at least four days less, even more preferably at least five days less, even more preferably at least six days less, and even more preferably at least seven days less. 22. The composition for use according to any one of the preceding claims, wherein the treatment reduces the cardiovascular SOFA score compared to the cardiovascular SOFA score without such treatment.23. The composition for use according to claim 22, wherein the reduction is at least 50%, preferably at least 60%, more preferably at least 70%, and even more preferably at least 80% 7 days after the start of treatment, more preferably after the start of treatment, and even more preferably after 5 days. Claims 2 / 2 Page 3 CN 121102236 A Treatment of sepsis and septic shock

[0001] This application is a divisional application of patent application No. 201980025257.3, filed on April 18, 2019, entitled "Treatment of sepsis and septic shock".

[0002] The present invention relates to a composition comprising a mixture of empty liposomes, wherein the mixture of empty liposomes comprises: (a) a first empty liposome comprising cholesterol, wherein the amount of cholesterol is at least 30% (w / w); and (b) a second empty liposome comprising sphingomyelin, the composition being used to treat sepsis, severe sepsis, septic shock, or prolonged and severe hypotension, preferably persistent hypotension in animals, preferably humans, for the treatment of hypotension in septic shock, sepsis, severe sepsis, acute respiratory distress syndrome, or acute lung injury, preferably persistent hypotension, or for the treatment of toxic shock syndrome in animals, preferably humans. Specifically, the present invention relates to compositions for the treatment of sepsis or septic shock in animals, preferably humans. Background Art

[0003] Sepsis is a potentially life-threatening organ dysfunction caused by a dysregulated host response to infection. It is characterized by physiological, pathological, and biochemical abnormalities, leading to organ dysfunction (Levy M et al., *Intensive Care Medicine*, 2003; 29:530-38; Singer M et al., *JAMA*, 2016; 315(8):801-810). Sepsis can lead to tissue damage, multi-system organ failure, and subsequently death (Cohen, 2002, *Nature*, 420, 885-891). Despite maximal care, approximately 30% to 50% of patients with sepsis die. The underlying mechanisms of this systemic inflammatory dysregulation are complex and may involve multiple pathways. Therefore, sepsis cannot be effectively treated with antimicrobial agents alone. In fact, although antibiotics are available, current treatments for sepsis have proven ineffective. Neutralization of certain inflammatory cytokines was also ineffective, highlighting the need for new therapies (Wenzel and Edmond, 2012, New England Journal of Medicine 366, 2122-2124).

[0004] Septic shock occurs in a subset of patients with sepsis and is associated with increased mortality.The pathophysiology of septic shock is not fully understood; it includes underlying circulatory and cellular / metabolic abnormalities severe enough to significantly increase mortality. Patients with septic shock can be identified by the clinical constructs of sepsis characterized by: persistent hypotension requiring vasopressors to maintain a mean arterial pressure of 65 mm Hg or higher despite adequate volume resuscitation; organ inadequacy; and serum lactate levels above 2 mmol / L (18 mg / dL) (Singer M et al., JAMA 2016; 315(8):801-10).

[0005] Sepsis and septic shock have lasting effects on patients. For example, prolonged tissue inadequacy can lead to long-term neurological and cognitive sequelae.

[0006] In addition to bacterial infections, viral infections also make patients more susceptible to infections that can cause sepsis or septic shock by increasing susceptibility to bacterial co-infections. For example, influenza patients often exhibit increased susceptibility to co-infection with Streptococcus pneumoniae, and sepsis has been reported as a common cause of death during influenza pandemics. The detailed mechanisms by which viral infections susceptible patients to bacterial infections and subsequently lead to sepsis are not fully understood, and therapies for treating and preventing sepsis and septic shock in patients with viral infections are still needed.

[0007] In recent years, customized empty liposomes, such as those composed of cholesterol and / or sphingomyelin, and their use in the treatment of bacterial infections have been described as acting as traps for virulence factors such as bacterial toxins, enzymes, and toxic appendages (WO 2013 / 186286; Henry BD et al., Nature Biotechnol 2015; 33(1):81-4; CN 121102236 A 88; Azeredo da Silveira, S and Perez, A, Expert Review of Anti-Infect Ther. 2015; 13(5):531-533; Azeredo da Silveira, S and Perez, A. Expert Review of Anti-Infect Ther. 2017; 15:973-975). These custom-designed empty liposomes have also been described as exhibiting antiviral activity and thus as a therapy for antiviral infections, particularly as a therapy for neutralizing enveloped viruses such as influenza virus (WO 2017 / 216282). Summary of the Invention

[0008] In the first human study in patients with severe pneumonia, the preferred compositions of the present invention showed surprisingly positive results in improving clinical signs and symptoms.Furthermore, and importantly, it has been surprisingly found that the preferred compositions of the present invention improve hemodynamic parameters, prevent hemodynamic deterioration, and accelerate the resolution of septic shock. Therefore, as revealed by accelerating the normalization of hemodynamic instability, thereby leading to patient recovery and faster discharge from the intensive care unit (ICU), the compositions of the present invention are effective in treating sepsis and septic shock. Based on this promising efficacy data and its credible mechanism of action, further efficacy in envisioned studies in patients suspected or confirmed to have an infection, regardless of the pathogen, and exhibiting signs of complications or progression of severity, particularly community-acquired pneumonia, hospital-acquired pneumonia, ventilation-associated pneumonia, intra-abdominal infections, skin and soft tissue infections, urinary tract infections, or bacteremia, is reasonable. Furthermore, based on this promising efficacy data and its credible mechanism of action, the compositions of the present invention are particularly considered highly beneficial for the treatment and prevention of sepsis or septic shock caused or associated with bacterial or viral pathogens that attack the host using specific lipid microstructural domains, and thereby attack animal, preferably human, patients.

[0009] Therefore, in a first aspect, the present invention provides a composition comprising a mixture of empty liposomes, preferably consisting of the mixture of said empty liposomes, wherein said mixture of empty liposomes comprises, preferably consists of: (a) a first empty liposome comprising cholesterol, wherein the amount of cholesterol is at least 30% (w / w); and (b) a second empty liposome comprising sphingomyelin; said composition is used to treat sepsis, severe sepsis, septic shock, or prolonged and severe hypotension, preferably persistent hypotension in animals, preferably humans, septic shock, sepsis, severe sepsis, acute respiratory distress syndrome, or hypotension in acute lung injury, preferably persistent hypotension, or to treat toxic shock syndrome in animals, preferably humans.

[0010] In another aspect, the present invention provides a composition comprising a mixture of empty liposomes, preferably consisting of the mixture of said empty liposomes, wherein said mixture of empty liposomes comprises, preferably consists of: (a) a first empty liposome comprising cholesterol, wherein the amount of cholesterol is at least 30% (w / w); and (b) a second empty liposome comprising sphingomyelin; said composition is intended for treating sepsis, preferably in humans, severe sepsis, septic shock, or prolonged and severe hypotension, preferably persistent hypotension.

[0011] In a further aspect, the present invention provides a composition comprising, preferably, a mixture of empty liposomes, wherein the mixture of empty liposomes comprises, preferably, the following: (a) a first empty liposome comprising cholesterol, wherein the amount of cholesterol is at least 30% (w / w); and (b) a second empty liposome comprising sphingomyelin; the composition is used to treat septic shock in animals, preferably humans.

[0012] Further aspects and embodiments of the invention will become apparent as this description continues. Figure Descriptions

[0013] Figure 1: Evolution of cardiovascular SOFA scores from baseline (before administration) to day 8 in the entire study population, presented as absolute values ​​in the placebo (diamond), low-dose CAL02 (triangle), and high-dose CAL02 (square) groups (Figure 1A), and evolution of cardiovascular SOFA scores from baseline (before administration) to day 8 in the entire study population excluding patients without any hypotensive events (three patients in the high-dose CAL02 group), presented as scores compared to baseline (Figure 1B). *p<0.05

[0014] Figure 2: Evolution of cardiovascular SOFA scores from baseline (before administration) to day 8 in patients already in septic shock at baseline, presented as absolute values ​​in the placebo (diamond), low-dose CAL02 (triangle), and high-dose CAL02 (square) groups. Detailed Description

[0015] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0016] The term “about” as used herein shall have a meaning of + / - 5%. For example, about 50% shall mean 47.5% to 52.5%. Preferably, the term “about” as used herein shall have a meaning of + / - 3%. For example, about 50% shall mean 48.5% to 51.5%.

