Composition for the treatment of cystic fibrosis

Abstract

Composition for the treatment of cystic fibrosis [Solution] A composition selected from (4R)-5-(3'-hydroxyphenyl)-γ-valerolactone (MIPV), (4R)-5-(3',4'-dihydroxyphenyl)-γ-valerolactone (DIPV), and mixtures thereof, for the treatment of cystic fibrosis, either alone or in combination with a CFTR protein modulator.

Description

Technical Field

[0001] The present invention relates to a composition for treating cystic fibrosis. In particular, the composition according to the present invention is for treating cystic fibrosis and contains (4R)-5-(3'-hydroxyphenyl)-γ-valerolactone and / or (4R)-5-(3',4'-dihydroxyphenyl)-γ-valerolactone.

Background Art

[0002] Cystic fibrosis is the most common hereditary disease among Caucasians, affecting more than 100,000 people worldwide and approximately 6,000 people in Italy.

[0003] Cystic fibrosis is characterized by chronic inflammation and repeated persistent infections.

[0004] People suffering from cystic fibrosis have two defective copies of the gene encoding a protein called cystic fibrosis transmembrane conductance regulator (CFTR).

[0005] In a normal state, the CFTR protein is produced in the endoplasmic reticulum, matured in the Golgi apparatus, and transported to the cell membrane of the cell, where it performs its function.

[0006] CFTR is a transmembrane channel located inside the cell membrane that allows chloride ions to pass from inside the cell to outside the cell. These ions attract water back to the outer surface of the cell, enabling mucus to maintain its physiological viscosity. A deficiency of chloride ions on the cell surface leads to the formation of mucus with a significantly high viscosity, rendering it unable to perform its physiological function.

[0007] Cystic fibrosis causes changes in the secretions of many organs, such as increased concentration, dehydration, and reduced fluidity, contributing to organ dysfunction. Generally, the bronchi and lungs are the most affected organs. Mucus tends to stagnate within these organs, leading to recurrent infections. Another target organ is the pancreas, which loses its normal function of secreting digestive enzymes into the intestines, leading to diarrhea, malabsorption, growth retardation in children, and malnutrition in adults. Other affected organs include the intestines, liver, nasal cavity, and the vas deferens in men, which can lead to infertility. Sweat gland function is usually impaired. Statistics suggest that the median life expectancy for patients with cystic fibrosis is approximately 40 years.

[0008] Various mutations can cause deficiencies in CFTR protein production. Over 2,000 mutations have been identified to date, and they are classified into the following five classes. 1. Class 1: Protein-producing mutations Nonsense mutations and splice mutations. 2. Class 2: Protein Processing Mutations Deletion mutations and missense mutations. This is the most common gene defect in the population (accounting for about 70% of mutations), caused by a deletion of phenylalanine at position 508 of the CFTR (F508del), resulting in a structural defect that prevents the protein from reaching the cell membrane. For this mutation, a combination of drugs (elexacaftol / tezacaftol / ibacaftol) that enables the correct folding of the channel and the restoration of its function is commercially available. 3. Class 3: Gating mutation A mutation that allows CFTR to reach the cell membrane, but the protein exhibits a defect in channel opening, preventing chloride ions from passing through the epithelial cell membrane. A drug called Ibaftol is commercially available for this class. 4. Class 4: Conductance mutation A CFTR-specific mutation that prevents sufficient transport of chloride ions by the channel. 5. Class 5: Protein Deficiency Mutation Splicing mutations and missense mutations result in the insufficient production of functional proteins. For mutations in this class, ibacaftol and the tezacaftol / ibacaftol combination are approved.

[0009] The drugs cited above are CFTR protein modulators. A description of such drugs can be found in International Publication No. WO2021 / 030556.

[0010] Simply put, there are mainly two types of CFTR modulators: CFTR collectors, which are molecules that can bind to channels, correct defects, and enhance the presence of channels within the cell membrane; and CFTR potenciers, which are molecules that, once channels are positioned within the membrane, can hold the gate and increase the efficiency of chloride ion transport.

[0011] Current treatments are mutation-dependent, blocking CFTR channels with specific mutations, and therefore, drugs addressing all mutation classes are not currently available. Currently, only about 11% of patients with cystic fibrosis have access to drug therapy.

[0012] Although the degree of involvement varies greatly depending on the mutation, all patients with cystic fibrosis share an inflammatory disease that primarily affects the gastrointestinal and respiratory systems, accompanied by persistent lung infections that tend to significantly worsen clinically over time.

