Compositions for treatment of pain in patients who underwent elective arthroplasty

Abstract

<DP=1>²The present invention discloses a composition which may enhance ²the recovery of patients undergoing elective arthroplasty by ²reducing and / or eliminating pain, preferably during ²rehabilitation. The composition comprises at least a first active ²agent which comprises the amino acids leucine, isoleucine, valine, ²lysine, threonine, histidine, phenylalanine, methionine, ²tryptophan, tyrosine, and cystine.²

Description

<DP=1>²CA 02995903 2018-02-1.6²WO 2017 / 051272 ²PCT / 1B2016 / 055354²1²"Compositions for treatment of pain in patients who ²underwent elective arthroplasty"²* * *²FIELD OF THE INVENTION ² The present invention concerns compositions useful²in the treatment of pain in patients who underwent²elective arthroplasty, preferably during²rehabilitation.² BACKGROUND OF THE INVENTION ²Elective hip arthroplasty (EHA) is a surgical ²technique used for patients with damaged hip joints ²after degenerative osteoarthritis or an injury. One and ²half million EHA are carried out all over the world² each year. In Italy, there are about 100,000 annual EHA ²operations at a cost of approximately 1.3 billion ²euros, of which 500 million euros should be added for ²subsequent rehabilitation treatment. The total economic ²burden of EHA plus rehabilitation is 1.6% of national²annual budget for the health care system.²EHA and Post-EHA rehabilitation allows patients to ²regain physical ability and improve their quality of ²life. However, a number of factors may hinder both ²duration and outcome of rehabilitation, including² preoperative functional state, postoperative pain, and ²infection. Specifically, persistence of pain can ²lengthen functional restoration time, reduce clinical ²outcome and increase the need for additional ²rehabilitation.² Limiting these post-surgery alterations could²accelerate and enhance the retrieval of operated hip-²joint dysfunction.²There is therefore the need of new compositions ²which may enhance the recovery of patients undergoing ² elective arthroplasty.²<DP=2>²2²OBJECT AND SUMMARY OF THE INVENTION ²The object of the present invention is to provide new compositions ²which may enhance the recovery of patients undergoing elective ² arthroplasty by reducing and / or eliminating pain, preferably during ²rehabilitation.²According to the invention, the above object is achieved thanks to ²the method specified in the present description.²In an embodiment, the instant disclosure discloses an amino acid² composition for use in the treatment of pain in patients who underwent ²elective arthroplasty comprising at least a first active agent, wherein ²the first active agent comprises the aminoacids leucine, isoleucine, ²valine, lysine, threonine, histidine, phenylalanine, methionine, ²tryptophan, tyrosine, cystine.² In a further embodiment, the instant disclosure discloses an amino²acid composition for use in the treatment of pain in patients who ²underwent elective arthroplasty comprising at least a first and a second ²active agent, wherein the first active agent comprises the aminoacids²leucine, isoleucine, valine, lysine, threonine, ²histidine,²phenylalanine, methionine, tryptophan, tyrosine, and cystine, and the ²second active agent comprises the aminoacids glutamine, glycine and ²serine.²The data disclosed in the present description show that ²administration of amino acid compositions as disclosed herein is able to ² treat pain in patients who underwent elective arthroplasty thus ²increasing their recovery.²CA 2995903 2023-04-27²<DP=3>²CA 02995903 2018-02-16²WO 2017 / 051272 ²PCT / 1B2016 / 055354²3²BRIEF DESCRIPTION OF THE DRAWINGS ²The invention will now be described, by way of ²example only, with reference to the enclosed figures, ² wherein:²- Figure 1 shows the values of Harris Hip Score ²for the placebo and EAA treated groups;²- Figure 2 shows the relative scores of the ²domains contributing to the determination of Harris Hip² Score.²DETAILED DESCRIPTION OF THE INVENTION²The invention will now be described in detail, by ²way of non limiting example, with reference to patients ² who underwent elective hip arthroplasty.