Collagen hydrolysate for use in the prevention and / or treatment of post-intensive care syndrome (PICS) - Patents.com

Abstract

The present invention relates to the use of collagen hydrolysate after intensive care unit (ICU) stay.Collagen hydrolysate improves recovery and prevents and / or treats post-intensive care syndrome (PICS) after ICU stay.Collagen hydrolysate is preferably administered as a supplement in the context of ICU stay and / or PICS.Collagen hydrolysate is generally recognized as safe and therefore can be considered as a preventative and long-term measure.

Description

[Technical field]

[0001] The present invention relates to a strategy for the prevention and / or treatment of post-intensive care syndrome (PICS), in particular to a supplement for the prevention and / or treatment of PICS. [Background technology]

[0002] Intensive care unit (ICU) survivors may typically suffer from a variety of (severe) disorders as a result of ICU admission. Post-intensive care syndrome (PICS) is a medical condition that may occur after a patient is admitted to an ICU and is associated with the characterization of persistent changes in physical, cognitive, and mental health status (Needham et al., Crit Care Med 2012; 40: 502-509). PICS complaints may persist for weeks to years after an ICU stay. PICS patients may experience persistent memory and concentration deficits, depression, and anxiety. In addition, PICS patients may be unable to work or participate in social gatherings. As a result, the quality of life of PICS patients is generally dramatically impaired (Schweickert et al., Lancet., 373(9678): 1874-1882).

[0003] Although several factors may contribute to the development of PICS, it is generally accepted that the acute complications of ICU admission (e.g., mechanical ventilation, immobilization, and deep sedation) are risk factors for developing the long-term symptoms that constitute PICS. In general, the likelihood of developing PICS is thought to be related to the time spent in the ICU. Most typically, the likelihood of developing PICS increases significantly with an ICU stay of 48 hours or more. Although the mechanism is not currently precisely understood, various aspects of PICS may have one or more common causes, even though the symptoms may be heterogeneous. PICS symptoms may be subtle at first, and as a result may not be easily recognized by patients and clinicians. Symptoms may progress, resulting in chronic symptoms that last from months to years after ICU admission (Colbenson et al., Breathe, 2019, 15:98-101).

[0004] Although various measurement instruments have been reported to diagnose PICS (Yuan et al., Nurs Crit Care, January 2022; Vol. 27(1): pp. 8-9), one that is particularly attractive and practical is the Post-Intensive Care Syndrome Questionnaire (PICSQ). The PICSQ is an 18-item self-report measurement tool encompassing physical, cognitive, and psychological domains. The PICSQ has been shown to be a reliable and consistent tool for diagnosing PICS in ICU survivors (Jeong et al., Intensive Crit Care Nurs, December 2019; Vol. 55: pp. 1027-56).

[0005] To date, there is no effective treatment for PICS. Instead, the American College of Critical Care Medicine and the American Society of Critical Care Medicine focus on the following pillars to prevent PICS (Marra et al., Crit Care Clin, 2017, 33:225-243): (1) Correction or elimination of the causative factor; (2) administration of anxiolytics and antipsychotics; (3) Reducing environmental stressors; and (4) Frequent patient and family communication.

[0006] As described above, currently there is no sufficient means that can effectively prevent or treat PICS. Instead, current strategies aim to reduce one or more symptoms of PICS, but do not seem to alleviate the medical condition itself or the underlying (common) cause of PICS. In addition, anxiolytics and antipsychotics cause side effects, so they are preferably avoided. Moreover, current treatments of PICS (symptoms) are time-consuming and complicated, i.e., they require different therapeutic interventions in parallel, which places additional burden on patients. Summary of the Invention [Problem to be solved by the invention]

[0007] There remains an unmet need for effective strategies to prevent and / or treat PICS. In particular, strategies that are considered safe and therefore can be considered as long-term (preventative) measures are desirable. The present invention aims to provide a solution therefor. [Means for solving the problem]

[0008] The inventors have surprisingly found that collagen hydrolysate improves recovery after a stay in the Intensive Care Unit (ICU) and prevents and / or treats Post Intensive Care Syndrome (PICS).

[0009] In one aspect, the invention relates to the use of collagen hydrolysate after an ICU stay.

[0010] In one aspect, the present invention relates to the use of collagen hydrolysate to improve recovery after a stay in an intensive care unit.

[0011] In one aspect the present invention relates to a collagen hydrolysate for use in the prevention and / or treatment of PICS after an ICU stay.

[0012] In one aspect, the invention relates to a collagen hydrolysate for use after an ICU stay.

[0013] In one aspect, the present invention relates to a collagen hydrolysate for use in subjects following an ICU stay.

[0014] In one aspect, the present invention relates to a collagen hydrolysate for use in subjects at risk of PICS after an ICU stay.

[0015] Detailed Description of the Invention

[0016] ICU stay The use of the present invention relates to the administration of collagen hydrolysate following an ICU stay and / or to improve recovery following an ICU stay.

[0017] The use of collagen hydrolysate according to the invention solves the problem of subjects experiencing (long-term) symptoms after a stay in the ICU and / or showing impaired recovery after a stay in the ICU.

[0018] The term "post-ICU stay" in the context of the present invention refers to any period of time, regardless of the amount of time, counted from the moment the subject leaves the ICU (and the subject may develop symptoms of PICS). PICS most typically establishes within months to years after an ICU stay, and the term "post-ICU stay" typically refers to within weeks to years (most typically within 2 years) after an ICU stay. The term "post-ICU stay" is not limited to any period of time when a subject has been diagnosed with PICS (i.e., associated with an ICU stay) and / or at least one symptom thereof, or has been diagnosed as being at high risk for developing PICS.

[0019] The likelihood of developing PICS is associated with the time spent in ICU.PICS is most typically seen in ICU stays of 48 hours or more.In one embodiment, the collagen hydrolysate of the present invention is intended for use in subjects who have stayed in ICU for at least 24 hours, preferably at least 48 hours, more preferably at least 72 hours, and even more preferably at least 7 days or 14 days.

[0020] It has been found that early administration of collagen hydrolysate is advantageous for the prevention and / or treatment of PICS after a stay in the ICU. It may further be advantageous to start said administration of collagen hydrolysate already during the stay in the ICU or upon admission to the ICU, for example, in order to further minimize the likelihood of developing PICS.

[0021] In one embodiment, the present invention relates to the administration of collagen hydrolysate to subjects entering or staying in an ICU. Said collagen hydrolysate administered to subjects entering and / or staying in an ICU is preferably formulated as a food for special medical purposes (FSMP). The term "food for special medical purposes (FSMP)" refers to a regulated foodstuff for feeding subjects with special medical purposes and / or subjects with nutritional requirements that cannot be met by consuming standard foodstuffs. In the case of an ICU stay, the administration of collagen hydrolysate (as a FSMP) can typically be provided as (enteral) tube feeding, oral nutritional supplements, and / or can be administered intravenously.

[0022] PICS is most typically diagnosed within a few months (e.g., onset 3-9 months after an ICU stay) to a few years (typically within 2 years). In the context of the present invention, when administering the collagen hydrolysate as a preventative measure, it is preferred to start said administration before PICS is routinely diagnosed or experienced. It may therefore be preferred to start the use or administration of collagen hydrolysate early (e.g., days to weeks) after leaving the ICU, or even during or immediately after the ICU stay.

