WO2026013252A1 - Mélange de mono-, di- et triglycérides d'acide nonanoïque destiné à être utilisé dans le traitement de l'atrophie musculaire, de la sarcopénie et d'une lésion musculaire - Google Patents

Mélange de mono-, di- et triglycérides d'acide nonanoïque destiné à être utilisé dans le traitement de l'atrophie musculaire, de la sarcopénie et d'une lésion musculaire

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Publication number
WO2026013252A1
WO2026013252A1 PCT/EP2025/069884 EP2025069884W WO2026013252A1 WO 2026013252 A1 WO2026013252 A1 WO 2026013252A1 EP 2025069884 W EP2025069884 W EP 2025069884W WO 2026013252 A1 WO2026013252 A1 WO 2026013252A1
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Prior art keywords
muscle
mixture
nonanoic acid
injury
use according
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English (en)
Inventor
Alessio PAOLI
Cristina LUCERI
Elisabetta BIGAGLI
Mario D'ambrosio
Lorenzo CINCI
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Definitions

  • the present invention refers to the field of substances for muscular disorders. STATE OF THE ART
  • Skeletal muscle injuries In contrast to chronic muscle diseases such as sarcopenia, muscle injuries inflict damage to localized muscle groups. Skeletal muscle injuries can stem from a variety of events, including surgery, direct trauma such as muscle lacerations and contusions or indirect insults such as muscle strains injuries (including muscle rupture and tearing, or tendon rupture) and are frequently observed in professional and amateur sport players.
  • Aim of the present invention is therefore to provide a substance for use in the treatment of sarcopenia and muscle-injury.
  • Subject matter of the present invention is a mixture of mono-, di- and triglycerides of nonanoic acid for use in the treatment of sarcopenia, muscle atrophy and muscleinjury.
  • the mixture as above described increases the myogenic differentiation of C2C12 cells, exerts a hypertrophic effect as measured by enhanced myotubes width and length, protects against dexamethasone-induced muscle atrophy and exerts reparative effects against muscle strain injury.
  • composition comprising a mixture of mono-, di- and triglycerides of nonanoic acid and at least a pharmaceutically acceptable excipient.
  • the mixture for use according to the invention is essentially consisting of mono-, di- and triglycerides of nonanoic acid and free glycerol (PC10).
  • the mixture for use according to the invention contains at least 10% of free glycerol, 40% of nonanoate monoglyceride and the remainder being nonanoate di- and triglyceride.
  • the mixture of the invention has the following composition: free glycerol 10-20 % monoglyceride of nonanoic acid 40-60 % diglyceride of nonanoic acid 20-40 % triglyceride of nonanoic acid 1 -5 %
  • the mixture for use according to the invention has the following composition: free glycerol 12-18 % monoglyceride of nonanoic acid 45-55 % diglyceride of nonanoic acid 25-35 % triglyceride of nonanoic acid 2-5 %
  • the mixture for use according to the invention has the following composition: free glycerol 14-16 % monoglyceride of nonanoic acid 47-53 % diglyceride of nonanoic acid 27-33 % triglyceride of nonanoic acid 3-4 %
  • sarcopenia and muscle atrophy include any condition characterized by atrophy and/or muscle wasting and/or loss of muscle function for example due to malignancy, some autoimmune disorders, aging, malnutrition, obesity, physical inactivity, immobility and chronic corticosteroids therapy
  • muscle injury incudes traumatic muscle injury resulting from high stresses and strains to skeletal muscle tissue (often due to muscle activation while the muscle is lengthening), resulting in indirect and noncontact muscle injuries (strains or ruptures), or from external impact, resulting in direct muscle injuries (contusion or laceration).
  • muscle injury include also that due by surgery.
  • the pharmaceutical composition according to the invention can be administered orally, topically, transdermally. Suitable excipients according to pharmacopeia can be used to properly formulate the pharmaceutical composition for each of these routes of administration.
  • the pharmaceutical composition according to the invention is preferably for use in the treatment of sarcopenia and muscle injury as above.
  • Figure 1 Effect of PC10 on the cell viability of C2C12 myoblasts.
  • Cells were treated with PC10, 100 pM for 48 h and compared to untreated control cells.
  • Cell viability was analyzed using the MTS assay. Data are expressed as mean ⁇ SE of three independent experiments.
  • Figure 2. Representing images of haematoxylin-eosin staining for myotubes evaluation: A) C2C12 control, untreated cells; B) C2C12 treated with 2% HS for 6 days; C) C2C12 treated with 2% HS in the presence of PC10 100 pM for 6 days. Final magnification 200x. Scale bar 50 pm.
  • Figure 3 Representing images of C2C12 immuno-stained for a-actinin: A) C2C12 control, untreated cells; B) C2C12 treated with 2% HS for 6 day; C) C2C12 treated with 2% HS for 6 days in the presence of PC10 100 pM. Red staining highlights a- actinin positive myotubes formation. Final magnification 200x. Scale bar 50 pm.
  • FIG. 4 Quantitative image analysis of myotube width (panel A) and length (panel B) in C2C12 control, untreated cells, in C2C12 treated with 2% HS for 6 day and in C2C12 treated with 2% HS for 6 days in the presence of PC10 100 pM.
  • the data are expressed as mean ⁇ SE. *P ⁇ 0.05 and ****P ⁇ 0.0001 vs HS; ⁇ vs CTRL by one-way ANOVA and Dunnett's multiple comparisons test.