²It is clear that the scope of this description is ²in no way limited to elective hip arthroplasty only; ²patients undergoing to other elective arthroplasty, ²like for example knee or shoulder joint, may get² beneficial effect in terms of pain treatment from the ²administration of the amino acid composition disclosed ²in the present description.²In the following description, numerous specific ²details are given to provide a thorough understanding ² of embodiments. The embodiments can be practiced ²without one or more of the specific details, or with²other methods, components, materials, etc. In ²other²instances, well-known structures, materials, or ²operations are not shown or described in detail to ²avoid obscuring aspects of the embodiments.²Reference throughout this specification to "one ²embodiment" or "an embodiment" means that a particular ²feature, structure, or characteristic described in ²connection with the embodiment is included in at least² one embodiment. Thus, the appearances of the phrases²<DP=4>²CA 02995903 2018-02-16²WO 2017 / 051272 ²PCT / 1B2016 / 055354²4²"in one embodiment" or "in an embodiment" in various ²places throughout this specification are not ²necessarily all referring to the same embodiment. ²Furthermore, the particular features, structures, or² characteristics may be combined in any suitable manner ²in one or more embodiments.²The headings provided herein are for convenience ²only and do not interpret the scope or meaning of the ²embodiments.² According to an embodiment of the instant²description, the amino acid composition for use in the ²treatment of pain in patients who underwent elective ²arthroplasty comprises at least a first active agent, ²wherein the first active agent comprises the aminoacids²leucine, isoleucine, valine, lysine, threonine, ²histidine, phenylalanine, methionine, tryptophan, ²tyrosine, cystine.²According to a further embodiment of the instant ²description, the amino acid composition for use in the² treatment of pain in patients who underwent elective ²arthroplasty comprises at least a first and a second ²active agent, wherein the first active agent comprises ²the aminoacids leucine, isoleucine, valine, lysine,²threonine, histidine, phenylalanine, ²methionine,²tryptophan, tyrosine, and cystine, and the second ²active agent comprises the aminoacids glutamine, ²glycine and serine.²According to a preferred embodiment of the instant ²description, the amino acid compositions herein ² disclosed are for use in the treatment of pain in ²patients who underwent elective hip arthroplasty. ²Further specifications, in terms of amounts and ²ratios among the various amino acids provided for by ²the compositions for use in the treatment of pain in ² patients who underwent elective arthroplasty are²<DP=5>²5²contained in the teachings provided herein.²According to a further embodiment, the amino acid composition may ²comprise pharmaceutically acceptable excipients, like for example ²proteins, vitamins, carbohydrates, natural and artificial sweeteners² and / or flavoring substances. In a preferred embodiment, the ²pharmaceutically acceptable excipients may be selected from whey ²proteins, maltodextrins, fructose, calcium caseinate, fish oil, citric ²acid or salts thereof, sucralose, sucrose esters, vitamin D3, group B ²vitamins.² The present study shows that in the rehabilitation phase of elective²hip arthroplasty the patients may be associated with pain, which may ²persist until the end of rehabilitation. Administration of the amino acid ²compositions disclosed in the instant application unexpectedly reduces ²pain and enhances the functional retrieval of hip joint function, as²witnessed in the Results section.²Post-EHA patients show, in fact, muscle soreness, pain and weakness ²particularly after each session of physical therapy. A reduction in ²muscle soreness explains the reduction in the domain relative to pain ²observed in the study and found more pronounced in treated groups than² in placebo ones.