[0017] Unless otherwise stated, when the term “an” or “a” is used herein, it means “at least one / a type”. Specifically, the term “an” or “a type” used in conjunction with the single empty liposome, the first empty liposome, and the second empty liposome to describe an empty liposome and a mixture of empty liposomes according to the invention shall typically and preferably refer to a single empty liposome and a mixture of empty liposomes including the first empty liposome and the second empty liposome.

[0018] All ranges of values ​​disclosed herein shall refer to all values ​​within the range, including the values ​​defining the range. For example, as an explanation, the value 12 to 13 should refer to the value 12 or 13, or any value between 12 and 13.

[0019] As used herein, the term “empty liposome” refers to a liposome having an average diameter of 20 nm to 10 μm, preferably 20 nm to 500 nm, and more preferably 20 nm to 400 nm, and even more preferably 40 nm to 400 nm or 20 nm to 200 nm, preferably an artificial liposome, and composed of one or more phospholipid bilayers, and typically and preferably monolayer vesicles and multilayer vesicles, more preferably small monolayer vesicles (SUVs). In preferred embodiments, the term “empty liposome” as used herein typically and preferably refers to a liposome without any drug incorporated, typically and preferably refers to a liposome without any pharmaceutical drug incorporated. As used herein and when referring to the empty liposomes of the present invention, “incorporated / incorporating” typically and preferably means encapsulated / encapsulating within the cavity of the liposome, within a potential bilayer of the liposome, or as part of the membrane layer of the liposome. In another preferred embodiment, as used herein, the term "empty liposome" typically and preferably refers to liposomes according to the invention composed of sphingomyelin and cholesterol or composed of sphingomyelin, and further comprises only water-soluble inorganic compounds and / or water-soluble organic molecules, wherein typically and preferably, the water-soluble inorganic compounds and / or water-soluble organic molecules are derived from the synthesis of the empty liposomes of the invention, and wherein typically and preferably, the water-soluble inorganic compounds are inorganic salts, preferably selected from NaCl, KCl, and MgCl2, and wherein the water-soluble organic molecules are buffers, wherein preferably, the water-soluble organic molecules are selected from glucose and HEPES. Typically and preferably, the water-soluble inorganic compounds and / or water-soluble organic molecules are incorporated into the empty liposomes of the invention due to their presence during the production of the empty liposomes of the invention. In another preferred embodiment, as used herein, the term "empty liposome" typically and preferably refers to liposomes according to the invention composed of sphingomyelin and cholesterol or composed of sphingomyelin, and wherein the empty liposomes do not include antioxidants.In a further preferred embodiment, as used herein, the term "empty liposome" typically and preferably refers to liposomes according to the invention composed of sphingomyelin and cholesterol or composed of sphingomyelin (see page 3 / 22 of CN 121102236 A), and further comprises only water-soluble inorganic compounds and / or water-soluble organic molecules, wherein typically and preferably, the water-soluble inorganic compounds and / or water-soluble organic molecules are derived from the synthesis of the empty liposomes of the invention, and wherein typically and preferably, the water-soluble inorganic compounds are inorganic salts, preferably selected from NaCl, KCl and MgCl2, and wherein the water-soluble organic molecules are buffers, wherein preferably, the water-soluble organic molecules are selected from glucose and HEPES, and wherein the empty liposomes according to the invention composed of sphingomyelin and cholesterol or composed of sphingomyelin do not contain antioxidants.

[0020] Sepsis or septic shock: Sepsis is a disease with an infectious cause and a pathology of systemic inflammatory response syndrome (SIRS); it is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection (Levy M et al., Intensive Care Medicine, 2003; 29:530-38; Singer M et al., JAMA, 2016; 315(8):801-810). Initial symptoms include chills, sweating, fever, and hypotension. Microcirculation becomes disordered as various inflammatory mediators and clotting factors increase throughout the body, leading to a worsening of the pathological condition. Septic shock involves abnormal organ perfusion, uncontrolled hypotension, and multiple organ dysfunction, which can lead to death. The clinical profile of sepsis is characterized by the presence of: persistent hypotension requiring vasopressors to maintain a mean arterial pressure (MAP) ≥ 65 mm Hg, despite adequate volume resuscitation; and serum lactate levels > 2 mmol / L (18 mg / dL). Therefore, the term “sepsis” as used herein should refer to life-threatening organ dysfunction resulting from a dysregulated host response to infection, as defined and recommended in Singer M et al., JAMA. 2016; 315(8):801–810 (Recommendation; Column 3). Organ dysfunction can be identified as a sharp change in the total SOFA (Sequential [Sepsis-Related] Organ Failure Assessment) score ≥ 2 post-infection. For patients with no known pre-existing organ dysfunction, the baseline SOFA score can be assumed to be zero. A SOFA score ≥ 2 reflects an overall mortality risk of approximately 10% in a general hospital population with suspected infection. Even patients presenting with moderate dysfunction may deteriorate further, highlighting the severity of the condition and the need for timely and appropriate intervention (if such intervention has not yet been implemented).If a suspected infected patient with a high risk of prolonged ICU stay or death in the hospital has at least two of the following clinical criteria that together constitute a new bedside clinical score (called the rapid SOFA (qSOFA)), the patient can be rapidly identified as more likely to have a sepsis-typical adverse outcome: a respiratory rate of 22 / min or higher; altered mental activity, i.e., altered mental status; or a systolic blood pressure of 100 mm Hg or lower. As used herein and as defined and recommended by Singer M et al., JAMA. 2016; 315(8):801-810 (recommendation; Column 3), the term “septic shock” is a subtype of sepsis in which underlying circulatory and cellular / metabolic abnormalities are severe enough to significantly increase mortality, and therefore, the risk of death associated with septic shock is higher than that of sepsis alone. Patients with septic shock can be identified by the clinical constructs of sepsis characterized by: persistent hypotension requiring vasopressors to maintain a mean arterial pressure (MAP) ≥65 mm Hg, despite adequate volume resuscitation (and therefore in the absence of hypovolemia); and serum lactate levels >2 mmol / L (18 mg / dL). In these criteria, hospital mortality exceeds 40%.

[0021] Animals: As used herein, the term “animal” refers to a living multicellular vertebrate organism, including, for example, mammals and birds. The term mammal includes both human and non-human mammals. Similarly, the term “subject” includes both human and livestock subjects.

[0022] As used herein, the terms “treating” or “therapy” refer to means of achieving the desired physiological effect. The effect may be therapeutic in terms of partially or completely curing a disease or symptom and / or symptoms attributable to said disease or symptom, including improving the signs or symptoms of a disease such as sepsis or septic shock, or the pathological state associated with said disease, such as reducing fever in a subject with septic shock or stabilizing the blood pressure of said subject, or improving symptoms such as, but not limited to, chills, sweating, or increasing organ function. As used in the most general sense herein, the term “treatment” should include and refer to “prevention” of a disease. “Preventing” or “prevention” of a disease means suppressing a disease or symptom such as sepsis or septic shock, that is, preventing the partial or complete development of a disease such as sepsis or septic shock in a person, for example, suffering from or at risk of bacterial infection. Therefore, the term “treatment” as used herein, for the purpose of defining and characterizing preferred aspects and embodiments of the invention, should exclude and not refer to “prevention” of a disease in its preferred meaning.Furthermore, in other embodiments and aspects of the invention’s prevention, particularly in animals, and preferably in humans at risk of sepsis or septic shock, the compositions used and the methods of the invention are subsequently used to delay or prevent the development of sepsis or septic shock. Thus, the method comprises: selecting a human patient at risk of sepsis or septic shock typically and preferably caused by infection; and administering one or more of the compositions disclosed herein to said human patient. The human patient may be, for example, an intubated person, i.e., a person under invasive mechanical ventilation, or a person who has been exposed to specific bacteria such as Streptococcus pneumoniae or Staphylococcus aureus.