  • Figure 5 Effect of PC10 on width (panel A) and length (panel B) of C2C12 myotubes expressed as the ratio of the average length of myotubes in the HS+ dexamethasone (HS+DEXA) group. Data are expressed as the mean ⁇ SE. **p ⁇ 0.01 and ****p ⁇ 0.0001 vs HS+DEXA; ⁇ p ⁇ 0.05 and ⁇ p ⁇ 0.001 vs CTRL by or Kruskal- Wallis and Dunn's multiple comparisons test.
  • Figure 6 Representing images of C2C12: A) C2C12 control, untreated cells after 6 hours from injury B) C2C12 treated with PC10 100 pM after 6 hours from injury. The scratch perimeter was drawn with a solid black line to better highlight its mean diameter. Final magnification 200x. Scale bar 50 pm.
  • Figure 7 Measurement of the length of the simulated muscle tear 6 hours after the damage, in the presence or absence of PC10 100pM. Values are means ⁇ SE. ***p ⁇ 0.001 , unpaired t test.
  • the esterification reaction was conducted in 10,000 kg batches in a reactor equipped with a vertical reflux condenser.
  • the mixture was heated up to 110°C by dropping the starting materials into the reactor via the vertical reflux condenser.
  • the reaction mixture was heated to 150 °C, raising the temperature by 2 °C at a time, keeping the pressure under control so that it did not exceed 0.5 BAR.
  • the temperature at the head of the vertical condenser was set to 110°C to allow evaporation of the water from the esterification reaction and the reactor temperature was raised up to 235°C (235°C are reached by raising the temperature 1 °C at a time, keeping the Pressure always ⁇ 0.5 BAR).
  • the reaction mixture reached a temperature of 235 °C, it was thermo-stabilized until the free acidity value (determined by ISO 660:2009 method) was equal to or less than 2%.
  • the product was then discharged into a refrigerant and cooled to room temperature.
  • Example 2 The product obtained according to Example 1 was characterized and analyzed using the following analytical methods shown in Table 2:
  • Table 2 Analytical methods used for the chemical characterization of the product.
  • Example 2.1 - Determination of Free Glycerol This method specifies a titration process for the determination of content of glycerol in products containing mono- and triglycerides of fatty/organic acids and glycerol. The method is applicable to both liquid and powdered products.
  • the formic acid produced by the reaction is titrated with a standard volumetric solution of potassium hydroxide, using the bromothymol blue indicator.
  • the titer of glycerol is given, as a weight percentage, by the formula: (Vi - Vo) - N ⁇ 9.209
  • Vi volume (ml) of the potassium hydroxide solution used for the titration of the sample
  • N normality factor of the standard volumetric potassium hydroxide solution
  • m mass (g) of the sample taken for determination
  • This calculation method is used to determine the total glyceride content in mixtures containing only free glycerol, water, glycerides, and free organic acids.
  • This method can only be applied after other parameters have been determined using the following methods:
  • GC glyceride content
  • GC glyceride content of fatty/organic acids
  • Table 3 shows the chemical-physical characterization of the products obtained from example 1 .
  • This method describes the procedure for the quantitative determination of glycerol monononanoate, glycerol dinonanoate, glycerol trinonanoate on both liquid and solid samples.
  • TMSE trimethyl silyl ether
  • Silanising agents are added to the sample and the reaction on free -OH groups of glycerol is carried out at room temperature, using pyridine as a catalyst. After dilution, the sample is injected into a Gas Chromatograph equipped with an on-column injector, non-polar capillary column and FID detector.
  • Carrier gas flow (Helium): 1 .5 ml/min
  • Table 6 shows the molecular weights of interest.
  • the corrected peak areas of each component are calculated as follows:
  • Glycerol monononanoate (MO) Glycerol monononanoate area I RRF
  • Glycerol dinonanoate (DI) Glycerol dinonanoate area I RRF
  • Glycerol trinonanoate Glycerol trinonanoate area I RRF
  • the weight percentages of the single components are calculated as follows:
  • Glycerol monononanoate (% m/m): 100 * MO I (MO+DI+TRI)
  • Glycerol dinonanoate (% m/m): 100 * DI / (MO+DI+TRI)
  • Glycerol trinonanoate (% m/m): 100 * TRI I (MO+DI+TRI)
  • Table 8 shows the amounts of Monoglycerides, Diglycerides and Triglycerides of the product of example 1 .
  • the C2C12 cell line derived from mouse skeletal muscle myoblasts is a common cell model for skeletal muscle research.
  • Murine C2C12 myoblasts were purchased from the American Type Culture Collection (ATCC, Manassas, VA, USA).
  • ATCC American Type Culture Collection
  • the cells were cultured in growth medium consisting of Dulbecco’s modified Eagle’s medium (DMEM), supplemented with 10% FBS, 100 U/ml penicillin and 100 pg/ml streptomycin in 5% CO2 at 37°C. The growth medium was changed every 2 days. All reagents were provided by Thermo Fisher Scientific (Milan, Italy).
  • C2C12 myoblasts were cultured in 96-well plates (5x103 cells/well) overnight in 5% CO2 incubator at 37°C. Then over a period of 48 h in 5% CO2 incubator at 37°C myoblasts were treated with PC10 100 pM.
  • the medium of each well was discarded after treatment and mitochondrial functionality and cell viability were assessed by the colorimetric method based on [3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt; MTS] and an electron coupling reagent (phenazine ethosulfate; PES) (Promega Corporation, Wl, USA) The optical density of the chromogenic product was measured at 490 nm (Cinci et al., Cancer Med. 2016 Jun;5(6):1279-91 ).