²Without wishing to be bound to any specific theory, it is reasonable ²to believe that supplementation with the amino acid compositions herein ²disclosed may influence the central nervous system contributing to reduce ²the domain of pain within HHS test, being the amino acids largely consumed² by nervous system cells and being several of them precursors of ²neurotransmitters, and consequently a better retrieval²CA 2995903 2023-04-27²<DP=6>²CA 02995903 2018-02-16²WO 2017 / 051272 ²PCT / 1B2016 / 055354²6²of hip joint dysfunction is achieved.²According to some embodiments of the present ²disclosure, the amino acids isoleucine, leucine and ²valine are present in an amount expressed in moles² percentage comprised in the range 50-70 mol% with ²respect to the total moles of the first active agent, ²preferably between 52-67 mol%.²In a further embodiment, the amino acids threonine ²and lysine are present in an amount expressed in moles² percentage comprised in the range 20-30 mol% with ²respect to the total moles of the first active agent, ²preferably between 22-27 mol%.²In another embodiment, the amino acids histidine, ²phenylalanine, methionine and tryptophan are present in² an amount expressed in moles percentage comprised in ²the range 5-15 mol% with respect to the total moles of ²the first active agent.²In a further embodiment, the amino acids tyrosine ²and cystine are present in an amount expressed in moles ² percentage comprised in the range 2-8 mol% with respect ²to the total moles of the first active agent.²In a still further embodiment, the first active ²agent comprises up to 70 mol% of isoleucine, leucine ²and valine, up to 50 mol% of threonine and lysine, up² to 23 mol% of cystine, histidine, phenylalanine, ²methionine, tryptophan and tyrosine, wherein threonine ²and lysine are present together in a mole amount higher ²than the other essential amino acids with the exception ²of isoleucine, leucine and valine.² In a further embodiment, the first active agent²consists of the amino acids leucine, isoleucine, ²valine, lysine, threonine, histidine, phenylalanine, ²methionine, tryptophan, tyrosine, and cystine.²In an embodiment, the composition herein disclosed ² may further comprise a second active agent comprising²<DP=7>²CA 02995903 2018-02-16²WO 2017 / 051272 ²PCT / 1B2016 / 055354²7²glutamine, serine and glycine.²In a further embodiment the amount of the second ²active agent expressed as moles percentage with respect ²to the total moles of the first active agent is² comprised between 35-45 mol%, preferably 37-42 mol%, ²more preferably about 40 mol%.²According to an embodiment, when the amino acid ²composition comprises the first and second active ²agents, tyrosine is present in a mole amount higher² than the mole amount of at least one of methionine, ²phenylalanine and cystine. In a preferred embodiment, ²tyrosine is present in a mole ratio with respect to ²methionine equal to or higher than 0.43 and / or tyrosine ²is present in a mole ratio with respect to²phenylalanine equal to or higher than 0.85 and / or ²tyrosine is present in a mole ratio with respect to ²cystine equal to or higher than 0.49.²According to an embodiment, when the amino acid ²composition comprises the first and second active² agents, histidine is present in a mole amount higher ²than the mole amount of threonine. In a preferred ²embodiment, histidine is present in a mole ratio with ²respect to threonine equal to or higher than 0.95.²According to an embodiment, when the amino acid² composition comprises the first and second active ²agents, glutamine is present in a mole amount higher ²than the mole amount of at least one of isoleucine and ²valine. In a preferred embodiment, glutamine is present ²in a mole ratio with respect to isoleucine equal to or²higher than 0.67 and / or glutamine is present in a mole ²ratio with respect to valine equal to or higher than ²0.92.²According to an embodiment, when the amino acid ²composition comprises the first and second active ² agents, glycine is present in a mole amount higher than²<DP=8>²8²the mole amount of at least one of isoleucine and valine. In a preferred ²embodiment, glutamine is present in a mole ratio with respect to ²isoleucine equal to or higher than 0.67 and / or glutamine is present in ²a mole ratio with respect to valine equal to or higher than 0.92.