[0023] Singer et al., in JAMA 2016, well described patients who might have sepsis: any two of the three clinical variables—a Glasgow Coma Scale score of 13 or lower; a systolic blood pressure of 100 mmHg or lower; and a respiratory rate of 22 / min or higher—provided predictive power similar to that of the full SOFA score outside the ICU. Based on external US and non-US datasets, this model has been shown to be robust to multiple sensitivity analyses, including simpler assessments of altered mental status (Glasgow Coma Scale score <15), performed in out-of-hospital, emergency room, and ward settings. For patients suspected of infection in the ICU, the predictive power of the SOFA score was superior to that of this model, which may reflect the moderating effect of interventions (e.g., vasopressors, sedatives, mechanical ventilation).

[0024] “Therapeutic effective amount” is the amount of composition that achieves the desired effect in the treated subject. For example, this could be an amount necessary to suppress septic shock, reduce fever, or prevent multiple organ failure in animals, preferably human patients, such as patients with pneumonia and / or patients infected with Streptococcus pneumoniae. When administered to animals, preferably human patients, a dose that will achieve an effective target tissue concentration will generally be used.

[0025] As used herein, “therapeutic dose” means a dose known to those skilled in the art to have a therapeutic effect.

[0026] As used herein, the term “pneumonia” should encompass “community-acquired pneumonia” (CAP), “hospital-acquired pneumonia” (HAP), or “ventilator-associated pneumonia” (VAP).

[0027] The terms “community-acquired pneumonia” or “CAP” are known to those skilled in the art, see, for example, the IDSA / ATS Guidelines for CAP in Adults (CID 2007:44(Supplement 2) S27). Specifically, the term refers to pneumonia acquired outside of a hospital.

[0028] The term “hospital-acquired pneumonia (HAP)” refers to pneumonia acquired during or after hospitalization for another illness or surgery, wherein the onset occurs within at least 48 to 72 hours of admission.

[0029] As defined herein, “ventilator-associated pneumonia (VAP)” is pneumonia that develops 48 hours or more after mechanical ventilation and is characterized by microbial invasion of the lower respiratory tract and lung parenchyma. VAP is a potentially serious medical condition.

[0030] Pneumonia is caused by infection with a variety of microorganisms, including bacteria such as Streptococcus pneumoniae, Haemophilus influenzae, Legionella pneumophilia, Staphylococcus aureus, and Pseudomonas aeruginosa against CAP, and Gram-negative bacilli such as Pseudomonas aeruginosa and Serratia marcescens, as well as Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, Stenotrophomonas maltophilia, Acinetobacter species, and Haemophilus influenzae (see Cilloniz et al., Thorax, April 2011; 66(4):340-6 and Jones) against HAP. RN. Clinical Infectious Diseases, August 2010; 51(Supplement 1): S81-7.

[0031] The terms “severe community-acquired pneumonia” or “sCAP” are known to those skilled in the art. Specifically, the term “severe community-acquired pneumonia” or “sCAP” refers to a subgroup of patients with community-acquired pneumonia who require intensive care.The Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) have published guidelines on the management of community-acquired pneumonia (sCAP), including a definition of sCAP (see Mandell et al., 2007, Infectious Diseases Society of America / American Thoracic Society Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults, Clin. Inf. Dis. 2007:44:S27-72(Supplement 2), Table 4). According to the IDSA / ATS guidelines, sCAP is defined as CAP requiring intensive care. Admission to the intensive care unit is recommended if a CAP patient exhibits one or both of the two primary criteria described in Example 1 and implemented in the presented studies, or if three secondary criteria from the list are present.

[0032] As used herein, the term “for” used in “composition for treating a disease” should also disclose the corresponding therapeutic method and the corresponding use of the formulation for preparing the medicament for treating the disease.

[0033] In one aspect, the present invention provides a composition comprising, preferably, a mixture of empty liposomes, wherein the mixture of empty liposomes comprises, preferably, the following: (a) a first empty liposome comprising cholesterol, wherein the amount of cholesterol is at least 30% (w / w); and (b) a second empty liposome comprising sphingomyelin; the composition is used to treat septic shock in animals, preferably humans.

[0034] In another aspect, the present invention provides a composition comprising, preferably, a mixture of empty liposomes, wherein the mixture of empty liposomes comprises, preferably, the following: (a) a first empty liposome comprising cholesterol, wherein the amount of cholesterol is at least 30% (w / w); and (b) a second empty liposome comprising sphingomyelin; the composition is used to treat hypotension, preferably persistent hypotension, in animals, preferably humans, wherein the hypotension, preferably the persistent hypotension, is associated with septic shock.

[0035] In a further aspect, the present invention provides a composition comprising a mixture of empty liposomes, preferably consisting of the mixture of said empty liposomes, wherein said mixture of empty liposomes comprises, preferably consists of: (a) a first empty liposome comprising cholesterol, wherein the amount of cholesterol is at least 30% (w / w); and (b) a second empty liposome comprising sphingomyelin; said composition is used to treat sepsis, preferably in humans, severe sepsis, septic shock, or prolonged and severe hypotension, preferably persistent hypotension, in animals, preferably in humans, septic shock, sepsis, severe sepsis, acute respiratory distress syndrome, or hypotension in acute lung injury, preferably persistent hypotension, or to treat toxic shock syndrome in animals, preferably in humans.

[0036] In another aspect, the present invention provides a composition comprising a mixture of empty liposomes, preferably consisting of the mixture of said empty liposomes, wherein said mixture of empty liposomes comprises, preferably consisting of: (a) a first empty liposome comprising cholesterol, wherein the amount of cholesterol is at least 30% (w / w); and (b) a second empty liposome comprising sphingomyelin; said composition is used to treat sepsis, preferably in humans, severe sepsis, septic shock, or prolonged and severe hypotension, preferably persistent hypotension.

[0037] In a further aspect, the present invention provides a composition comprising a mixture of empty liposomes, preferably consisting of the mixture of said empty liposomes, wherein said mixture of empty liposomes comprises, preferably consisting of: (a) a first empty liposome comprising cholesterol, wherein the amount of cholesterol is at least 30% (w / w); and (b) a second empty liposome comprising sphingomyelin; said composition is used to treat sepsis, preferably in humans, severe sepsis.

[0038] In a further aspect, the present invention provides a composition comprising, preferably, a mixture of empty liposomes, wherein the mixture of empty liposomes comprises, preferably, the following: (a) a first empty liposome comprising cholesterol, wherein the amount of cholesterol is at least 30% (w / w); and (b) a second empty liposome comprising sphingomyelin; the composition is used to treat septic shock in animals, preferably humans.

[0039] In a further aspect, the present invention provides a composition comprising a mixture of empty liposomes, preferably consisting of the mixture of said empty liposomes, wherein said mixture of empty liposomes comprises, preferably consists of: (a) a first empty liposome comprising cholesterol, wherein the amount of cholesterol is at least 30% (w / w); and (b) a second empty liposome comprising sphingomyelin; said composition is used to treat animals, preferably humans, with long-term and severe hypotension, preferably with persistent hypotension.

[0040] In a further aspect, the present invention provides a composition comprising a mixture of empty liposomes, preferably consisting of the mixture of said empty liposomes, wherein said mixture of empty liposomes comprises, preferably consists of: (a) a first empty liposome comprising cholesterol, wherein the amount of cholesterol is at least 30% (w / w); and (b) a second empty liposome comprising sphingomyelin; said composition is used to treat animals, preferably humans, with hypotension in septic shock, sepsis, severe sepsis, acute respiratory distress syndrome or acute lung injury, preferably with persistent hypotension.

[0041] In a further aspect, the present invention provides a composition comprising a mixture of empty liposomes, preferably consisting of the mixture of said empty liposomes, wherein said mixture of empty liposomes comprises, preferably consists of: (a) a first empty liposome comprising cholesterol, wherein the amount of cholesterol is at least 30% (w / w); and (b) a second empty liposome comprising sphingomyelin; said composition is used to treat persistent hypotension in septic shock in animals, preferably humans.

[0042] In a further aspect, the present invention provides a composition comprising a mixture of empty liposomes, preferably consisting of the mixture of said empty liposomes, wherein said mixture of empty liposomes comprises, preferably consists of: (a) a first empty liposome comprising cholesterol, wherein the amount of cholesterol is at least 30% (w / w); and (b) a second empty liposome comprising sphingomyelin; said composition is used to treat hypotension in septic shock in animals, preferably humans, preferably persistent hypotension.