[0023] It has been found to be advantageous to start administering collagen hydrolysate within 3 weeks after ICU stay. In a preferred embodiment, the collagen hydrolysate administration regimen comprises administering collagen hydrolysate within 3 weeks, preferably within 2 weeks, more preferably within 1 week (e.g. within 6 days, or within 5 days, or within 4 days, or within 3 days, or within 2 days, or within 1 day, or immediately) after ICU stay and / or at the time of ICU discharge.

[0024] In one embodiment, the stay in ICU is due to one or more of the following: - Infectious diseases, preferably sepsis and / or COVID-19 (i.e. due to SARS-CoV-2 infection); -Surgery; -Trauma; -(severe) inflammation; - respiratory failure; - Myocardial infarction; - Stroke; - Hypoxemia; and -Hypoglycemia.

[0025] In one embodiment, the present invention relates to the use of collagen hydrolysate to improve non-therapeutic or therapeutic recovery after an ICU stay.

[0026] The term "improving recovery after an ICU stay" in the context of the present invention includes one or more of: reducing the time to resume work or school, reducing the time to resume exercise, or reducing the time to resume self-care (i.e., not needing assistance from a health care professional in daily life). Additionally or alternatively, "improving recovery after an ICU stay" preferably includes improving quality of life (QOL) levels by comparing with a reference population experiencing PICS but not receiving collagen hydrolysate or another known effective treatment for PICS. Reference values ​​can be easily found in systematic reviews and the like (e.g., in the systematic review by Oeyen et al., Crit Care Med. 2010;38(12):2386-2400). QOL is preferably determined using QOL assessment tools known in the art, such as the Medical Outcomes Study 36-Item Short Form (SF-36) health survey, Nottingham Health Profile (NHP), Disease Impact Profile (SIP), Dartmouth Primary care Cooperative Information Project (COOP) charts, Quality of Well-Being (QWB) scale, Health Utilities Index (HUI), or EuroQol instrument (EQ-5D). Additionally or alternatively, the term "improving recovery after an ICU stay" encompasses reducing the likelihood of developing one or more, preferably two or more, most preferably all three of one or more conditions associated with an ICU stay, such as a physical condition (i.e. physical symptoms, preferably physical conditions in the PICS), a mental condition (i.e. mental symptoms, preferably mental conditions in the PICS), and a cognitive condition (i.e. cognitive symptoms, preferably cognitive conditions in the PICS).

[0027] The term "exercise" as used herein means any physical activity that can be planned, structured, and repeated, and has a final or intermediate purpose. The term "exercise" as used herein typically has the improvement or maintenance of physical health as a goal. For example, "exercise" can include all professional or non-professional activities, including sports, strength or weight training, and endurance or aerobic activities. Additionally or alternatively, "exercise" can include endurance training. The term endurance training generally refers to training the aerobic system, as opposed to the anaerobic system, by performing physical exercise at an increased heart rate for an extended period of time (e.g., at least 30 minutes at 70% maximum heart rate (MHR)), for example, during walking, running, jogging, cycling, swimming, jumping rope, etc. The term "exercise" in the context of the present invention encompasses physical activities that can be undertaken by non-athletes, including, but not limited to, walking or hiking, dancing, swimming, water aerobics, jogging or running, aerobic exercise, yoga, cycling, or gardening (such as raking and pushing a lawnmower).

[0028] The use of collagen hydrolysate in the context of the present invention is preferably therapeutic.In certain embodiments, said use can be non-therapeutic.Subjects who need therapeutic or non-therapeutic treatment can be divided according to the nature of their ICU stay, their subsequent recovery, and / or whether said subject is at risk of developing one or more pathological symptoms (of PICS) after their ICU stay.

[0029] The subject that benefits from non-therapeutic use of collagen hydrolysate is characterized by the absence of pathology after ICU stay, and therefore does not have therapeutic benefit from treatment with collagen hydrolysate.For example, the subject that benefits from non-therapeutic use of collagen hydrolysate may be when admission to ICU does not cause / is expected not to cause health problems, pain symptoms, or suffering.In addition to this, or alternatively, the subject that benefits from non-therapeutic use of collagen hydrolysate may be when ICU stay is expected to have a nature or severity such that the subject will recover naturally without intervention, but it is still advantageous to shorten the time to recovery.Non-therapeutic use may also mean that the collagen hydrolysate improves the general performance of an otherwise healthy subject (i.e., does not have PICS or other pathologies), for example, by achieving one or more of the following effects: - Improving the aesthetic or cosmetic appearance of the body (e.g., gaining weight to a more desirable body weight); -Increasing productivity in daily life, such as by providing more energy, stamina, endurance or physical performance; -improving general functioning and / or well-being; -Improve concentration; -Reducing anxiety; -Improve your sleep.

[0030] In case of doubt, specialized medical personnel can decide on a case-by-case basis whether a therapeutic or non-therapeutic intervention is required after an ICU stay (i.e. whether the person falls into the group of healthy or pathological subjects). Said specialized medical personnel can, for example, establish whether the (nature and / or duration) of an ICU stay leads to health and psychological risks.

[0031] PICS Said use according to the invention preferably relates to the prevention and / or treatment of PICS after an ICU stay.

[0032] The present inventors have found that administration of collagen hydrolysate effectively prevents and / or treats PICS. Surprisingly, collagen hydrolysate is found to be superior to drugs known to target specific physical, cognitive or mental symptoms seen in PICS, including fluoxetine (antidepressant) or whey protein (muscle enhancer). This suggests that known strategies for treating physical, cognitive or mental symptoms are insufficient for treating PICS. Instead, collagen hydrolysate supplementation appears to combat the underlying causes of PICS and the pathophysiology of PICS itself, rather than the symptoms (only). Several common features can be seen in PICS patients, suggesting that PICS symptoms have a common underlying condition. Without being bound by theory, collagen hydrolysate supplementation appears to play a role in one or more of limiting excessive stem cell activation, improving epithelial barrier dysfunction, limiting epithelial-mesenchymal transition, and limiting fibrosis and inflammation.

[0033] In the context of PICS, administration of collagen hydrolysate appears to treat and / or prevent the pathophysiology of PICS itself, instead of or in addition to treating and / or preventing the symptoms.

[0034] Said use of collagen hydrolysate in the prevention and / or treatment of PICS provides the advantage / benefit that collagen hydrolysate is generally recognized as safe (GRAS) even after frequent administration (e.g. as a (daily) supplement). In comparison, anxiolytics and antipsychotics used in the treatment of PICS are frequently accompanied by side effects and therefore undesirable. Furthermore, there may be resistance to using such drugs in the early stages of PICS, i.e. when symptoms are subtle and not yet fully recognized. ICU survivors greatly benefit from preventive measures with collagen hydrolysate, as they can be taken early after ICU discharge (or even at the time of admission or during ICU stay) to more effectively prevent PICS.

[0035] The use of collagen hydrolysate in the prevention and / or treatment of PICS solves the problem that there is still no single method that can simultaneously improve different aspects of PICS and / or target the underlying pathophysiology of PICS (i.e., the PICS condition itself).Prior art strategies aim to combat various symptoms of PICS, which are generally less efficient and effective.The administration of collagen hydrolysate appears to treat or eliminate the underlying cause of PICS and the pathophysiology of PICS itself.