² According to an embodiment, when the amino acid composition²comprises the first and second active agents, glycine is present in a ²mole amount higher than the mole amount of at least one of isoleucine ²and valine. In a preferred embodiment, glycine is present in a mole ratio ²with respect to isoleucine equal to or higher than 0.57 and / or glutamine²is present in a mole ratio with respect to valine equal to or higher ²than 0.78.²According to an embodiment, when the amino acid composition ²comprises the first and second active agents, the non essential amino ²acids tyrosine, cystine, glutamine, serine and glycine are present in a² mole amount lower than the mole amount of the essential amino acids ²contained in the composition; preferably tyrosine, cystine, glutamine, ²serine and glycine are present in an amount expressed in moles percentage ²comprised in the range 25-45 mol% with respect to the total moles of the ²composition, preferably between 30-40 mol%, more preferably about 34²mol%.²In a further embodiment, the second active agent consists of the²amino acids glutamine, glycine and serine.²The presence of glutamine in the second active agent enhances the²anabolic effect promoted by the essential amino acids contained in the² first active agent, i.e. counteracting muscle proteolysis.²Furthermore, in particular, when preparing the compositions ²according to the instant disclosure, and specifically the active agents, ²the amino acids proline, alanine, and, above all, arginine are preferably ²avoided, given that they can be counterproductive or even harmful.² Proline and alanine may, in fact, favour hypertension; arginine may ²interact negatively with drugs used in the treatment of pain.²The amino acids contained in the disclosed compositions can be ²replaced by respective²CA 2995903 2023-04-27²<DP=9>²CA 02995903 2018-02-16²WO 2017 / 051272 PCT / 1B2016 / 055354 ²9²pharmaceutically acceptable derivatives, namely salts. ²In a preferred embodiment, the composition object ²of the instant description has a composition (expressed ²as a single dose sachet of 5 mg of amino acids) as ² disclosed in the following table 1.²Table I²Preferred²Range²Ingredient mg / sachet mole / sachet mol / mol% ²range²mol / mol%²mol / mol%²L Leucine 1562.50 11.9175 31.97 15....50 ²25....37²L-isoleucIne 781.25 5.9587 15.98 5-30 10-²20²L-Valine 781.25 6.6722 17.90 5-30 12-²22²L-Lysine 812.50 5.5601 14.92 5-30 10-²20²L-Threonine 437.50 3.6740 9.86 2-20 5-15²L-Histidine 187.50 1.2090 3.24 1-5 2-4²L-Phenylalanine 125.00 0.7572 2.03 0.5-6 1-4²L-Tryptophan 62.50 0.1225 0.33 0.1-0.5 0.2-²0.4²L-Methi_om_ne 25.00 0.4191 1.12 0.5-2 0.75-²1.5²L-Tyrosine 37.50 0.2071 0.56 0.1-1 0.2-²0.7²L-Cysti_ne 187.50 0.7805 2.09 0.5-5 1.5-²2.5²Total 5000.00 37.28 100%²From the data of Table 1 it is possible to ²calculate the molar ratios of the individual amino ²acids either with respect to the overall composition or ² with respect to each individual amino acid.²In a further preferred embodiment, the composition ²object of the instant description has a composition ²(expressed as a single dose sachet of 6651.00 mg of ²amino acids) as disclosed in the following table 2.²Table 2²Preferred²Range²Ingredient mg / sachet mole / sachet mol / mol% ²range²mol / mol%²mol / mol%²L-Leucine 1500.00 11.4408 22.58 15-30 20-²25²l l²<DP=10>²ll l² Preferred²Ingredient mg / sachet mole / sachet mol / mol%²mRangeol / mol% range²mol / mol%²L-Isoleucine 450.00 3.4322 6.77 ²3-10 5-8²L-Valine 550.00 4.6972 9.27 ²5-15 7-12²L-Lysine 1000.00 6.8432 13.51 6-²20 10-15²L-Threonine 246.00 2.0658 4.08 ²2-6 3-5²L-Histidine 336.00 2.1665 4.28 ²2-7 ' 3-6²L-² 264.00 1.5991 3.16 1-5 2-4²Phenylalanine²L-Tryptophan 75.00 0.3674 0.73 ² 0.3-1 0.5-0.9²L-Methionine 121.00 0.8114 1.60 ²0.5-3 1-2²L-Tyrosine 340.00 1.8775 3.71 ²1.5-6 3-4²L-Cystine 219.00 0.9116 1.80 ² 0.9-2.7 1.5-2.0²L-Glutamine 750.00 5.1317 10.13 ²5-15 7-12²L-Glycine 450.00 5.9944 11.83 ²5-20 7-15²L-Serine 350.00 3.3305 6.57 ²3-10 5-9²Total 6651.00 50.67 100%²From the data of Table 2 it is possible to calculate the molar²ratios of the individual amino acids either with respect to the overall ²composition or with respect to each individual amino acid.² 5 Supplementation of the herein disclosed amino acids compositions²to patients, who underwent elective arthroplasty, both during post-²exercise recovery and during the day, allows patients to continue ²rehabilitation, which on the contrary could be discontinued, thanks to ²the unexpected reduction of pain and muscle soreness.