[0043] In a further aspect, the present invention provides a composition comprising, preferably, a mixture of empty liposomes, wherein the mixture of empty liposomes comprises, preferably, the following: (a) a first empty liposome comprising cholesterol, wherein the amount of cholesterol is at least 30% (w / w); and (b) a second empty liposome comprising sphingomyelin; the composition is used to treat persistent hypotension in septic shock in humans.

[0044] In a further aspect, the present invention provides a composition comprising a mixture of empty liposomes, preferably consisting of the mixture of said empty liposomes, wherein said mixture of empty liposomes comprises, preferably consists of: (a) a first empty liposome comprising cholesterol, wherein the amount of cholesterol is at least 30% (w / w); and (b) a second empty liposome comprising sphingomyelin; said composition is used to treat hypotension, preferably persistent hypotension, in animals, preferably humans, with sepsis or severe sepsis.

[0045] In a further aspect, the present invention provides a composition comprising a mixture of empty liposomes, preferably consisting of the mixture of said empty liposomes, wherein said mixture of empty liposomes comprises, preferably consists of: (a) a first empty liposome comprising cholesterol, wherein the amount of cholesterol is at least 30% (w / w); and (b) a second empty liposome comprising sphingomyelin; said composition is used to treat toxic shock syndrome in animals, preferably humans.

[0046] In a further aspect and in a very preferred embodiment, the present invention provides a composition of the invention, the composition described in the specification 7 / 22 pages 10 CN 121102236 A, for treating hypotension, preferably persistent hypotension, in the animal, preferably the human, suffering from sepsis. In a further aspect and in a very preferred embodiment, the present invention provides a composition of the invention for treating hypotension, preferably persistent hypotension, in the human, suffering from sepsis. In a further aspect and in a very preferred embodiment, the present invention provides a composition of the invention for treating persistent hypotension, preferably persistent hypotension, in the human, suffering from sepsis.

[0047] In a further aspect and in a very preferred embodiment, the present invention provides a composition of the invention for treating hypotension, preferably persistent hypotension, in the animal, preferably the human, suffering from septic shock. In a further aspect and in a very preferred embodiment, the present invention provides a composition of the invention for treating hypotension, preferably persistent hypotension, in the human, suffering from septic shock. In a further aspect and in a very preferred embodiment, the invention provides a composition of the invention for treating persistent hypotension in the person suffering from septic shock.

[0048] In another aspect, the invention provides a method for treating sepsis or septic shock in an animal, preferably a person, preferably suffering from septic shock, the method comprising administering a therapeutically effective amount of the composition as defined in the appended claims. Preferably, the human patient suffers from pneumococcal pneumonia, or the sepsis or septic shock, preferably the septic shock is caused by pneumococcal pneumonia.

[0049] For all aspects and embodiments disclosed herein, therapeutically effective amounts of the composition of the invention are typically and preferably used for the disclosed treatment.

[0050] Furthermore, all embodiments and preferred embodiments disclosed herein should be understood as embodiments and preferred embodiments of any and all aspects of the invention.

[0051] A first study compared the preferred composition of the invention plus standard antibiotic therapy with placebo plus standard antibiotic therapy in adult patients admitted to the intensive care unit (ICU) for severe community-acquired pneumococcal pneumonia. Two different doses of the preferred composition of the invention were compared, namely a low dose (4 mg / kg - low dose) and a high dose (16 mg / kg - high dose). The results showed a synergistic effect of the preferred composition of the invention (named CAL02) with antibiotic therapy.

[0052] As a result, the preferred composition of the invention thus captures and neutralizes toxins released from a variety of bacteria associated with severe infections in a synergistic manner with antibiotic therapy in human patients. The preferred composition of the invention works regardless of the resistance profile of the target pathogen and does not induce resistance.

[0053] In a preferred embodiment, the second empty liposome (b) comprises sphingomyelin as the sole lipid component. In a preferred embodiment, the second empty liposome (b) is composed of sphingomyelin.

[0054] In a preferred embodiment, the first empty liposome (a) contains 30% to 70% (w / w) cholesterol, and preferably 35% to 60% (w / w) cholesterol.

[0055] In a preferred embodiment, the empty liposome (a) contains 45% to 55% (w / w) cholesterol, and preferably about 50% (w / w) cholesterol.

[0056] In a preferred embodiment, the first empty liposome (a) is composed of cholesterol and sphingomyelin, and preferably 45% to 55% (w / w) cholesterol, and further preferably about 50% (w / w) cholesterol.

[0057] In a preferred embodiment, the first empty liposome (a) comprises the cholesterol and the sphingomyelin as the sole lipid components.

[0058] In a preferred embodiment, the amount of cholesterol in the empty liposome (a) is 45% to 55% (w / w), and the specification page 8 / 22 11 CN 121102236 A, and preferably the amount of cholesterol in the empty liposome (a) is about 50% (w / w), and wherein the second empty liposome (b) is composed of sphingomyelin.

[0059] In a preferred embodiment, the first empty liposome (a) is composed of cholesterol and sphingomyelin, and wherein the amount of cholesterol in the empty liposome (a) is 45% to 55% (weight / weight), and wherein preferably the amount of cholesterol in the empty liposome (a) is about 50% (weight / weight), and wherein the second empty liposome (b) is composed of sphingomyelin.

[0060] In a preferred embodiment, the first empty liposome (a) is composed of cholesterol and sphingomyelin, and wherein the amount of cholesterol in the empty liposome (a) is 45% to 55% (weight / weight), and wherein preferably the amount of cholesterol in the empty liposome (a) is about 50% (weight / weight), and wherein the first empty liposome (a) includes the cholesterol and the sphingomyelin as the only lipid components, and wherein the second empty liposome (b) is composed of sphingomyelin.

[0061] In a preferred embodiment, the mixture of empty liposomes comprises at least 20% (by weight) of the first empty liposome (a) and the second empty liposome (b), and wherein preferably the mixture of empty liposomes comprises at least 30% (by weight) of the first empty liposome (a) and the second empty liposome (b).

[0062] In a preferred embodiment, the mixture of empty liposomes comprises at least 40% (by weight) of the first empty liposome (a) and the second empty liposome (b).

[0063] In a preferred embodiment, the first empty liposome (a) is composed of cholesterol and sphingomyelin, and wherein, more preferably, the amount of cholesterol in the empty liposome (a) is about 50% (by weight), and wherein the mixture of empty liposomes comprises at least 40%, preferably at least 45% (by weight) of the first empty liposome (a) and the second empty liposome (b).

[0064] In a preferred embodiment, the first empty liposome (a) is composed of a 1:1 (weight / weight-w / w) mixture of the first empty liposome and the second liposome, wherein the first empty liposome is composed of cholesterol and sphingomyelin in a 1:1 weight ratio (1:1 w / w; molar ratio 35:65), and the second empty liposome is composed of sphingomyelin alone.

[0065] In a preferred embodiment, the first empty liposome (a) is composed of a 1:1 (weight / weight-w / w) mixture of the first empty liposome and the second liposome, wherein the first empty liposome is composed of cholesterol and sphingomyelin in a 1:1 weight ratio (1:1 w / w; molar ratio 35:65), and the second empty liposome is composed of sphingomyelin alone, wherein the first empty liposome (a) includes the cholesterol and the sphingomyelin as the sole lipid components, and the second empty liposome (b) includes the sphingomyelin as the sole lipid component.

[0066] In a preferred embodiment, the average diameter of the first empty liposome is about 130 nm, and the average diameter of the second empty liposome is about 90 nm.

[0067] In a preferred embodiment, the composition is used to treat hypotension in septic shock, sepsis, severe sepsis, acute respiratory distress syndrome, or acute lung injury, preferably persistent hypotension, preferably for treating hypotension in septic shock, preferably persistent hypotension, wherein the hypotension, preferably the persistent hypotension, is associated with systolic blood pressure <90 mmHg or mean arterial pressure <70 mmHg.