[0036] Regarding the diagnosis of PICS, there may be no single applied instrument for PICS adopted by a specialized medical practitioner or health care institution. Instead, specialized medical practitioners or medical centers may (and tend to) use their own measuring instruments for PICS. Such measuring systems generally include a combination of measuring systems covering the physical, cognitive, and mental domains in PICS. In the context of the present invention, the presence of PICS may be defined according to any one of the local practices (i.e., medical professionals or health care institutions), preferably the local practice of the health care center of the ICU stay. In the present disclosure, a subject is considered to have PICS if so diagnosed by a specialized health care professional responsible for the diagnosis and / or treatment of conditions or symptoms associated with PICS and / or (long-term) ICU admission. Additionally or alternatively, a subject is considered to have PICS when he / she experiences two or more PICS symptoms as disclosed herein. Additionally or alternatively, the subject treated in the context of the present invention may be at risk of experiencing PICS or PICS-related symptoms, for example, when experiencing poor recovery after an ICU stay, when experiencing early signs of PICS, and / or when experiencing risk factors that increase the likelihood of establishing PICS. The likelihood of developing PICS increases dramatically after 3 days or more of ICU stay. Thus, in one embodiment, the subject treated in the context of the present invention is a subject who has stayed in the ICU for 3 days or more, for example, to prevent PICS from occurring when the subject is at high risk of developing PICS.

[0037] A preferred method of diagnosing PICS in the context of the present invention is the PICS Questionnaire (PICSQ) reported by Jeong et al. (Intensive Crit Care Nurs, December 2019; Vol. 55:102756). The PICSQ has three factors (mental, cognitive and physical domains) and 18 items, and has been shown to be a valid and reliable tool for establishing PICS simply and relatively quickly. The 18 items (Table 4 of Jeong et al., incorporated herein by reference) are assigned a score of 0 (none), 1 (sometimes), 2 (most of the time), or 3 (always) by the subject. The total PICSQ score can be 0-54. In the context of the present invention, a subject has PICS if the PICSQ score is 20 or more (mild PICS) or 30 or more (average PICS) or 40 or more (severe PICS). In one embodiment, "reduction", "improvement" or "treatment" of PICS means that the PICSQ score is reduced to less than 20 points. In one embodiment, "reduction," "amelioration," or "treatment" of PICS means a decrease in the PICSQ score of at least 10 points (compared to an untreated control and / or when comparing the PICSQ score before treatment to after treatment with a collagen hydrolysate of the invention, etc.), preferably at least 20 points, and more preferably at least 30 points.

[0038] Additionally or alternatively, in the context of the present invention, a subject has PICS when he or she experiences at least one, preferably at least two, and most preferably at least all three of the physical, mental and cognitive conditions, which is associated with an ICU stay, preferably an ICU stay lasting at least 48 hours.

[0039] The physical condition disclosed herein is preferably one or more of: decreased muscle strength, decreased exercise tolerance, and decreased motor coordination.

[0040] The mental conditions disclosed herein are preferably one or more of anxiety, depression and post-traumatic stress disorder.

[0041] The cognitive condition disclosed herein is preferably one or more of: impaired memory and impaired concentration.

[0042] The decline in physical, mental or cognitive status is preferably determined relative to (peak) values ​​before and / or after the ICU stay. Furthermore, the physical, mental or cognitive status can be compared with normative data, for example in a healthy population (such as those reported in systematic reviews).

[0043] "Muscle strength" as used herein is preferably established as a reduction in two or more of grip strength (Jamar dynamometer), leg strength (HHD (i.e., Handheld dynamometry) quadriceps), and arm strength (HHD biceps), each of which are tests well known in the art and familiar to those of skill in the art.

[0044] As used herein, "exercise tolerance" (i.e., exercise capacity) is preferably established with the 6-minute walk distance (6MWD) test, a test well known in the art. Preferably, the 6MWD is performed in a hallway (minimum 30 meters) and measurements are compared with normative data such as those reported by Gibbons et al. (J Cardiopulm Rehabil, 2001;21(2):87-93).

[0045] "Motor coordination" as used herein is preferably established with the Kippert-Schilling Coordination Test (KTK), a test well known in the art. Based on the four items of the KTK, a "Motor Quotient" (MQ) can be determined, i.e. a global index of motor coordination adjusted for age and sex (Popovic et al., Int J Environ Res Public Health. August 2020; 17(16):5902. Motor coordination impairment is considered when the MQ is 71-85 (moderately impaired) or 56-70 (severely impaired).

[0046] "Anxiety" as used herein is preferably established using the Generalized Anxiety Disorder Scale-7 (GAD-7). Using the scoring system disclosed in FIG. 1 of Spitzer et al. (Arch Intern Med, May 22, 2006; Vol. 166(10): pp. 1092-7), which is incorporated herein by reference, a GAD-7 score of 5-9 (mild anxiety), 10-14 (moderate anxiety), or 15-21 (severe anxiety) is considered anxiety. "Depression" as used herein is preferably established using the depression item of the Hospital Anxiety and Depression Scale (HADS), a test well known in the art.

[0047] Using the scoring system disclosed in FIG. 1 of Richi et al. (Indian J Ophthalmol, 2017 Nov;65(11):1203-1208), which is incorporated herein by reference, a score of 8-10 (borderline) or 11-21 (abnormal) on the depression item of the HADS score (i.e., total score of 21) is considered to be depression.

[0048] "Post-traumatic stress disorder" as used herein is preferably established using the PCL-5, a test well known in the art, which is a 20-item self-report scale assessing the 20 DSM-5 symptoms of post-traumatic stress disorder. Post-traumatic stress disorder is considered when the total score (out of 80) is 33 or greater.

[0049] "Memory" or "concentration" as used herein is preferably established with the 30-point Montreal Cognitive Assessment (MoCA) test, a test well known in the art. Memory or concentration is considered inadequate with a score of 20-25 (mild impairment) or a score of 19 or less (high impairment).

[0050] In a preferred embodiment, the present invention relates to a collagen hydrolysate for use in the treatment of a subject experiencing one or more, preferably two or more, most preferably three symptoms of PICS, said two or more symptoms preferably coming from different PICS domains (i.e. physical domain, mental domain, cognitive domain) as disclosed herein.

[0051] In one embodiment, the collagen hydrolysate is for use in improving at least one, preferably two, and most preferably all of the following: - physical condition (i.e., physical symptoms), preferably a physical condition in the PICS; - Mental conditions (i.e. mental symptoms), preferably mental conditions in the PICS; - A cognitive condition (i.e. a cognitive symptom), preferably a cognitive condition in the PICS.

[0052] Collagen hydrolysate of the present invention The term "collagen hydrolysate" in the context of the present invention means a mixture of short chains of amino acids (di-, tri-, oligo-, polypeptides) resulting from (partial) hydrolysis of native (full-length) collagen. The degree of hydrolysis, preferably enzymatic hydrolysis, affects the average molecular weight (expressed in Daltons, Da) of the final product. The term "collagen hydrolysate" may be used interchangeably and synonymously with the terms "hydrolyzed collagen" or "collagen peptides". "Collagen hydrolysate" in the context of the present invention encompasses collagen that has undergone hydrolysis or partial hydrolysis.