[0013] The paper by Mena Pedro et al., "5-(3',4'-dihydroxyphenyl)-[gamma]valerolactone and its sulfate conjugate are representative circulating metabolites of flavan-3-ol and exhibit anti-adhesion activity against urinary tract pathogenic Escherichia coli in bladder epithelial cells," Journal of Functional Foods, Elsevier BV, NL, Vol. 29, January 7, 2017 (2017-01-07), pp. 275-280, XP029886736, ISSN:1756-4646, DOI:10.1016 / J.JFF.2016.12.035, discloses that DIPV inhibits the adhesion of Escherichia coli to bladder epithelial cells. It also discloses that cranberries are a natural source of valerolactone.

[0014] Japanese Patent Publication No. 2018-118939 discloses that DIPV has the effect of lowering blood glucose levels, and also discloses its use as a nutritional supplement and food additive.

[0015] The paper "Efficient and diverse enantioselective synthesis of DHPV and its anti-inflammatory effects on IEC-6 cells" by Kim Hyun Su et al., Molecules, Vol. 25, No. 9, May 8, 2020 (2020-05-08), p. 2215, XP093112902, CH ISSN:1420-049, DOI:10.3390 / molecules25092215, discloses that DHPV has anti-inflammatory effects.

[0016] In the paper "Flavonoid-derived human phenyl[gamma]-valerolactone metabolite selectively detoxifies amyloid[beta] oligomers and prevents memory impairment in a mouse model of Alzheimer's disease" by Ruotolo Roberta et al., Molecular Nutrition & Food Research, Vol. 64, No. 5, January 16, 2020 (2020-01-16), XP093112900, DE ISSN:1613-4125, DOI:10.1002 / mnfr.201900890, it was revealed that MIPV had the effect of reducing the accumulation of A-11-reactive amyloid oligomers in yeast cells, a model of Alzheimer's disease. MIPV was extracted from plant-derived catechins.

[0017] U.S. Patent Application Publication No. 2020 / 179312 discloses compounds useful for the treatment of cystic fibrosis.

[0018] A review by Lopes-Pacheco Miqueias, "CFTR Modulators: Transforming Cystic Fibrosis in the Age of Precision Medicine," Frontiers in Pharmacology, Vol. 10, February 21, 2020 (2020-02-21), XP055910442, CH ISSN:1663-9812, DOI:10.3389 / fphar.2019.01662, discloses compounds used in the treatment of cystic fibrosis. In particular, it describes compounds called collectors, including ibacaftol.

[0019] A review by Hamed Baharara et al., "Therapeutic Potential of Phytochemicals for Cystic Fibrosis," Biofactors, Oxford University Press, Oxford, UK, Vol. 49, No. 5, May 16, 2023 (2023-05-16), pp. 984-1009, XP072509746, ISSN:0951-6433, DOI:10.1002 / BIOF.1960, reviews various phytochemicals that may be used to treat cystic fibrosis. [Prior art documents]

Patent Documents

[0020]

Patent Document 1

Patent Document 2

Patent Document 3

Non-Patent Documents

[0021]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

[0022] In light of the above-mentioned latest technologies, the object of the present invention is to provide an active ingredient that can be used to treat cystic fibrosis, regardless of the underlying gene mutation. [Means for solving the problem]

[0023] Such objectives were achieved by using compositions selected from (4R)-5-(3'-hydroxyphenyl)-γ-valerolactone, (4R)-5-(3',4'-dihydroxyphenyl)-γ-valerolactone, and mixtures thereof, as defined in independent claim 1.

[0024] In one embodiment, the composition according to the present invention is administered alone.

[0025] In one embodiment, the composition according to the present invention is administered as an adjunct to treatment with a CFTR modulator.

[0026] In further embodiments, the present invention relates to a composition for administering the active ingredient according to the present invention in the form of a drug, a food supplement, or a nutritional supplement composition. [Effects of the Invention]

[0027] The features and advantages of the present invention will become apparent from the following detailed description, from the embodiments presented as exemplary and non-limiting examples, and from the following accompanying drawings. [Brief explanation of the drawing]

[0028] [Figure 1] Figure 1 shows the structural formula of gamma-valerolactone, the subject of the present invention, in a ring-closed form of the lactone ring. [Figure 2] Figure 2 shows graphs of cell viability assays performed on HEK293T cells and HT1080 cells under high cell density conditions. [Figure 3] Figure 3 shows Western blot analysis and protein quantification when the concentration of gamma-valerolactone according to the present invention is increased. CFTR and GAPDH are shown as loading markers. The treatment was performed on 16HBE (not shown) cells and CFBE cells. [Figure 4] Figure 4 shows the oxidation events that occur in vivo with gamma-valerolactone administered according to the present invention. [Figure 5] Figure 5 shows the structural formula of gamma-valerolactone, the subject of the present invention, in a ring-opened form of the lactone ring. [Figure 6] Figure 6 shows the Wushing chamber measurement for CFTR chloride current functional analysis. [Modes for carrying out the invention]

[0029] The present invention relates to compositions selected from (4R)-5-(3'-hydroxyphenyl)-γ-valerolactone, (4R)-5-(3',4'-dihydroxyphenyl)-γ-valerolactone, and mixtures thereof, for use in the treatment of cystic fibrosis.