[0068] In a preferred embodiment, the composition is used to treat hypotension in septic shock, sepsis, severe sepsis, acute respiratory distress syndrome, or acute lung injury, preferably persistent hypotension, preferably for treating hypotension in septic shock, preferably persistent hypotension, wherein the hypotension, preferably the persistent hypotension, is associated with systolic blood pressure <90 mmHg.

[0069] In a preferred embodiment, the composition is used to treat hypotension in septic shock, sepsis, severe sepsis, acute respiratory distress syndrome, or acute lung injury, preferably persistent hypotension, preferably for treating hypotension in septic shock, preferably persistent hypotension, wherein the hypotension, preferably persistent hypotension, is associated with a mean arterial pressure < 70 mmHg.

[0070] In a preferred embodiment, the composition is used to treat hypotension in septic shock, sepsis, severe sepsis, acute respiratory distress syndrome, or acute lung injury, preferably persistent hypotension, preferably for treating hypotension in septic shock, preferably persistent hypotension, wherein the hypotension, preferably persistent hypotension, is associated with a systolic blood pressure < 90 mmHg or a mean arterial pressure < 70 mmHg, and wherein the hypotension, preferably persistent hypotension, is pretreated with a vasopressor for at least 2 hours.

[0071] In a preferred embodiment, the composition is used to treat hypotension, preferably persistent hypotension, in septic shock, sepsis, severe sepsis, acute respiratory distress syndrome or acute lung injury, preferably in the treatment of hypotension in septic shock, preferably in the treatment of persistent hypotension, wherein the hypotension is associated with systolic blood pressure <90 mmHg or mean arterial pressure <70 mmHg, and wherein the hypotension, preferably the persistent hypotension, is pretreated with vasopressors for at least 2 hours after fluid resuscitation.

[0072] In a preferred embodiment, the composition is used to treat hypotension in septic shock, sepsis, severe sepsis, acute respiratory distress syndrome or acute lung injury, preferably persistent hypotension, preferably for treating hypotension in septic shock, preferably the persistent hypotension, wherein the hypotension, preferably the persistent hypotension, is associated with systolic blood pressure <90 mm Hg or mean arterial pressure <70 mm Hg, and wherein the hypotension, preferably the persistent hypotension, is pretreated with at least one, preferably a therapeutic dose of a vasopressor for at least 2 hours.

[0073] In a preferred embodiment, the composition is used to treat hypotension in septic shock, sepsis, severe sepsis, acute respiratory distress syndrome or acute lung injury, preferably persistent hypotension, preferably for treating hypotension in septic shock, preferably the persistent hypotension, wherein the hypotension, preferably the persistent hypotension, is associated with systolic blood pressure <90 mm Hg or mean arterial pressure <70 mm Hg, and wherein the hypotension, preferably the persistent hypotension, is pretreated with at least one, preferably a therapeutic dose of a vasopressor for at least 2 hours, wherein the vasopressor is selected from dopamine, adrenaline, noradrenaline, phenylephrine or vasopressin.

[0074] In a preferred embodiment, the composition is used to treat hypotension, preferably persistent hypotension, in septic shock, sepsis, severe sepsis, acute respiratory distress syndrome, or acute lung injury. The persistent hypotension is preferably associated with a systolic blood pressure <90 mmHg or a mean arterial pressure <70 mmHg, and is pretreated for at least 2 hours with at least one, preferably a therapeutic dose, of a vasopressor. The therapeutic dose of the vasopressor is >5 mg / kg / min of dopamine or a corresponding dose of the vasopressor, preferably a corresponding dose of adrenaline, noradrenaline, phenylephrine, or vasopressin.

[0075] In a preferred embodiment, the composition is used to treat and prevent septic shock. In a preferred embodiment, the composition is used to treat hypotension, preferably persistent hypotension. In a preferred embodiment, the hypotension, preferably persistent hypotension, is associated with septic shock. In a preferred embodiment, the composition is used to treat persistent hypotension. In a preferred embodiment, the persistent hypotension is associated with septic shock.

[0076] In a preferred embodiment, the hypotension, preferably persistent hypotension, is associated with a systolic blood pressure <90 mmHg (or a mean arterial pressure <70 mmHg).In a preferred embodiment, although the hypotension, preferably the persistent hypotension, is associated with a systolic blood pressure <90 mmHg (or a mean arterial pressure <70 mmHg) after adequate fluid resuscitation for at least 2 hours following treatment with a therapeutic dose of a vasopressor (i.e., dopamine >5 mg / kg / min or any dose of epinephrine, noradrenaline, phenylephrine, or vasopressin).

[0077] In a preferred embodiment, the treatment is adjunctive to antibiotic therapy, preferably adjunctive to standard antibiotic therapy. In a preferred embodiment, the antibiotic therapy, preferably the standard antibiotic therapy, comprises antibiotics selected from: ceftriaxone, spiramycin, amoxicillin, amoxicillin / clavulanic acid, gentamicin, piperacillin / tazobactam, cefuroxime, penicillin, azithromycin, clarithromycin, erythromycin, doxycycline, cefotaxime, ampicillin, ertapenem, cefepime, imipenem, meropenem, ciprofloxacin, levofloxacin, vancomycin, linezolid, moxifloxacin, and gemifloxacin, and wherein the antibiotic therapy, preferably the standard antibiotic therapy, comprises antibiotics selected from: ceftriaxone, spiramycin, amoxicillin, gentamicin, levofloxacin, piperacillin / tazobactam, amoxicillin / clavulanic acid, cefuroxime, and penicillin. In a preferred embodiment, the antibiotic therapy, preferably the standard antibiotic therapy, is intravenous (IV) or oral antibiotic therapy, preferably the standard antibiotic therapy.

[0078] In a preferred embodiment, the human patient has pneumonia, wherein the pneumonia is preferably selected from community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP). In a preferred embodiment, the human patient has pneumonia, wherein the pneumonia is community-acquired pneumonia (CAP). In a preferred embodiment, the human patient has pneumonia, wherein the pneumonia is hospital-acquired pneumonia (HAP). In a preferred embodiment, the human patient has pneumonia, wherein the pneumonia is ventilator-associated pneumonia (VAP). In a preferred embodiment, the human patient has pneumonia, wherein the pneumonia is severe pneumonia, preferably severe community-acquired pneumonia (sCAP) or severe community-acquired pneumococcal pneumonia (sCAPP). In a preferred embodiment, the human patient has pneumonia, wherein the pneumonia is community-acquired pneumonia (CAP) or community-acquired pneumococcal pneumonia (CAPP).

[0079] In a preferred embodiment, the human patient has pneumonia, and the pneumonia is caused by: Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecium, Legionella pneumophila, Haemophilus influenzae, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumanii, Bordetella pertussis, Serratia marcescens, Stenotrophomonas maltophilia, Moraxella catarrhalis, or Mycobacterium tuberculosis. In a preferred embodiment, the human patient suffers from pneumonia, and the pneumonia is severe pneumonia caused by: Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis, Legionella pneumophila, Haemophilus influenzae, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, Bordetella pertussis, Serratia marcescens, Stenotrophomonas maltophilia, Moraxella catarrhalis, or Mycobacterium tuberculosis, and preferably the pneumonia, preferably the severe pneumonia, is caused by: Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis, Haemophilus influenzae, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, Bordetella pertussis, Serratia marcescens, or Mycobacterium tuberculosis, and further preferably the pneumonia, preferably the severe pneumonia, is caused by: Streptococcus pneumoniae, Staphylococcus aureus, Klebsiella pneumoniae, or Pseudomonas aeruginosa, and again, more preferably the pneumonia or the severe pneumonia is caused by Streptococcus pneumoniae.

[0080] In a preferred embodiment, the composition is in the form of a solution for intravenous administration, preferably intravenous infusion, comprising a mixture of the empty liposomes between 10 grams and 40 grams per liter of solution, preferably between 10 grams and 20 grams per liter of solution.

[0081] In a preferred embodiment, the intravenous administration is administered over a period of up to 3 hours, and preferably over a period of 10 minutes to 2 hours.