[0053] A "collagen hydrolysate" in the present invention is preferably produced from a collagen-containing material in a one-step process or via an intermediate gelatin stage (i.e., "hydrolyzed gelatin" is obtained). The terms "collagen hydrolysate" and "hydrolyzed gelatin" can be used interchangeably in the context of the present invention. The term "gelatin" as used herein means an irreversible form of collagen obtained by partial hydrolysis of collagen, which reduces the protein fibrils of collagen to smaller peptides. Depending on the process used, two types of gelatin are generally obtained, namely type A (acid hydrolysis) and type B (alkaline hydrolysis). In the context of the present invention, "gelatin" is preferably either type A or type B gelatin. Depending on the physical and chemical method of partial hydrolysis, the molecular weight of the peptides falls within a wide range (typically 15-40 kDa). Partial hydrolysis provides the gelatin with the ability to retain water and the ability to gel. The term "hydrolyzed gelatin" in the context of the present invention means a product obtained by (partial) hydrolysis of gelatin, resulting in a (further) mixture of peptides and a lower molecular weight of gelatin. Hydrolyzed gelatin is distinguished from gelatin, inter alia, with regard to its gelling ability and / or its molecular weight (for example, gelatin has a Bloom strength of 30 or less and / or a molecular weight of 10 kDa or more, preferably 15 kDa or more), whereas hydrolyzed gelatin has no / almost no gelling ability (preferably a Bloom strength of less than 30) and / or a lower molecular weight (preferably less than 15 kDa, more preferably less than 10 kDa). "Gelatin" can be hydrolyzed by acid (hydrogen ions), i.e. to obtain "acid hydrolyzed gelatin". "Gelatin" can be hydrolyzed by alkali (hydroxyl ions), i.e. to obtain "alkaline hydrolyzed gelatin". "Gelatin" can be hydrolyzed by one or more enzymes (for example pepsin, trypsin), i.e. to obtain "enzymatically hydrolyzed gelatin". In all cases, the reaction consists of one or more breaks of the peptide bonds by the addition of one molecule of water.

[0054] Collagen hydrolysate in the context of the present invention may be derived from one or more types of collagen selected from collagen types I to collagen type XXVII, preferably one or more of collagen types I, II, III, V or X, more preferably one or more of collagen types I, II or III. Additionally or alternatively, collagen hydrolysate as disclosed herein may be a mixture of two or more types of collagen, preferably one or more of collagen types I, II and III.

[0055] The collagen disclosed herein may be derived from any one or more animals or species of animals, such as bovine, porcine, chicken, and fish.

[0056] In one embodiment, the collagen is from bovine. In one embodiment, the collagen is from porcine. In one embodiment, the collagen is from fish. In one embodiment, the collagen is from chicken. In various embodiments, the collagen is a mixture of collagens from different sources, such as collagens from multiple animal species and / or collagens from different tissues. For example, the collagen disclosed herein can be a mixture of two or more collagens selected from the group consisting of fish collagen, porcine collagen, chicken collagen, and bovine collagen.

[0057] The use of porcine collagen hydrolysate may be most advantageous in the context of the present invention, since it may have the highest bioavailability and / or bioactivity (especially compared to fish and bovine collagen hydrolysates). It is assumed that porcine collagen hydrolysate provides the highest efficacy in the prevention and / or treatment of PICS.

[0058] In preferred embodiments, the collagen disclosed herein is porcine collagen and / or the collagen hydrolysate disclosed herein is derived from the hydrolysis of porcine collagen.

[0059] Collagen in the context of the present invention may be derived from one or more tissues selected from the group consisting of skin, scales, antlers, processes (e.g., humps), horns, head, brain, neck, ears, eyes, nose, tongue, lips, mouth, esophagus, trachea, sternum, larynx, bronchi, limbs, feet, toes, palms, nails, bones, cartilage, bone marrow, joints, membranes, back, ligaments, tendons, ribs, diaphragm, muscles, skeletal muscles, smooth muscles, intestines, blood vessels, bladder, stomach, aorta, heart, liver, kidneys, chest, lungs, spleen, pancreas, eggs, sperm, testes, ovaries, nerves, gallbladder, and abdomen. The term "skin" disclosed herein encompasses "hide", i.e., the outer covering of a large animal, such as a cow (species) or any other large animal. The terms "skin" and "hide" may be used interchangeably herein and may refer to the outer covering of an animal, regardless of size.

[0060] In a preferred embodiment, the collagen taught herein is derived from skin and / or dermal connective tissue. In a preferred embodiment, the collagen taught herein is derived from cartilage. In a preferred embodiment, the collagen taught herein is derived from bone. In a preferred embodiment, the collagen taught herein is derived from sternum.

[0061] The collagen disclosed herein may be a mixture of collagens derived from two or more tissues and / or two or more animals. In one embodiment, the collagen disclosed herein is a mixture of two or more collagens selected from the group consisting of skin collagen, cartilage collagen, sternum, cartilage and bone collagen.

[0062] In various embodiments of the invention, the collagen hydrolysate may be produced by enzymatic or partial enzymatic hydrolysis of collagen, and the enzymes used for this purpose may be one or more selected from the group consisting of serine proteases, alkaline proteases, neutral proteases, flavor proteases, complex proteases, thiol proteases, bromelain, metalloproteases, aspartame, proteases, carboxypeptidases, pepsin, chymotrypsin, trypsin, cathepsin K, chymotrypsin, papain, and subtilisin.

[0063] Collagen hydrolysate in the context of the present invention may have an average molecular weight of at least 300 Da, 400 Da, 500 Da, 1000 Da, 1500 Da, 1600 Da, 1700 Da, 1800 Da, 2000 Da, 2100 Da, 2200 Da, 2500 Da, 3000 Da, 3500 Da, 4000 Da, 4500 Da, 5000 Da, 5500 Da, 6000 Da, 6500 Da, 7000 Da, 7500 Da, 8000 Da, 8500 Da, 9000 Da, 9500 Da, or 10000 Da. Additionally or alternatively, a collagen hydrolysate in the context of the present invention may have an average molecular weight of less than or equal to 10000 Da, 9500 Da, 9000 Da, 8500 Da, 8000 Da, 7500 Da, 7000 Da, 6500 Da, 6000 Da, 5500 Da, 5000 Da, 4500 Da, 4000 Da, 3500 Da, 3000 Da, 2500 Da, 2100 Da, 2000 Da, 1800 Da, 1700 Da, 1600 Da, 1500 Da, 1000 Da, 500 Da, 400 Da, or 300 Da.

[0064] In a preferred embodiment, the collagen hydrolysate of the present invention has an average molecular weight of 1000 to 9000 Da. In one embodiment, the collagen hydrolysate of the present invention has an average molecular weight of less than 5000 Da. In one embodiment, the collagen hydrolysate of the present invention has an average molecular weight of 1400 to 2200 Da, more preferably 1600 to 2000 Da. In one embodiment, a collagen hydrolysate derived from porcine collagen and having a molecular weight of less than 5000 Da (e.g. 1400 to 2200 Da) is used.

[0065] It is believed that the improvement of PICS can be achieved with collagen hydrolysates from various sources and with a wide range of molecular weights, for example in the range of at least 1000-9000 Da (typical for collagen hydrolysates). By carrying out a study aimed at investigating the single-dose bioavailability of collagen hydrolysates from various sources (bovine, fish and porcine) and with various average molecular weights (2000 Da and 5000 Da for bovine collagen hydrolysate), evidence was found that various collagen hydrolysates may be suitable for improving PICS. The study showed that the uptake of collagen hydrolysates in blood was similar for collagen hydrolysates from porcine, bovine and fish sources, as well as for hydrolysates with a relatively high average molecular weight (5000 Da) and a relatively low average MW (2000 Da).