  • the C2C12 myoblasts at 80-90% confluence were transferred to differentiation medium composed of DMEM supplemented with 2% horse serum (HS) to initiate the differentiation of the myoblasts into myotubes.
  • the medium was changed with fresh differentiation medium and fresh PC10 every day.
  • Myotube differentiation was induced for 6 days in presence or absence of PC10 100 pM.
  • C2C12 cells were seeded, 10 5 cells in glass dishes and treated as described above.
  • specimens were fixed in 4% formaldehyde (freshly prepared from paraformaldehyde as normally used for experiments in optical microscopy) in 0.1 mol/L phosphate buffer, pH 7.4, for 10 min and stained with hematoxylin-eosin.
  • 1 specimens were incubated with hematoxylin for 2 minutes; 2) washed in tap water for 10 minutes; 3) incubated in 50% ethanol for 2 minute; 4) incubated in eosin for 1 minute; 5) washed in 96% and 100% ethanol; 6) incubated in xylene for 2 minute and then mounted.
  • C2C12 cells were seeded and treated as described above. At the end of treatments, specimens were fixed in 4% formaldehyde (freshly prepared from paraformaldehyde as normally used for experiments in optical microscopy) in 0.1 mol/L phosphate buffer, pH 7.4, for 10 min and then preincubated in 0.1 % (v/v) Triton (Sigma Aldrich) and 1 % (w/v) bovine serum albumin (Sigma Aldrich) in PBS for 15 min at room temperature. The cells were incubated with primary antibody anti-mouse a-Actinin (Cell Signaling Technology, Danvers, Massachusetts, USA) at final dilution of 1 :40 overnight at 4°C.
  • primary antibody anti-mouse a-Actinin Cell Signaling Technology, Danvers, Massachusetts, USA
  • Immunoreaction was revealed by using the secondary antibody Alexa Fluor 568 anti-rabbit (Invitrogen, San Diego, CA) 1 :200 for 2 h at room temperature. At least 10 microscopic fields were randomly taken for each specimen. a-Actinin presence and myotube measurements were carried out.
  • DEXA Dexamethasone
  • C2C12 myotubes were used to induce muscle atrophy in C2C12 myotubes.
  • DEXA is a synthetic glucocorticoid that is often used as a representative inducer of muscle atrophy in in vitro and in vivo models (Li et al., Biomed Pharmacother. 2023 Nov; 167:115517).
  • To induce muscle atrophy fully differentiated C2C12 cells were treated with DEXA (1 pM) for 48 h in the presence or absence of PC 100 pM.
  • Muscle injury was simulated by mechanical disruption of a culture of C2C12 myoblasts. C2C12 cells were seeded into glass-embedded plates and allowed to grow to confluence. Two hours before the experiment, the cells were starved in serum-free DMEM so that they synchronized. Muscle injury was then simulated by scraping the cells at confluence with a sterile 1000 pL pipette tip. After washing with PBS, the cells were incubated for 6 hours at 37°C with DMEM medium with 10% FBS in the presence or absence of 100 pM PC10.
  • PC 10 is not cytotoxic to C2C12 cells.
  • PC10 Before testing PC10 in the process of muscle differentiation, first was determined the effects of PC10 on cell viability. As shown in Figure 1 , at concentration 100 pM, PC10 did not reduce cell viability compared to untreated control cells, demonstrating that PC 10 was not cytotoxic to C2C12 cells.
  • PC 10 increases the myogenic differentiation of C2C12 cells.
  • C2C12 cells are murine myoblasts derived from satellite cells, which can spontaneously differentiate into myotubes when moved from high-serum medium to low-horse serum medium.
  • C2C12 cells were therefore used to examine the effects of PC10 on myogenic differentiation.
  • the effects of PC10 on the morphological changes of C2C12 cells (such as the loss of their typical triangular morphology and the gradual change in cell shape with the acquisition of an elongated shape) that are associated with the differentiation process (Figure 2).
  • myotubes formation was increased by HS treatment (Figure 2 panel B) compared to control cells ( Figure 2 panel A).
  • PC10 further increased myotubes formation (Figure 2 panel C).
  • PC 10 exerts a hypertrophic effect as measured by enhanced myotubes width and length.
  • the immune-cytological analysis was carried out to identify the a-actinin protein and to measure myotubes width and length.
  • the differentiation of myoblasts in fact involves the exit from the cell cycle, the subsequent alignment of the myoblasts with each other and finally, the fusion between cells to form myotubes, multinucleated syncytia which present most of the characteristics of skeletal muscle fibers.
  • the resulting myotube undergoes a phenotypic change dependent on the activation of muscle-specific genes encoding for proteins such as actin, myosin, troponin and a-actinin.
  • a-actinins constitute the cytoskeleton of the muscle fiber and have the function of maintaining the stability and integrity of the cell membrane during muscle contraction.
  • Myotube width and length were determined at day 6th day of differentiation.
  • PC10 100 pM treatment significantly increased muscle fiber length (panel B) and width (panel A) compared to the HS group (p ⁇ 0.0001 and p ⁇ 0.05, respectively. This effect was associated with the activation of muscle-specific genes, such as a-actinin ( Figure 3).
  • PC 10 protects against dexamethasone-induced muscle atrophy.
  • a muscle tear is an injury to one or more bundles of muscle fibers generally caused by excessive stress on the muscles which exceeds the physiological limit of tension that the muscle can withstand. Following muscle damage, repair and regeneration processes of the muscle begin with the migration of myoblasts to the site of the injury. The aim of this part of the experiments was to simulate a muscle tear on a myoblast cell culture and test the repair activity of PC10.