[0082] In a preferred embodiment, the composition is administered in at least two doses. In a preferred embodiment, the composition is administered in at least two doses: a first dose and a second dose, wherein the interval between the first dose and the second dose is 6 hours to 96 hours, preferably 12 hours to 72 hours, more preferably 24 hours to 48 hours, and even more preferably 24 hours or 48 hours.Instructions for Use, Page 11 / 22, 14 CN 121102236 A

[0083] In a preferred embodiment, the composition is administered in 2 to 4 doses, preferably two doses, over 12 to 72 hours, more preferably two doses over 24 to 48 hours, preferably with an interval of 24 or 48 hours.

[0084] In a preferred embodiment, the composition is administered to the human patient in at least two doses: a first dose and a second dose, wherein the interval between the first dose and the second dose is 20 to 28 hours, preferably 24 hours.

[0085] In a preferred embodiment, the composition is administered to the human patient in two doses: a first dose and a second dose, wherein the interval between the administration of the first dose and the administration of the second dose is 20 to 28 hours, preferably 24 hours.

[0086] In a preferred embodiment, each of the doses is from 1 mg / kg to 64 mg / kg, preferably from 2 mg / kg to 32 mg / kg, more preferably from 3 mg / kg to 25 mg / kg, and even more preferably from 4 mg / kg to 16 mg / kg.

[0087] In a preferred embodiment, each of the doses is from 2 mg / kg to 8 mg / kg, preferably from 2 mg / kg to 6 mg / kg, more preferably from 3 mg / kg to 5 mg / kg, and even more preferably from 4 mg / kg.

[0088] In a preferred embodiment, each of the doses is from 10 mg / kg to 22 mg / kg, preferably from 12 mg / kg to 20 mg / kg, more preferably from 14 mg / kg to 18 mg / kg, and even more preferably from 16 mg / kg.

[0089] In a preferred embodiment, the composition is administered in the form of a solution for intravenous administration.

[0090] In a preferred embodiment, the composition is administered to the human patient, preferably in at least two doses: a first dose and a second dose, wherein the administration of the first dose and the administration of the second dose are spaced 20 to 48 hours, preferably 24 hours apart, and wherein the composition is in the form of a solution for intravenous administration.

[0091] In a preferred embodiment, the composition is used to treat sepsis, severe sepsis, septic shock, or prolonged and severe hypotension, preferably persistent hypotension, and wherein the composition is preferably used to treat septic shock in animals, preferably humans, and wherein the sepsis, severe sepsis, septic shock, or prolonged and severe hypotension, preferably persistent hypotension, preferably septic shock requires hospitalization.

[0092] In a preferred embodiment, the composition is used to treat sepsis, septic shock, or hypotension in animals, preferably humans, preferably persistent hypotension.

[0093] In a preferred embodiment, the composition is used to treat sepsis, septic shock, or hypotension in a human, preferably persistent hypotension. In a very preferred embodiment, the composition is used to treat sepsis in a human. In a very preferred embodiment, the composition is used to treat septic shock in a human. In a very preferred embodiment, the composition is used to treat hypotension in a human, preferably persistent hypotension. In a preferred embodiment, the sepsis, septic shock, or hypotension, preferably persistent hypotension, requires hospitalization, preferably in a hospital's intensive care unit (ICU).

[0094] In a preferred embodiment, the composition is used to treat sepsis, severe sepsis, septic shock, or prolonged and severe hypotension, preferably persistent hypotension, and wherein preferably the composition is used to treat septic shock in animals, preferably humans, and wherein the sepsis, severe sepsis, septic shock, or prolonged and severe hypotension, preferably persistent hypotension, preferably septic shock, requires hospitalization in an intensive care unit (ICU), preferably in a hospital's intensive care unit (ICU).

[0095] In a preferred embodiment, the composition is used to treat sepsis, severe sepsis, septic shock, or prolonged and severe hypotension, preferably persistent hypotension, and wherein preferably the composition is used to treat septic shock in animals, preferably humans, and wherein the sepsis, severe sepsis, septic shock, or prolonged and severe hypotension, preferably persistent hypotension, preferably septic shock requires hospitalization, and wherein the treatment reduces the length of hospital stay in the hospital compared to the length of hospital stay without such treatment.

[0096] In a preferred embodiment, the reduction in hospital stay due to the treatment is at least one day, preferably two days, further preferably three days, even more preferably four days, even more preferably five days, even more preferably six days, even more preferably seven days, even more preferably eight days, even more preferably nine days. In a preferred embodiment, the length of hospital stay is at most 18 days.

[0097] In a preferred embodiment, the composition is used to treat sepsis, severe sepsis, septic shock, or prolonged and severe hypotension, preferably persistent hypotension, and wherein the composition is preferably used to treat septic shock in animals, preferably humans, wherein the sepsis, severe sepsis, septic shock, or prolonged and severe hypotension, preferably persistent hypotension, preferably septic shock requires hospitalization in an intensive care unit (ICU), preferably in a hospital intensive care unit (ICU), and wherein the treatment reduces the length of hospitalization in the intensive care unit (ICU) compared to the length of hospitalization in the intensive care unit (ICU) without such treatment.

[0098] In a preferred embodiment, the length of stay in the intensive care unit (ICU) is reduced to at least one day, preferably two days, more preferably three days, even more preferably four days, even more preferably five days, even more preferably six days, and even more preferably seven days. In a preferred embodiment, the length of stay in the intensive care unit (ICU) is at most 18 days.

[0099] In a preferred embodiment, the composition is used to treat sepsis, severe sepsis, septic shock, or prolonged and severe hypotension, preferably persistent hypotension, and wherein the composition is preferably used to treat septic shock in animals, preferably humans, and wherein the recovery time for the sepsis, severe sepsis, septic shock, or prolonged and severe hypotension, preferably persistent hypotension, preferably septic shock is shorter compared to when such treatment is not performed.

[0100] In a preferred embodiment, the cure time is less than one day, preferably less than two days, or more preferably less than three days, even more preferably less than four days, even more preferably less than five days, even more preferably less than six days, and even more preferably less than seven days.

[0101] In a preferred embodiment, the composition is used to treat sepsis, severe sepsis, septic shock, or prolonged and severe hypotension, preferably persistent hypotension, and wherein the composition is preferably used to treat septic shock in animals, preferably humans, and wherein the treatment reduces the cardiovascular SOFA score compared to when such treatment was not performed.

[0102] In a preferred embodiment, the composition is used to treat sepsis, severe sepsis, septic shock, or prolonged and severe hypotension, preferably persistent hypotension, and wherein the composition is preferably used to treat septic shock in animals, preferably humans, and wherein the treatment reduces the cardiovascular SOFA score compared to when such treatment was not performed, and wherein the reduction is at least 50%, preferably at least 60%, further preferably at least 70%, and even more preferably at least 80% after 7 days of treatment, preferably after 6 days of treatment, more preferably after 5 days.

[0103] Examples

[0104] Liposomes:

[0105] Sphingomyelin from egg yolk (CAS No.: 85187-10-6) was purchased from Sigma (S0756), Avanti Polar Lipids (860061) or Lipoid GmbH. Cholesterol from sheep lanolin (CAS No.: 57-88-5) was purchased from Sigma (C-8667), Avanti Polar Lipids (70000) or Dishman Netherlands BV.According to the present invention, the sphingomyelin and cholesterol included or composed of the mixture of empty liposomes of the present invention can be obtained from natural sources as described above, or alternatively obtained by chemical synthesis.

[0106] Liposome preparation:

[0107] Monolayer sphingomyelin: Cholesterol (molar ratio of 35:65) and sphingomyelin-only (100%) liposomes are prepared by ultrasonic treatment or microfluidization (e.g., high-pressure homogenization) or according to the process specification 13 / 22 pages 16 CN 121102236 A.

[0108] Ultrasonic treatment:

[0109] The lipids are dissolved in chloroform at a concentration of 1 mg / ml and stored at -20°C. To prepare liposomes, the chloroform solutions of each lipid are mixed in proportion as needed to routinely produce a final solution of 50 μl to 500 μl. The chloroform is completely evaporated at 60°C for 20 to 50 minutes. Add 50 μl or 100 μl of Tyrode's buffer (140 mM NaCl, 5 mM KCl, 1 mM MgCl2, 10 mM glucose, 10 mM HEPES; pH = 7.4) containing 2.5 mM CaCl2 to a tube containing a dried lipid membrane and vortex vigorously. Incubate the lipid suspension in an Eppendorf hot mixer at 45 °C for 20 to 30 minutes with vigorous shaking. To generate liposomes, sonicate the final lipid suspension at 6 °C for 3 × 5 seconds at 70% power in a Bandelin Sonopuls sonicator. Incubate the liposome formulation at 6 °C for at least 1 hour before using it in experiments.