²10 MATERIALS AND METHODS²Patients²Sixty-eight subjects at 17 1.12 days after elective hip ²arthoplasty (EHA) were recruited at admission to the rehabilitation ²center. The patients were selected on the basis of the type of surgical ² access they had had (lateral approach) in order to get a more uniformity²in terms of recovery time. The causes ² ,²CA 2995903 2023-04-27²<DP=11>²CA 02995903 2018-02-16²WO 2017 / 051272 ²PCT / 1B2016 / 055354²11²for a EHA were: aseptic necrosis of the femoral head ²(5%), rheumatoid arthritis (1.6%), congenital hip ²dysplasia (1.6%), osteoarthritis (91.8%) of grade 3 and ²4 diagnosed through preoperatory X-ray. Eight subjects² were excluded for diabetes on insulin and / or oral ²hypoglycemic drugs (n=5), hyperthyroidism (n=1), ²chronic renal disease (n=2). Thus a total of 60 ²patients were studied.²On the second day after admission, the patients ² underwent the following procedures:²a) Anthropometric measurements: body weight (BW; kg) ²and height (m). Body mass index (BMI) was calculated as ²kg / m2.²b) Biohumoral variables:²- Routine Variables, including serum total protein²(g / dL) and protein electrophoresis.²c) Clinical-functional status: this was measured ²using the Harris hip score (HHS) [1]. This is a test ²consisting of several domains relative to: pain, limp,²support, distance walked, sitting, enter public ²transportation, stairs, putting shoes and socks on, ²absence of deformity and range of motion; the score ²range for each domain is shown in Figure 2. The test ²gave outcome classification as poor (<70 scores),²sufficient (70-79 scores), good (80-89 scores) or ²excellent (90-100 scores) [2].²After carrying out these procedures, the patients ²were randomly allocated to 14-d supplementation with ²the amino acid compositions herein disclosed (EAA) or a ² placebo (maltodextrin).²The treatment of 14 days was dictated by the ²rehabilitation center policy permitting patients to ²stay for at maximum 20 days.²Rehabilitation protocol² This protocol aimed to restore the complete²<DP=12>²CA 02995903 2018-02-16²WO 2017 / 051272 ²PCT / 1B2016 / 055354²12²functional recovery of the altered body statics and the ²resumption of a normal pattern of walking. The ²rehabilitation program included 2 daily therapy ²sessions lasting 45 min each (morning and afternoon)² with patients assisted by the same physical therapist. ²The entire rehabilitation cycle encompasses 24 ²sessions. The rehabilitation program consisted of:²1) Passive mobilization of the hip with movements ²in triple flexion (hip, knee and ankle).² 2) Stretching the adductor and flexor muscles of²the operated limb.²3) Hip extension using isotonic contraction of the ²gluteus.²4) Isotonic contraction of the quadriceps muscles²against a resistance of 1 kg.²5) Assisted gait training with the use of walking ²sticks and training for the stairs.²6) Maintenance of cardiorespiratory capacity.²The patients and physicians who evaluated on the ² subjects' functional status were blinded to the ²protocol. Within 2 days before patient discharge all ²procedures were repeated.²The local ethical scientific committee approved ²the protocol (# 118 in the Maugeri Foundation ² Scientific Annals 2011, page 432) after the subjects ²gave their informed consent.²The amino acid composition (EAA# / )²The experimental group (EAA group) received the ²composition herein disclosed in Table 4 (briefly named ² EAA#1) that provided 10 g of essential aminoacids / day ²(5 g in the morning + 5 g in the afternoon diluted in ²about half a glass of water until patient discharge).²Table 4²Main ingredients mg²<DP=13>²CA 02995903 2018-02-16²W02017 / 051272 ²PCT / 1B2016 / 055354²13²5000²Total amino acids including the²(in²following²total)²L- LeucIne (131.17)* 1562.50²L-Isoleucine (131.17)* 781.25² (117.15)* 781.25²L-Lysine (146.19)* 812.50²L-Threonine (119.12)* 437.50²L-Histidine (155.16)* 187.50²L-Phenylalan.Lne (165.19)* 125.00²L-Methionine (149.21)* 62.50²L-Tryptophan (204.23)* 25.00²L-Tyrosine (181.19)* 37.50²L-Cystine (240.30)* 187.50²Excipients mg²Vitamin B6 0.15²Vitamin B1 0.15²Carbohydrates - Maltodextrins 5454.10²Banana flavour 200.00²Sodium citrate tribasic²150.00²dehydrate²Aspartame powder 30.00²Acesulfame potassium 17.50²* Molecular weight from "Amino Acid, Nucleic Acids & Related ²Compounds - Specification / General Tests", 8th Ed., Kyowa Hakko ²Kogyo Co., Ltd.