[0066] In the context of the present invention, it may be most advantageous to use collagen hydrolysates having a relatively low molecular weight, for example, an average molecular weight of less than 5000 Da, more preferably 1400-2200 Da, even more preferably 1600-2000 Da. A relatively low molecular weight in the context of the present invention is likely to be associated with the highest bioavailability and / or bioactivity. It is estimated that collagen hydrolysates having a relatively low molecular weight will provide the highest efficacy for the prevention and / or treatment of PICS.

[0067] The molecular weight of the collagen hydrolysate appears to play a role in improving recovery after an ICU stay and / or improving PICS. Relatively low molecular weights, e.g., less than 5000 Da, preferably in the range of 1400-2200 Da, appear to be most effective.

[0068] In a preferred embodiment, the collagen hydrolysate of the present invention has an average molecular weight of less than 5000 Da.

[0069] In a preferred embodiment, the collagen hydrolysate of the present invention has an average molecular weight of 1400 to 2200 Da, more preferably 1600 to 2000 Da.

[0070] In a particular embodiment, in the context of the present invention, it is preferred to use collagen hydrolysate derived from porcine collagen and having a molecular weight of less than 5000 Da (for example between 1400 and 2200 Da).

[0071] The average molecular weights disclosed herein are preferably weight average molecular weights.

[0072] A suitable and preferred method for measuring the molecular weight of the collagen hydrolysate is by high-performance size-exclusion chromatography (HP-SEC), for example by treating the collagen hydrolysate with a sodium acetate-ethanol solution to precipitate the protein-poor fraction (including glycosaminoglycans) and then using the protein-rich fraction (supernatant) for HP-SEC of the collagen hydrolysate. Additionally or alternatively, a preferred method for determining the molecular weight of the collagen hydrolysate is according to Edgar et al. (Sci.Rep. 2018-07-11; Vol. 8 (1): 10474).

[0073] formulation The collagen hydrolysates disclosed herein may be provided in a food formulation, a food supplement formulation, or a pharmaceutical formulation, preferably a food supplement formulation.

[0074] In one embodiment, the collagen hydrolysate of the present invention is provided in one or more formulations selected from the group consisting of drinkable solutions or suspensions, beverages such as syrups, artificially flavored beverages, carbonated beverages, beer, tea, (water-soluble) powder mixtures, (water-soluble) pastes, (water-soluble) powders, (water-soluble) tablets, (water-soluble) pills, (water-soluble) dragees, (water-soluble) caplets, (water-soluble) sachets, or (water-soluble) capsules. Additionally or alternatively, the collagen hydrolysate taught herein may be present in juices, shakes, dairy drinks, yogurts, yogurt drinks, sweets, energy bars, nutrition bars, slimming bars, confectioneries such as gummies or centre-filled gummies, candies or functional foods such as chocolate pastilles.

[0075] In one embodiment, preferably in the context of administration in a hospital environment or ICU, said collagen hydrolysate is provided as a food for special medical purposes (FSMP) and / or as a (enteral) tube feeding or oral nutritional supplement. In one embodiment, preferably in the context of administration in a hospital environment or ICU, said collagen hydrolysate is administered intravenously.

[0076] In one embodiment, the collagen hydrolysate is provided in a liquid dosage form.

[0077] In one embodiment, the collagen hydrolysate is provided in a solid dosage form, preferably a capsule, tablet, or powder, preferably a powder.

[0078] Dosing regimen In different embodiments, the unit dose and / or daily dose of the collagen hydrolysate disclosed herein is at least 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 grams, all in grams. Additionally or alternatively, in different embodiments, the unit dose and / or daily dose of the collagen hydrolysate disclosed herein is less than or equal to 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, or 1 g, all in grams.

[0079] The term "daily dose" in the context of the present invention means the total dry weight of a compound, substance or composition administered to a subject per day. Said daily dose can be administered as a single unit dose or as two, three, four or more unit doses. Said two or more unit doses can be equal or different in amount.

[0080] The term "unit dose" in the context of the present invention means an amount or unit of, e.g., a compound, substance, or composition, administered to / taken by a subject in a single dose. The unit dose may, e.g., be in a pre-prepared form (e.g., a pre-filled dose) ready for administration. The unit dose may, e.g., be identifiable from the product packaging or label. The total daily dose may be divided into a number of unit doses, each having a reduced dose compared to the total daily dose. The daily dose of the compositions disclosed herein is preferably administered as 2 unit doses, more preferably as 2 unit doses each corresponding to 30-70%, preferably 40-60% (e.g., 50%) of the amount of the daily dose.

[0081] The dosages of collagen hydrolysate disclosed herein are preferably based on the dry weight of the collagen hydrolysate.

[0082] In a preferred embodiment, the use of the collagen hydrolysate disclosed herein comprises administering said collagen hydrolysate in a daily dose of 1-100 g, preferably 10-95 g, more preferably 20-90 g.

[0083] Recovery after an ICU stay and / or improvement in PICS has been found to be most evident following continuous daily administration of collagen hydrolysate, particularly in combination with continuous administration for at least three weeks.

[0084] In clinical practice, after ingestion of collagen hydrolysate, amino acids have been found to rapidly increase in the blood, reaching maximum levels after approximately 1 hour. Amino acid levels then decline to near baseline levels over the course of several hours (e.g., 6-10 hours). Without wishing to be bound by theory, daily ingestion (or twice daily ingestion) of collagen hydrolysate appears to result in improved prevention and / or treatment of PICS by maintaining the amino acid profile in the blood and achieving the highest bioactivity.

[0085] In one embodiment, the collagen hydrolysate is administered to a subject repeatedly, preferably at least once every day or at least once every other day.

[0086] In one embodiment, the collagen hydrolysate is administered to a subject for at least 2 consecutive weeks, preferably at least 4 consecutive weeks or at least 5 consecutive weeks, more preferably at least 6 consecutive weeks or at least 7 consecutive weeks, and most preferably at least 8 consecutive weeks.

[0087] It has been found that it is advantageous to administer said collagen hydrolysate within 3 weeks after ICU stay.This is surprising, because PICS generally develops later, such as within a few months after ICU stay.Without being bound by theory, early administration of collagen hydrolysate may better target the underlying cause of PICS if it is administered already at an early stage.

[0088] In a preferred embodiment, the collagen hydrolysate administration regimen comprises administering collagen hydrolysate starting within 3 weeks, preferably starting within 2 weeks, more preferably starting within 1 week after stay in the intensive care unit.

[0089] In some embodiments, the collagen hydrolysate administration regimen comprises administration of collagen hydrolysate within (starting within) 12 weeks, or within 11 weeks, or within 10 weeks, or within 9 weeks, or within 8 weeks, or within 7 weeks, or within 6 weeks, or within 5 weeks, or within 4 weeks, or within 3 weeks, or within 2 weeks, or within 1 week, or within 6 days, or within 5 days, or within 4 days, or within 3 days, or within 2 days, or within 1 day after ICU stay (after leaving the ICU).