[0110] Hydration, extrusion and percolation process:

[0111] In alternative methods, each liposome formulation is prepared by ethanol hydration and extrusion. The lipids are dissolved in ethanol and tert-butanol, respectively, while being mixed at high temperature (~55 °C). The lipid solution was then added to a PBS buffer solution (sodium chloride, monosodium phosphate dihydrate, and disodium phosphate dihydrate dissolved in water for injection, adjusted to a pH of 7.0 to 7.4 with hydrochloric acid (HCl) or sodium hydroxide (NaOH) as needed, and filtered through a 0.2 μm filter) while mixing at high temperature (~65°C) for approximately 30 minutes. The resulting process fluid was then repeatedly extruded through a series of polycarbonate track-etched membranes under high pressure and high temperature (~65°C) until the desired particle size, as measured by dynamic light scattering, was achieved (example of an extruder: extruder). The resulting process fluid was then concentrated approximately 2-fold using a hollow fiber filter cartridge with a molecular weight cutoff of 100,000, and then percolated against approximately 10-fold volume exchange with the PBS buffer solution to remove ethanol and n-butanol. At the end of percolation, the process fluid was concentrated approximately 30% to allow for subsequent dilution to the target lipid concentration.Prior to dilution, the process fluid was filtered through a 0.2 μm sterile-grade filter to remove any larger liposomes that might clog the filter during aseptic filtration. The process fluid was then diluted with PBS buffer to a target total lipid concentration of 40 mg / mL. The final formulation was aseptically filtered through two tandem 0.2 μm sterile-grade filters and aseptically filled into glass tubular vials.

[0112] The concentration of individual lipids in the liposomes is always given as a weight / weight ratio. In liposomes containing sphingomyelin and cholesterol, a 1:1 (weight / weight) ratio corresponds to 50% (weight / weight) or a 35:65 molar ratio. Specifications are described in Table 1.

[0113] Table 1: Liposome Specifications

[0114] Average Diameter (nm) Polydispersity Index ζ Potential (mV) Permeability (mmol / kg) pH 40 to 400 <0.45 -25 to +2 250 to 400 6.5 to 8.0

[0115] CURB-65 Score:

[0116] CURB-65 (also known as the CURB criteria) is a clinically proven predictive rule well known to those skilled in the art for predicting mortality from community-acquired pneumonia (Lim WS et al. (2003), Thorac 58(5):377–82). The British Thoracic Society recommends CURB-65 for assessing the severity of pneumonia (British Thoracic Society Standards of Care Committee (2001). "BTS Guidelines for the Management of Community Acquired Pneumonia in Adults". Thorac. 56. Supplement 4: IV1–64).

[0117] The score is an acronym for each of the risk factors measured. Each risk factor is scored on one point, with a maximum score of 5: Instructions for Use 14 / 22 Page 17 CN 121102236 A

[0118] - New onset of confusion (defined as 8 or fewer AMTS)

[0119] - Blood urea nitrogen greater than 7 mmol / L (19 mg / dL)

[0120] - Respiratory rate of 30 breaths per minute or more

[0121] - Blood pressure less than 90 mm Hg, with systolic or diastolic blood pressure of 60 mm Hg or less

[0122] - Age 65 years or older

[0123] APACHE II:

[0124] APACHE II is an acronym for Acute Physiology and Chronic Health Evaluation, and is calculated according to Table 2 (Knaus WA et al. APACHE II: a severity of disease classification system. Crit Care Med. October 1985; 13(10):818-29):

[0125] Table 2: APACHE II score

[0126] Instruction manual 15 / 22 pages 18 CN 121102236 A

[0127] Instruction manual 16 / 22 pages 19 CN 121102236 A

[0128] Instruction manual 17 / 22 pages 20 CN 121102236 A

[0129]

[0130] APACHE The Apache II score aims to provide an approximate estimate of the likelihood of death for a patient or a group of patients based on the total score obtained. The mortality interpretation of the score is described in Table 3:

[0131] Table 3: Apache II score / approximate mortality interpretation

[0132]

[0133] SOFA:

[0134] SOFA score is an acronym for Sequential Organ Failure Assessment and is calculated according to Table 4 (S. Vosylius, J. Sipylaite and J. Ivaskevicius, Croatian Medical Journal, 45(2004), 715-20):

[0135] Table 4: SOFA score

[0136] Instructions for use 18 / 22 pages 21 CN 121102236 A

[0137]

[0138] Cardiovascular hypotension:

[0139] Cardiovascular hypotension is a major feature of septic shock. It may be caused by low cardiac output or low systemic vascular resistance.Its severity can be assessed using the cardiovascular SOFA (Sequential Organ Failure Assessment) score, which is defined by mean arterial pressure or by the need for vasopressor administration, as shown in Table 5 (S. Vosylius, J. Sipylaite and J. Ivaskevicius, Croatian Medical Journal, 45(2004), 715-20):

[0140] Table 5: Cardiovascular SOFA Score

[0141] Mean Arterial Pressure or Need for Vasopressor Administration Score No Hypotension 0 MAP < 70 mm / Hg 1 Dopamine ≤ 5 μg / kg / min or Dobutamine (any dose) 2 Dopamine > 5 μg / kg / min or Epinephrine ≤ 0.1 μg / kg / min or Norepinephrine ≤ 0.1 μg / kg / min 3 Dopamine >15 μg / kg / min or adrenaline >0.1 μg / kg / min or norepinephrine >0.1 μg / kg / min 4

[0142] Example 1

[0143] Treatment of sepsis and septic shock in patients with severe infections

[0144] In a subsequently reported study, a highly preferred mixture of empty liposomes of the present invention (named CAL02) was administered intravenously (IV) as adjunctive therapy in addition to standard antibiotic therapy to patients admitted to the intensive care unit (ICU) with severe community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae. The highly preferred mixture of empty liposomes of the invention (CAL02) consists of a 1:1 (weight / weight-w / w) mixture of the first empty liposome and the second liposome, wherein the first empty liposome is composed of sphingomyelin and cholesterol in a 1:1 weight ratio (1:1 w / w; molar ratio 35:65), and the second empty liposome is composed of sphingomyelin alone.

[0145] In addition to standard antibiotic therapy (Mandel et al., CID 2007:44(Supplement 2), S27-S72), each patient received two infusions of either CALO2 or placebo (physiological 0.9% NaCl solution) (with an interval of 24 or 48 hours between these administrations). The first administration was given shortly after the severity was diagnosed.The diagnosis of severity is based on at least one of the following severity criteria:

[0146] i. Invasive mechanical ventilation support

[0147] ii. Treatment with a therapeutic dose of vasopressor (i.e., dopamine >5 mg / kg / min or any dose of epinephrine, norepinephrine, phenylepinephrine, or vasopressin) for at least 2 hours after adequate fluid resuscitation to maintain or attempt to maintain systolic blood pressure >90 mm Hg (or mean arterial pressure >70 mm Hg)

[0148] or based on at least three of the following minor severity criteria:

[0149] i. Respiratory rate ≥30 breaths / min

[0150] ii. PaO2 / FiO2 ratio ≤250 mm Hg

[0151] iii. Multilobular infiltration

[0152] iv. Confusion / disorientation (must be documented before use of sedatives or other new psychotropic drugs)

[0153] v. Urea >7mM (>40mg / dL)

[0154] vi. Leukopenia (white blood cell count <4,000 cells / mm3)

[0155] vii. Thrombocytopenia (platelet count <100,000 cells / mm3)

[0156] viii. Hypothermia (core temperature <36°C)

[0157] ix. Systolic blood pressure <90mmHg or mean arterial pressure <70mmHg, and received fluid resuscitation at ≥40mL / kg for at least 2 hours.

[0158] Two dose levels of CAL02 (4mg / kg (low dose) and 16mg / kg (high dose)) were tested. Five patients were randomly assigned to the placebo group, 11 patients were assigned to the high-dose CAL02 group, and 3 patients were assigned to the low-dose CAL02 group.