² Statistical analysis²Descriptive statistics were carried out for all ²recorded variables, reporting mean and standard ²deviations for quantitative variables and distribution ²frequencies for qualitative variables. Chi-squared test² was used for categorical variables. Repeated ²measurement analysis of variance was used to assess any ²trend differences over time between patients on EAAs or ²placebo. Differences in plasma amino acids between ²patients and healthy controls and between the EAAs and²placebo groups were analysed by unpaired Student t-²test. Differences in the variables in the entire²<DP=14>²CA 02995903 2018-02-16²WO 2017 / 051272 ²PCT / 1B2016 / 055354²14²patient population observed at admission to and ²discharge from rehabilitation were tested by paired t-²test. Statistical significance was set at p <0.05.² RESULTS²Baseline characteristics of patient population at ²admission to rehabilitation²At admission thirty-five percent of patients ²(n=21) were on antibiotic therapy for infection (mainly ² of urinary tract). Seventy percent (n=42) had received ²blood transfusions during their acute stage.²Functionally, the patients had severe reduction of ²hip function as indicated by their HHS test (40.78 ²2.70 scores). Within the test, the domain relative to² pain showed that the patients had moderate pain (19.5 ²1.7 score).²After randomization²a) At admission ²After randomization, the EAA and placebo groups² were similar for nutritional status, dietary intake, ²distribution in infection complications (40% in ²placebo, 30% in EAAs; n.s.). Compared to the placebo ²group, EAA subjects had lower serum transferrin ²(p=0.04) and circulating total proteins (p=0.04). Hip²dysfunction was similar between the two patient groups ²(39.78 4.89 score in placebo vs 41.80 1.15 score in ²EAA group; n.s.). Within the test, all the domains ²including that relative to pain were similar between ²placebo and EAA subjects.² b) After 14-d treatment ²During rehabilitation, blood Hb and serum ²transferrin increased: +0.84 0.3 mg / dL in placebo vs ²+0.87 0.19 mg / dL in EAA group, interaction p=0.8 for ²Hb; +1.34 2.5 mg / dL in placebo vs +11.45 3.1 mg / dL² in EAA group, interaction p=0.005 for transferrin. All²<DP=15>²CA 02995903 2018-02-16²WO 2017 / 051272 ²PCT / IB2016 / 055354² the other biohumoral variables measured showed no ²significant changes both intra- and between the groups. ²All patients improved hip dysfunction (from ²baseline 48.78 2.70 to 73.18 7.1 score; p < 0.001) ²5 but EAA subjects improved more with respect to placebo ²group (from baseline 41.8 1.15 to 76.37 6.6 score ²vs 39.78 4.89 to 70.0 7.10 score) (interaction ²p=0.02); (Figure 1).²Within the HHS test the EAA group showed a more ²10 marked reduction of the pain (from 20 0 to 39.2 ²5.59 score) than the placebo patients did (from 18.7 ²3.4 to 32.4 6.2 score) (interaction p=0.01).²Table 5 shows HHS and pain scores for the EAA and ²placebo groups.² Table 5²Interaction²Placebo group EAA treated group²P²admission discharge Admission Discharge ²Harris²hip 39.78 4.89 70.0 ²7.10 41.8 1.15 76.37 6.6 0.02²score²Pain²18.7 3.4 32.4 6.2 20 0 39.2 5.59 0.01²score²<DP=16>²CA 02995903 2018-02-16²WO 2017 / 051272 ²PCT / 1B2016 / 055354²16²REFERENCES ²1. Harris WH. Traumatic arthritis of the hip after ²dislocation and acetabular fractures: treatment by mold² arthroplasty. An end-result study using a new method of ²result evaluation. J Bone Joint Surg Ann 1969; 51: 737-²55.²2. Marchetti P, Binazzi R, Vaccari V, Girolami M, ²Morici F, Impallomeni C, et al. Long-term results with ² cementless Fitek (or Fitmore) cups. J Arthroplasty ²2005; 20: 730-7.²

Claims