[0090] The term "administer" or "administration" in the context of the present invention means providing a compound, substance, or composition to a subject who will consume it. A subject who consumes a compound, substance, or composition may administer it to himself or herself. In such cases, the term "administer" may be read as "ingest."

[0091] The term "subject" in the context of the present invention means any animal (e.g., a mammal), preferably a human. The term "subject" can be used interchangeably with "human" or "individual" in the context of the present invention. A "subject" can be a patient.

[0092] General definition The reference to an element by the indefinite article "a" or "an" does not exclude the possibility that more than one of the element is present, unless the context clearly requires that only one of the element is present. Thus, the indefinite article "a" or "an" normally means "at least one."

[0093] As used herein, the terms "comprising" or "to comprise" and their conjugations are used in an open-ended sense to mean that the items following the word are included, but not to exclude items not specifically mentioned. It also encompasses the more restrictive verbs "consisting essentially of" and "consisting of."

[0094] The term "prevent" means to ensure that a subject does not develop a condition (e.g., PICS). In this specification, an intervention is also considered to be a form of "prevention" when the condition is delayed, reduced in severity, and / or reduced in incidence, even if the condition is not kept from occurring completely. In the context of the present invention, the term "prevent" or "prevention" by an intervention encompasses a situation where a subject has previously experienced a condition (e.g., PICS), but the intervention does not cause the condition to recur. "Prevent" or "prevention" can have a therapeutic effect and / or a non-therapeutic effect. When "prevent" or "prevention" is therapeutic in nature, it can also be directed to the symptoms of a disease or condition and / or its underlying pathology. "Prevent" or "prevention" can be defined by any delay, change in severity, and / or change in incidence, such as at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, as measured by any standard technique, compared to a control or reference.

[0095] In the context of the present invention, "treating" means that the intervention reduces and / or cures the condition (e.g., PICS) when the condition already exists. "Treatment" can have a therapeutic effect and / or a non-therapeutic effect. When "treating" is therapeutic in nature, it can be directed at the symptoms of the disease or condition and / or its underlying pathology. Treatment can be any reduction in the severity, incidence, and / or frequency of the condition, such as at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or complete (100%), as compared to a control or reference, as measured by any standard technique.

[0096] The term "ameliorating" in the context of the present invention encompasses both "preventing" and "treating" a condition. As used herein, "ameliorating" also encompasses "curing." The term "ameliorating" may be used interchangeably with "reducing" or "lowering" in the context of the present invention.

[0097] The terms "increase" and "increased level" and "decrease" and "decreased level" (or "reduce" and "decreased level") preferably refer to a change of at least 5%, such as at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% higher or lower, respectively, than the corresponding level in a control or reference. Additionally or alternatively, a level in a sample may be increased or decreased when it is statistically significantly increased or decreased compared to the level in a control or reference, regardless of the magnitude of the change.

[0098] The term "continuous" or "sequentially" used in the context of collagen hydrolysate administration means that the administration follows one after the other without any gaps in a given period.For example, "administering collagen hydrolysate for 4 consecutive days" means that the collagen hydrolysate is administered at least once a day for 4 consecutive days (e.g., on Monday, Tuesday, Wednesday, and Thursday of the same week), regardless of the number of administrations per day or the total number of administrations.For example, "administering collagen hydrolysate for 4 consecutive weeks" means that the collagen hydrolysate is administered at least once a week for 4 consecutive weeks, regardless of the number of administrations per day, per week, or the total number of administrations. [Brief description of the drawings]

[0099] [Figure 1] FIG. 1 shows the PICS scores (mean) of the "control," "PICS," "PICS + low-dose CH," and "PICS + high-dose CH" groups. [Figure 2A]Figure 1 shows the concentration-time curves (mean, SD) of free Hyp response [μg / mL] after ingestion of the test products; n = 6. CH = collagen hydrolysate; LMW = low molecular weight; HMW = high molecular weight. [Figure 2B] Figure 1 shows the concentration-time curves of total Hyp response [μg / mL] after ingestion of test products (mean, SD); n = 6. CH = collagen hydrolysate; LMW = low molecular weight; HMW = high molecular weight. [Diagram 3] FIG. 1 shows human plasma levels of free glycine before and after oral ingestion of porcine-based hydrolyzed collagen (approximately 1800 Da). Data are shown as mean + SEM (n=6). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0100] Working Example

[0101] Example 1: PICS Animal Study method

[0102] Animal models A validated PICS mouse model based on the model of Hujinami et al. (J Clin Med, April 2021;10(8):1593) was used. The model has been proven to induce PICS by mimicking ICU care after polymicrobial sepsis. This is achieved by intraperitoneal injection of cecal slurry followed by other typical ICU-related interventions (i.e., antibiotics and saline administration) for 72 hours. The model incorporates a specific combination of physical (grip strength test), mental (anxiety level), and cognitive (discrimination index, habituation index, exploration time) parameters that often characterize PICS.

[0103] Pilot Testing The onset of PICS in this model was first confirmed in a pilot study (not shown here). Mice develop PICS after about one week.

[0104] The molecular weight (i.e., about 1800 Da) and source (porcine) of the collagen hydrolysate used in this (full) comparative study was based on earlier experiments comparing collagen hydrolysates of about 1800 Da and about 5000 Da derived from either fish, bovine or porcine collagen sources. It was found that porcine collagen hydrolysates with a relatively low molecular weight (<5000 Da, e.g., about 1800 Da) have the greatest predicted effect in improving PICS.

[0105] Initial experiments have shown that relatively early administration of collagen hydrolysate results in the most effective improvement of PICS in the current model compared to delayed administration (delayed administration means, for example, starting from day 21 onwards in the current model).

[0106] treatment Mice (C57BL6J, Charles River laboratories, France) are administered collagen hydrolysate ("CH", Peptan, porcine approx. 1800 Da, Rousselot BV) or relevant controls according to the following experimental groups: 1. No PICS + vehicle (saline), i.e. "control" 2. PICS + vehicle (saline), i.e. "PICS" 3. PICS+CH 1.8g / kg (clinical dose of approximately 10g), i.e. "PICS+low-dose CH" 4. PICS+CH 8g / kg (clinical dose of approximately 44g), i.e. "PICS+high-dose CH"

[0107] The mice are dosed once daily from day 12 through day 47.

[0108] The collagen hydrolysate used in Example 1 has the same composition as that used in the clinical trial in Example 3 (Table 2).

[0109] Treatment begins 4 days after induction of PICS. CH or vehicle is administered by daily oral gavage for a period of 7 weeks (days 12-47).

[0110] In a follow-up study, the efficacy of Group 3 (1.8 g / kg CH) will be compared with that of fluoxetine (20 mg / kg) and whey protein (high in cysteine, 1.8 g / kg) administered in the same manner.

[0111] PICS Rating PICS subcomponent #1 was determined with a grip strength meter (UGO Basile) to measure forelimb grip strength and record maximum force (g). The mouse was pulled slightly backwards by the tail while the forelimbs gripped the bar, which drives a counter pull and automatically records the peak tension. Measurements were repeated three times and the maximum force of the three measurements was recorded. Data are quantified in % grip loss.

[0112] PICS subcomponent #2 relates to PICS-related changes in anxiety levels. Mice are subjected to an open field test (Ethovison XT, Noldus) with an open field of 46×46×40 cm divided into peripheral and central zones. The time spent in the central and peripheral zones is recorded. PICS subcomponent #2 is calculated as the ratio of the time spent in the central area to the total movement time, and expressed as a percentage of the total movement time. A shorter time spent in the central area indicates a higher anxiety level.