[0030] For the sake of brevity, in the following explanation, (4R)-5-(3'-hydroxyphenyl)-γ-valerolactone (CAS number 21618-91-7) will be referred to as MIPV, and (4R)-5-(3',4'-dihydroxyphenyl)-γ-valerolactone (CAS number 191666-22-5) will be referred to as DIPV.

[0031] The structural formulas for MIPV and DIPV are shown in Figure 1.

[0032] Surprisingly, administration of the composition according to the present invention increases the expression of mutant CFTR channels in the cell membranes of cells in patients with cystic fibrosis to a degree comparable to that of known drugs.

[0033] The main advantage of the proposed treatment according to the present invention is that it is mutation-independent and can be administered to patients with mutations for which there are currently no approved pharmacological treatments. In fact, MIPV and DIPV exert their therapeutic effects without directly blocking the mutated CFTR channel.

[0034] Observing the structural formulas of MIPV and DIPV shown in Figure 1, it is easy to see that the γ carbon atom of the lactone ring is a chiral carbon atom.

[0035] In one embodiment, a racemic mixture is administered for treatment.

[0036] In one embodiment, the enantiomer R is preferably administered.

[0037] In one embodiment, the enantiomer S is administered.

[0038] In one embodiment, the salt is administered.

[0039] In one embodiment, MIPV and / or DIPV are administered with the lactone ring open, and may be administered as an esterified formulation if necessary.

[0040] Extracts derived from grape seeds of various cultivars of European grape (Vitis vinifera L.), containing doctrinally derived polyphenols, have long been used as a treatment for chronic peripheral venous insufficiency and as a supplement / food supplement (nutritional supplement) particularly related to cardiovascular health. Such extracts are known by the trade name Ecovitis® and contain multiple active ingredients. Food supplements in capsule form, based on grape seed extract and labeled to contain 300-600 mg of proanthocyanidins, are available on the market.

[0041] International Publication WO2022 / 144762 of the same applicant as this application describes a process for preparing a grape seed extract from selected unfermented pomace, the extract thus obtained, and its use in dietary supplements and pharmaceutical compositions.

[0042] Grape seed extract is metabolized to MIPV and DIPV by the human metabolome. In other words, MIPV and DIPV are present as prodrugs in the grape seed extract. More than 80% of the total grape seed extract contained in the composition prepared according to International Publication No. WO2022 / 144762 is metabolized to MIPV and DIPV.

[0043] Preferably, the composition according to the present invention is administered in the form of an extract obtained from grape seeds of different cultivars of European grapes.

[0044] The aforementioned metabolites may also be found in other types of plant extracts that are characterized not only by high concentrations of oligopolymer proanthocyanidins but also by several other active molecules. Examples of plant extracts include apple, cranberry, cacao (Theobroma cacao), and maritime pine (Pinus pinaster).

[0045] Ecovitis® is an optimal precursor for the active valerolactones MIPV and DIPV, and contains only proanthocyanidins that primarily possess oligopolymer properties.

[0046] The therapeutic composition for cystic fibrosis according to the present invention is preferably administered in the form of a unit dose. Preferably, the unit dose of the composition according to the present invention is administered at least once a day. For the purposes of the present invention, the term "day" means 24 hours.

[0047] The aforementioned dose unit preferably contains 0.1 mg to 1,000 mg of MIPV and / or DIPV, and more preferably contains 20 mg to 200 mg of MIPV and / or DIPV.

[0048] As explained at the beginning, currently, specific drugs are unavailable for more than 80% of the mutations. Therefore, in one embodiment, the composition according to the present invention is administered alone.

[0049] In a further embodiment, the present invention relates to a pharmaceutical composition substantially comprising MIPV and / or DIPV, or a mixture thereof, or a grape seed extract. The term "substantially comprising" means that MIPV and / or DIPV, or a mixture thereof, is the sole active ingredient present in the composition, and no other ingredients or excipients inhibit its action.

[0050] In a further embodiment, the present invention relates to a nutritional supplement composition or food supplement substantially comprising MIPV and / or DIPV, or a mixture thereof, or grape seed extract. The term "substantially comprising" means that MIPV and / or DIPV, or a mixture thereof, is the sole active ingredient present in the composition, and no other ingredients or excipients inhibit its action.