[0159] At the time of treatment, 56% of the patients already had septic shock: 2 patients in the placebo group, 5 patients in the high-dose CAL02 group, and all three patients in the low-dose CAL02 group.

[0160] Results

[0161] Table 6: Patient characteristics at baseline 20 / 22 pages 23 CN 121102236 A

[0162]

[0163] When considering the entire study population and when only patients presenting with septic shock at baseline were assessed, a faster decline in the cardiovascular SOFA score was observed in the CAL02 group compared to the placebo group: in the CAL02 group, the SOFA score decreased by 100% within 6 days, while at the same time point, the placebo group did not reach a 40% reduction (Figures 1 and 2).

[0164] In patients presenting with septic shock, on day 8 post-treatment, hypotension and septic shock were completely resolved in all patients (5 / 5, 100%) in the high-dose CAL02 group and in 66% (2 / 3) of patients in the low-dose CAL02 group, compared to no patients (0 / 2, 0%) in the placebo group.

[0165] In the placebo group, of the three patients who were not in septic shock at baseline, one patient had hypotension at baseline and developed septic shock on day 4, and two patients did not have hypotension at baseline but developed hypotension within the first 8 days. In contrast, in the CAL02 group, three patients did not have hypotension at baseline and did not develop any hypotension, and all other patients improved to a state of resolution by day 6. This indicates that CAL02 prevents hypotension and hemodynamic instability and prevents the occurrence of septic shock.

[0166] The resolution of septic shock was accompanied by a significant reduction in the mean ICU stay, from 32 days in the placebo group to 5.4 days and 15 days in the high-dose CAL02 group and the low-dose CAL02 group, respectively. Furthermore, the mortality rate was lower in the CAL02 group compared to the placebo group (50%) (20% and 33% mortality rates in the high-dose and low-dose CAL02 groups, respectively) (Table 7).

[0167] Table 7: Results Presentation 21 / 22 pages 24 CN 121102236 A

[0168]

[0169] The effects of CAL02 treatment on vital signs (including heart rate, systolic and diastolic blood pressure, and core body temperature) and lactate levels were also evaluated.22 / 22 pages of the specification, 25 CN 121102236 A, Figure 1A, Figure 1B, Figure 2, 1 / 1 page of the drawings of the specification, 26 CN 121102236 A Abstract Abdominal ultrasound examination method, system and device The present invention relates to a composition comprising a mixture of empty liposomes, wherein said mixture of empty liposomes comprises (a) a first empty liposome comprising cholesterol, wherein the amount of cholesterol is at least 30% (weight per weight); and (b) a second empty liposome comprising sphingomyelin, for use in the treatment of sepsis, severe sepsis, septic shock, or prolonged and severe hypotension, preferably persistent hypotension, for use in the treatment of hypotension, preferably said persistent hypotension, in septic shock, sepsis, severe sepsis, acute respiratory distress syndrome or acute lung injury, or for use in the treatment of toxic shock syndrome in an animal, preferably in a human.。

Claims

1. A composition comprising a mixture of empty liposomes, preferably consisting of said mixture of empty liposomes, wherein said mixture of empty liposomes comprises, preferably, the following: (a) A first empty liposome containing cholesterol, wherein the amount of cholesterol is at least 30% (by weight); as well as (b) A second empty liposome comprising sphingomyelin, wherein preferably the second empty liposome (b) comprises sphingomyelin as the sole lipid component; The composition is used to treat sepsis in animals, preferably humans.

2. The composition for use according to claim 1, wherein the composition is used to treat septic shock in the animal, preferably the human.

3. The composition for use according to claim 1, wherein the composition is used to treat hypotension, preferably persistent hypotension, in the animal, preferably the human, suffering from sepsis.

4. The composition for use according to claim 2, wherein the composition is used to treat hypotension, preferably persistent hypotension, in the animal, preferably the human, suffering from septic shock.

5. The composition for use according to any one of the preceding claims, wherein the amount of cholesterol in the empty liposome (a) is 45% to 55% (by weight), and wherein the second empty liposome (b) is composed of sphingomyelin.

6. The composition for use according to any one of the preceding claims, wherein the first empty liposome (a) is composed of cholesterol and sphingomyelin, and wherein the amount of cholesterol in the empty liposome (a) is about 50% (w / w), and wherein the mixture of the empty liposomes comprises at least 40%, preferably at least 45% (w / w) of the first empty liposome (a) and the second empty liposome (b).

7. The composition for use according to any one of the preceding claims, wherein the first empty liposome (a) comprises a 1:1 (weight / weight-w / w) mixture of the first empty liposome and the second liposome, wherein the first empty liposome is composed of cholesterol and sphingomyelin in a 1:1 weight ratio (1:1 w / w; molar ratio 35:65), and the second empty liposome is composed of sphingomyelin alone, wherein the first empty liposome (a) comprises the cholesterol and the sphingomyelin as the sole lipid component, and the second empty liposome (b) comprises the sphingomyelin as the sole lipid component.

8. The composition for use according to any one of claims 3 to 7, wherein the hypotension, preferably the persistent hypotension, is associated with a mean arterial pressure <70 mm Hg.

9. The composition for use according to claim 8, wherein the hypotension, preferably the persistent hypotension, is pretreated with a vasopressor for at least 2 hours.

10. The composition for use according to any one of the preceding claims, wherein the treatment is an adjunct to antibiotic therapy.

11. The composition for use according to claim 10, wherein the antibiotic therapy is intravenous (IV) or oral antibiotic therapy.

12. The composition for use according to any one of the preceding claims, wherein the animal is a human patient, and wherein the human patient has pneumonia, wherein preferably the pneumonia is selected from community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP), and ventilator-associated pneumonia (VAP).

13. The composition for use according to claim 12, wherein the pneumonia is severe pneumonia, preferably severe community-acquired pneumonia (sCAP) or severe community-acquired pneumococcal pneumonia (sCAPP).

14. The composition for use according to claim 12 or 13, wherein the pneumonia or the severe pneumonia is caused by: Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis, Legionella pneumophila, Haemophilus influenzae, Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, Bordetella pertussis, Serratia marcescens, Stenotrophomonas maltophilia, Moraxella catarrhalis, or Mycobacterium tuberculosis, wherein preferably the pneumonia or the severe pneumonia is caused by Streptococcus pneumoniae.

15. The composition for use according to any one of the preceding claims, wherein the composition is in the form of a solution for intravenous administration.

16. The composition for use according to any one of the preceding claims, wherein the composition is administered to the animal, preferably to the human, in at least two doses: a first dose and a second dose, and wherein the interval between the first dose and the second dose is 6 hours to 96 hours, preferably 12 hours to 72 hours, more preferably 24 hours to 48 hours, and even more preferably 24 hours or 48 hours.

17. The composition for use according to any one of the preceding claims, wherein the sepsis, septic shock, or the hypotension, preferably persistent hypotension, requires hospitalization, preferably in a hospital intensive care unit (ICU).

18. The composition for use according to claim 17, wherein the treatment reduces the length of hospital stay in the hospital compared to the length of hospital stay without such treatment.

19. The composition for use according to claim 17 or claim 18, wherein the reduction in hospitalization time due to the treatment is at least one day, preferably two days, more preferably three days, even more preferably four days, even more preferably five days, even more preferably six days, even more preferably seven days, even more preferably eight days, even more preferably nine days.

20. The composition for use according to any one of the preceding claims, wherein the sepsis, septic shock, or hypotension, preferably persistent hypotension, takes less time to heal compared to the absence of such treatment.

21. The composition for use according to claim 20, wherein the cure time is less than one day, preferably less than two days, or more preferably less than three days, even more preferably less than four days, even more preferably less than five days, even more preferably less than six days, and even more preferably less than seven days.

22. The composition for use according to any one of the preceding claims, wherein the treatment reduces the cardiovascular SOFA score compared to the cardiovascular SOFA score without such treatment.

23. The composition for use according to claim 22, wherein the reduction is at least 50%, preferably at least 60%, more preferably at least 70%, and even more preferably at least 80% seven days after the start of treatment, preferably six days after the start of treatment, and even more preferably five days after the start of treatment.

Images