[0113] PICS subcomponents #3, #4, #5 concern PICS-related behavioral changes. Object recognition tests were performed using an open field consisting of a 46 x 46 x 40 cm box, and behavioral videos were recorded using a digital camera. Videos were recorded and the time the mouse spent with each object was calculated. First, the mouse was allowed to explore and become accustomed to the empty open field box. Then, the test consisted of two sessions (10 min each, with a 30 min interval between each session). In the training session (acquisition phase), two similar objects were placed and the mouse was allowed to explore them. In the test session (test phase), one object was replaced by a novel object. The interaction of the mouse with both objects (familiar and novel) was recorded. The exploration activity and the time spent sniffing each object during the training and test sessions were scored by Ethovision XT software. Percent discrimination index was calculated as 100 x the time spent exploring the novel object minus the time spent exploring the familiar object (Tnovel-Tfamiliar) divided by the total exploration time (Tnovel+Tfamiliar). The familiarity index indicates the recognition of the familiar object and is calculated as the difference between the average time spent exploring the object in the training phase and the average time spent exploring the novel object in the test phase (based on A Ennaceur et al., Behav Brain Res., 1988 November 1;31(1):47-5).

[0114] PICS parameters were investigated over a period of 3 to 7 weeks after induction of PICS. Table 1 shows the PICS scores normalized to the "control" group.

[0115] Results are presented for sample sizes of 9–11.

[0116] result Figure 1 shows the PICS scores in the "Control", "PICS", "PICS + Low Dose CH" and "PICS + High Dose CH" groups. It can be seen that the overall PICS is reduced by about 38% in the "PICS + Low Dose CH" group and about 23% in the "PICS + High Dose CH" group compared to the "PICS" group (i.e., without collagen hydrolysate). Thus, both CH doses are effective in improving PICS.

[0117] Table 1 shows the improvement of individual PICS parameters in the "PICS + low dose CH" and "PICS + high dose CH" groups compared to the "PICS" group. It can be seen that both doses improve the individual PICS subcomponents overall.

[0118] [Table 1]

[0119] The effects of high-dose CH are compared with fluoxetine and whey protein, drugs with demonstrated efficacy in conditions associated with PICS. Fluoxetine has been shown to provide neuroprotection in conditions of stress, emotion and emotional behavior in mice with PICS-related symptoms (Wang et al., Aging (Albany NY), February 22, 2021; Vol. 13 (No. 6): pp. 8720-87360). It is therefore hypothesized that fluoxetine can improve PICS by restoring mental and cognitive health in the PICS model. Whey protein has been suggested to promote healing and recovery in critically ill patients, for example, by limiting muscle atrophy and promoting metabolic stability (Tsutsumi et al., JPEN J Parenter Enteral Nutr. July 2015; Vol. 39 (No. 5): pp. 552-61). It is therefore hypothesized that fluoxetine can improve PICS by restoring physical health in the PICS model.

[0120] As expected, in contrast to collagen hydrolysate, treatment with whey protein or fluoxetine resulted in little / no improvement in PICS scores, indicating that drugs that target only specific subcomponents or individual symptoms of PICS may not be able to improve PICS as a whole.

[0121] PICS subcomponent #1 was assessed for all groups at week 1 and weeks 3-7 (six time points). Improvements in PICS subcomponent #1 were observed primarily beginning at week 5. Similar timing effects were observed for the other PICS subcomponents.

[0122] Example 2: Effect of collagen hydrolysate source and molecular weight

[0123] the purpose To investigate the single-dose bioavailability of collagen hydrolysates of different average molecular weights from different sources. The ability of collagen hydrolysates to improve PICS may be related to this bioavailability.

[0124] method Bioavailability was assessed by evaluating the incorporation of free and peptide-bound hydroxyproline (Hyp) as a marker amino acid.A randomized, double-blind, crossover clinical trial was conducted using healthy volunteers.

[0125] A single dose of 10 g of collagen hydrolysate was provided in low average molecular weight (2000 Da). For bovine collagen hydrolysate, a single dose of 10 g of either low average molecular weight (2000 Da, "LMW") or high average molecular weight (5000 Da, "HMW") was provided. Blood was sampled for analysis over a 6-hour period following collagen hydrolysate ingestion.

[0126] result FIG. 2 shows the concentration-time curves of the free Hyp response (A) or the total Hyp response (B) after ingestion of the test product.

[0127] Ingestion of 10 g of the collagen hydrolysate increased the free Hyp concentration in plasma (ΔC max ) was found to be significantly increased, with an average factor of 7.2 for fish, 9.9 for porcine and 6.2 for both bovine low molecular weight (LMW) and high molecular weight (HMW) collagen hydrolysates. Regarding the bioavailability of free Hyp, there were no significant differences between the incremental area under the curve (iAUC) responses of the investigated products. The Hyp content in blood samples after total hydrolysis was also determined. Significantly higher concentrations of total Hyp were determined compared to the iAUC of free and total Hyp. Total Hyp concentrations in plasma (ΔC max ) was also significantly increased for both fish and porcine collagen hydrolysates, as well as for both bovine collagen hydrolysate LMW and bovine collagen hydrolysate HMW.

[0128] Overall, this study shows that uptake of collagen hydrolysates in blood appears to be similar for collagen hydrolysates from porcine, bovine and fish sources, and for hydrolysates with relatively high average molecular weight (5000 Da) and relatively low average MW (2000 Da).

[0129] Example 3: PICS Clinical Trials

[0130] the purpose Based on the findings of the PICS animal model, a clinical trial was performed to validate the use of collagen hydrolysate in the prevention and / or treatment of PICS in a clinical setting. The aim was to test the effect of a 6-week intervention of porcine collagen hydrolysate versus control (maltodextrin) on PICS after an ICU stay.

[0131] method

[0132] Study design Randomized controlled (double-blind) study in 72 ICU patients >18 years old discharged from the ICU (minimum ICU stay 72 hours). One group receives 22 g porcine collagen hydrolysate (20 g protein, 80 kcal) twice daily, thus a total of 44 g per day (40 g protein, 160 kcal). The other group receives 21 g maltodextrin (0 g protein, 82 kcal) twice daily, thus a total of 42 g (0 g protein, 164 kcal). The interventions are isocaloric. Collagen hydrolysate or maltodextrin are provided in the morning and in the afternoon.

[0133] Research product The porcine collagen hydrolysate is provided in powder form. The powder contains about 97% dry weight protein. Pork protein supplement (per 100g) contains, on average, 360kcal, 0g fat, 0g carbohydrate (including 0g sugar), 90g protein and 0g fiber. Amino acid content can be found in Table 2 below. The average molecular weight of collagen hydrolysate is about 1800Da.

[0134] The control group receives maltodextrin daily for 6 weeks. Maltodextrin is a polysaccharide and is also provided as a white powder. The intervention product consists of primary protein and no carbohydrates, whereas maltodextrin contains carbohydrates and no protein. Maltodextrin (per 100 g) contains, on average, 390 kcal, 0 g fat, 97.5 g carbohydrates (including 8.8 g sugar), 0 g protein and 0 g fiber. The collagen hydrolysate and maltodextrin have a similar appearance and the doses provided in the study are isocaloric.