<DP=1>²17²CLAIMS ²1. A composition for use in the treatment of pain in patients ²who underwent elective arthroplasty, the composition comprising at ²least a first active agent, wherein the first active agent ²comprises the amino acids leucine, isoleucine, valine, lysine, ²threonine, histidine, phenylalanine, methionine, tryptophan, ²tyrosine, and cystine.²2. The composition for use according to claim 1, wherein the ²amino acids isoleucine, leucine and valine are present in the range ²of 50-70 mol% with respect to the total mole amount of the first ²active agent.²3. The composition for use according to claim 2, wherein the ²amino acids isoleucine, leucine and valine are present in the range ²of 52-67 mol% with respect to the total mole amount of the first ²active agent.²4. The composition for use according to claim 1, 2 or 3, ²wherein the amino acids threonine and lysine are present in the ²range of 20-30 mol% with respect to the total mole amount of the ²first active agent.²5. The composition for use according to claim 4, wherein the ²amino acids threonine and lysine are present in the range of 22-²27 mol% with respect to the total mole amount of the first active ²agent.²6. The composition for use according to any one of claims 1-²5, wherein the amino acids histidine, phenylalanine, methionine ²and tryptophan are present in the range of 5-15 mol% with respect ²to the total mole amount of the first active agent.²7. The composition for use according to any one of claims 1-²CA 2995903 2024-01-04²<DP=2>²18²6, wherein the amino acids tyrosine and cystine are present in the ²range of 2-8 mol% with respect to the total mole amount of the ²first active agent.²8. The composition for use according to any one of claims 1-²7, further comprising at least a second active agent, wherein the ²second active agent comprises the amino acids glutamine, serine ²and glycine.²9. The composition for use according to claim 8, wherein the ²amount of the second active agent is between 37-45 mol% with respect ²to the total mole amount of the first active agent.²10. The composition for use according to claim 9, wherein the ²amount of the second active agent is between 35-42 mol% with respect ²to the total mole amount of the first active agent.²11. The composition for use according to claim 10, wherein ²the amount of the second active agent is about 40 mol% with respect ²to the total mole amount of the first active agent.²12. The composition for use according to any one of claims 8-²11, wherein the amino acid tyrosine is present in a mole amount ²higher than the mole amount of at least one of the amino acids ²methionine, phenylalanine and cystine.²13. The composition for use according to any one of claims 8-²12, wherein the amino acid histidine is present in a mole amount ²higher than the mole amount of the amino acid threonine.²14. The composition for use according to any one of claims 8-²13, wherein the amino acid glutamine is present in a mole amount ²higher than the mole amount of at least one of the amino acids ²isoleucine and valine.²CA 2995903 2024-01-04²<DP=3>²19²15. The composition for use according to any one of claims 8-²14, wherein the amino acid glycine is present in a mole amount ²higher than the mole amount of at least one of the amino acids ²isoleucine and valine.²16. The composition for use according to any one of claims 8-²15, wherein the amino acids tyrosine, cystine, glutamine, serine ²and glycine are present in the range of 25-45 mol% with respect to ²the total mole amount of the composition.²17. The composition for use according to claim 16, wherein ²the amino acids tyrosine, cystine, glutamine, serine and glycine ²are present in the range of 30-40 mol% with respect to the total ²mole amount of the composition.²18. The composition for use according to claim 16, wherein ²the amino acids tyrosine, cystine, glutamine, serine and glycine ²are present in an amount of about 34 mol% with respect to the total ²mole amount of the composition.²19. The composition for use according to any one of claims 1-²18, wherein the composition is free of arginine.²20. The composition for use according to any one of claims 1-²19, wherein the composition comprises at least one excipient.²21. The composition for use according to claim 20, wherein ²the at least one excipient is selected from the group consisting ²of proteins, vitamins, carbohydrates, natural sweeteners, ²artificial sweeteners, and flavouring substances.²CA 2995903 2024-01-04²