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Abstract

La présente invention concerne un mélange de glycérol libre et de mono-, di- et triglycérides d'acide nonanoïque destiné à être utilisé dans le traitement de l'atrophie musculaire de la sarcopénie ou d'une lésion musculaire.
PCT/EP2025/069884 2024-07-12 2025-07-11 Mélange de mono-, di- et triglycérides d'acide nonanoïque destiné à être utilisé dans le traitement de l'atrophie musculaire, de la sarcopénie et d'une lésion musculaire Pending WO2026013252A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002083120A2 (fr) * 2001-04-18 2002-10-24 Prometic Biosciences Inc. Acides gras a longueur de chaine moyenne, glycerides et analogues de ces acides, utilises comme facteurs de survie et d'activation des neutrophiles
WO2011115184A1 (fr) * 2010-03-18 2011-09-22 日清オイリオグループ株式会社 Inhibiteur de protéolyse in vivo
WO2020234345A1 (fr) * 2019-05-21 2020-11-26 Société des Produits Nestlé S.A. Butyrate alimentaire
WO2022176677A1 (fr) * 2021-02-19 2022-08-25 株式会社Ｊ－オイルミルズ Composition pour l'amélioration musculaire et son utilisation
WO2022189588A1 (fr) * 2021-03-10 2022-09-15 Nutrition Sciences N.V. Acide pélargonique destiné à être utilisé contre des infections virales

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002083120A2 (fr) * 2001-04-18 2002-10-24 Prometic Biosciences Inc. Acides gras a longueur de chaine moyenne, glycerides et analogues de ces acides, utilises comme facteurs de survie et d'activation des neutrophiles
WO2011115184A1 (fr) * 2010-03-18 2011-09-22 日清オイリオグループ株式会社 Inhibiteur de protéolyse in vivo
WO2020234345A1 (fr) * 2019-05-21 2020-11-26 Société des Produits Nestlé S.A. Butyrate alimentaire
WO2022176677A1 (fr) * 2021-02-19 2022-08-25 株式会社Ｊ－オイルミルズ Composition pour l'amélioration musculaire et son utilisation
WO2022189588A1 (fr) * 2021-03-10 2022-09-15 Nutrition Sciences N.V. Acide pélargonique destiné à être utilisé contre des infections virales

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CINCI ET AL., CANCER MED, vol. 5, no. 6, June 2016 (2016-06-01), pages 1279 - 91
LI ET AL., BIOMED PHARMACOTHER, vol. 167, November 2023 (2023-11-01), pages 115517

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