[0135] [Table 2]

[0136] Route of administration Collagen hydrolysate or maltodextrin are provided in powder form packaged in identical sachets. Each dosage sachet contains 22 g and each maltodextrin sachet contains 21 g. Both powders are easy to dissolve and can therefore be dissolved in liquids. For example, with only slight stirring, 10 g of collagen hydrolysate can be easily dissolved in 200 ml of lemonade, and even larger amounts are possible (more concentrated).

[0137] PICS Rating The PICS is assessed according to local hospital measurement equipment using a combination of the following parameters: - A composite score consisting of grip strength (Jamar dynamometer); -Leg strength (HHD quadriceps); -Arm strength (HHD biceps); -Motor ability (6MWD); -Grip strength (Jamar dynamometer); -Leg strength (HHD quadriceps); -Arm strength (HHD biceps); -Motor ability (6MWD); -Lower limb strength (TCST); -CPAx; -MRCsum; - health-related quality of life (assessed by EQ-5D); - Barthel score; -Lockwood Clinical Frailty Scale.

[0138] Amino acid bioabsorption The time course of free glycine appearance in human plasma following ingestion of the collagen hydrolysate was measured hourly in six subjects.

[0139] Outcome The clinical trial uses the same administration scheme as the PICS animal model in Example 1. Administration of collagen hydrolysate after ICU stay improves recovery from critical illness and prevents the development of PICS. From previous clinical trials, the administration and dosage of collagen hydrolysate is considered safe (e.g., based on adverse events, laboratory creatinine, urea, CK, glucose, Hb, CRP). The clinical trial confirmed earlier results, and collagen hydrolysate can be used specifically in ICU survivors to prevent and / or treat PICS in routine practice.

[0140] After ingestion of collagen hydrolysate, glycine levels were found to increase to a maximum concentration at 1 hour, after which the glycine decreased to near baseline levels over several hours (Figure 3). This observation suggests that one of the important (abundant) amino acids is rapidly absorbed and / or excreted from the body over time. <Additional Notes> The present invention includes the following aspects. <Section 1> Collagen hydrolysate for use in the prevention and / or treatment of Post Intensive Care Syndrome (PICS) following a stay in an intensive care unit. <Section 2> Item 1. The collagen hydrolysate for use according to item 1, which is administered in a total dose of 10 to 100 g per day based on the dry weight of the collagen hydrolysate. <Section 3> Item 3. The collagen hydrolysate for use according to item 1 or 2, wherein the administration regimen of the collagen hydrolysate comprises administering the collagen hydrolysate continuously for at least 3 weeks after a stay in an intensive care unit. <Section 4> Item 4. The collagen hydrolysate for use according to any one of items 1 to 3, wherein the administration regimen of the collagen hydrolysate comprises administration of the collagen hydrolysate starting within 3 weeks after a stay in an intensive care unit. <Section 5> Item 5. The collagen hydrolysate for use according to any one of items 1 to 4, wherein the administration regimen of the collagen hydrolysate comprises administering the collagen hydrolysate at least once every day or at least once every other day. <Section 6> Item 6. The collagen hydrolysate for use according to any one of items 1 to 5, having an average molecular weight of 1,000 to 9,000 Da. <Section 7> Item 7. The collagen hydrolysate for use according to any one of items 1 to 6, having an average molecular weight of less than 5000 Da. <Section 8> Item 8. A collagen hydrolysate for use according to item 7, having an average molecular weight of 1400 to 2200 Da, preferably 1600 to 2000 Da. <Section 9> Item 9. The collagen hydrolysate for use according to any one of items 1 to 8, wherein the collagen is porcine collagen and / or the collagen hydrolysate is derived from hydrolysis of porcine collagen. <Section 10> Use of collagen hydrolysate after an intensive care unit stay. <Section 11> Use of collagen hydrolysate to improve recovery after an intensive care unit stay. <Section 12> Item 12. The use according to item 10 or 11, wherein the collagen hydrolysate is administered in a total dose of 10 to 100 g per day, based on the dry weight of the collagen hydrolysate. <Section 13> Item 13. The use according to any one of items 10 to 12, wherein the administration regimen of the collagen hydrolysate comprises administering the collagen hydrolysate continuously for at least 3 weeks after a stay in an intensive care unit. <Section 14> The use according to any one of claims 10 to 13, wherein the administration regimen of the collagen hydrolysate comprises administration of the collagen hydrolysate starting within 3 weeks after a stay in an intensive care unit. <Section 15> Item 15. The use according to any one of items 10 to 14, wherein the administration regimen of the collagen hydrolysate comprises administering the collagen hydrolysate at least once every day or at least once every other day. <Section 16> Item 16. The use according to any one of items 10 to 15, wherein the collagen hydrolysate has an average molecular weight of 1000 to 9000 Da. <Section 17> Item 17. The use according to any one of items 10 to 16, wherein the collagen hydrolysate has an average molecular weight of less than 5000 Da. <Section 18> Item 18. The use according to item 17, wherein the collagen hydrolysate has an average molecular weight of 1400 to 2200 Da, preferably 1600 to 2000 Da. <Section 19> Item 19. The use according to any one of items 10 to 18, wherein the collagen is porcine collagen and / or the collagen hydrolysate is derived from hydrolysis of porcine collagen. <Section 20> Collagen hydrolysate for use in subjects following an ICU stay. <Section 21> 21. The collagen hydrolysate for use according to claim 20, which is administered as defined in any one of claims 2 to 5. <Section 22> Item 22. A collagen hydrolysate for use according to item 20 or 21, as defined according to any one of items 6 to 9.

Claims

1. 1. A composition for preventing and / or treating post-intensive care syndrome (PICS) following a stay in an intensive care unit, comprising a collagen hydrolysate, said collagen hydrolysate being a collagen hydrolysate derived from one or more of porcine, bovine and fish, said collagen hydrolysate having an average molecular weight of 1000-9000 Da.

2. 10. The composition of claim 1, wherein the collagen hydrolysate is administered in a total dosage of 10-100 g per day, based on the dry weight of the collagen hydrolysate.

3. 10. The composition of claim 1, wherein the administration regimen of the composition comprises administering the composition continuously for at least three weeks following an intensive care unit stay.

4. 10. The method of claim 1, wherein the administration regimen of the composition comprises administration of the composition beginning within three weeks after an intensive care unit stay.

5. The composition of claim 1 , wherein the administration regimen of the composition comprises administering the composition at least once every day or at least once every other day.

6. The composition described in claim 1, wherein the collagen hydrolysate has an average molecular weight of less than 5000 Da.

7. The composition of claim 6, wherein the collagen hydrolysate has an average molecular weight of 1,400 to 2,200 Da.

8. The composition of claim 7, wherein the collagen hydrolysate has an average molecular weight of 1600 to 2000 Da.

9. The composition of claim 1, wherein the collagen hydrolysate is a collagen hydrolysate derived from one or more of pigs and cows.

10. The composition of claim 1, wherein the collagen hydrolysate is a collagen hydrolysate derived from a pig.

11. The composition described in claim 1, wherein the prevention and / or treatment promotes recovery after a stay in an intensive care unit.

12. The composition according to any one of claims 1 to 11, wherein the composition is a food composition.

13. A composition described in any one of claims 1 to 11, wherein the composition is a food supplement composition.

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