[0051] In a further embodiment, the present invention relates to the administration of compositions according to the present invention as adjuvants in the treatment of CFTR modulators, particularly elexacaftol, tezacaftol, and ibacaftol. The concomitant administration can be carried out simultaneously, separately, or sequentially.

[0052] The compositions according to the present invention are administered via systemic routes, preferably by oral routes. For oral administration, the components can be mixed with one or more excipients to form, for example, capsules, tablets, softgel capsules, granules, microgranules, pellets, multiplicities, fine particles, powders, solutions, suspensions, dispersions, etc. As is known in this art, the compositions are to which appropriate physiologically acceptable excipients are added.

[0053] Examples of physiologically acceptable excipients include acidulants, acidity modifiers, anticaking agents, antioxidants, bulking agents, resistance agents, gelling agents, coating agents, modified starches, metal ion chelating agents, thickeners, sweeteners, diluents, solvents, dispersants, flow enhancers, colorants, binders, lubricants, stabilizers, adsorbents, preservatives, humectants, fragrances, film-forming agents, emulsifiers, wetting agents, release retarders, and mixtures thereof.

[0054] Preferably, the excipients include starch, modified starch, cellulose, modified cellulose, microcrystalline cellulose, sodium carboxymethylcellulose, pectin, tragacanth gum, mannitol, dicalcium phosphate, xanthan gum, carrageenan, sodium alginate, guar gum, maltodextrin, silicon dioxide, or mixtures thereof.

[0055] Since the electron charge on the γ carbon atom is influenced by the carboxyl group of the lactone ring, it is thought that such a ring-opened form can also exist in vivo. Furthermore, because the active part of the molecule is the phenyl ring, it is thought that MIPV and DIPV (MIPVa and DIPVa, respectively), in which the lactone ring is open, can maintain clinical activity in vivo.

[0056] Examples of the present invention are shown below, but these examples are for illustrative purposes only to demonstrate the non-toxicity and efficacy of MIPV and DIPV in the treatment of cystic fibrosis, and do not impose any limitations. [Examples]

[0057] Example 1. Cell viability assay MIPV and DIPV were tested in human cell lines HT1080 (fibrosarcoma) and HEK293T (human embryonic kidney cells). Cell viability obtained by the rezazurin assay was evaluated using a wide range of concentrations (100 nM to 50 μM) of the composition, and the range of non-toxic concentrations of the composition for use in cell testing was estimated.

[0058] The viability assay was concentrated on two cell lines, HT1080 and HEK293T, which may be more susceptible to the potential toxic effects of the composition. Cells treated with dimethyl sulfoxide (indicated as DMSO in the figure) were used as a control, and the amounts of MIPV and DIPV were increased in stages (100 nM, 200 nM, 375 nM, 1.5 μM, 3 μM, 6 μM, 12 μM, 25 μM, 50 μM). Treatment was carried out for 24 hours.

[0059] In both cases, as shown in Figure 2, MIPV and DIPV were confirmed to be non-toxic, even at particularly high concentrations.

[0060] Example 2. Western blot analysis of CFBE cells Next, we investigated the ability of the composition to directly intervene in CFTR defects in a cystic fibrosis model.

[0061] The aforementioned tests were performed on CFBE cells (CF bronchial epithelial cells with the delF508CFTR mutation), which is a model of cystic fibrosis with the most common mutation.

[0062] In fact, the approved treatment proposed by Vertex is currently available, and this treatment consists of a combination of three drugs (of which VX445 was used as a control in experiments), but all of these drugs target defective channels, and as mentioned above, there is no treatment that can intervene in the majority of mutations, in particular a treatment that can restore intramembrane CFTR channels and readjust the balance of the cellular redox state.

[0063] As described above, under normal conditions, CFTR channels are generated in the endoplasmic reticulum, mature in the Golgi apparatus, and transported to the cell membrane where they perform their function. This maturation corresponds to the degree of glycosylation of the channel. In the case of the delF508CFTR mutation, as with other mutations, the structural defect of the channel prevents maturation in the Golgi apparatus and transport to the membrane. The direct result can be visualized in Western blotting. Indeed, under normal conditions, CFTR exhibits a partially glycosylated band B (150 kDa), primarily located in the endoplasmic reticulum, and a fully glycosylated band C (180 kDa), representing the channel located at the cell membrane. In the case of CFTR mutations, band B is significantly accumulated, while band C is virtually absent. All of this means that Western blotting represents a valid method for direct screening of compositions in cystic fibrosis models, particularly for screening the ability of such compositions to restore mutant CFTR in the cell membrane.

[0064] Specific experiments are shown in Figure 3. CFBE cells were treated with MIPV and DIPV at different concentrations (100 nM, 500 nM, 1 μM) for 24 hours. The controls are shown as dimethyl sulfoxide (DMSO), VX445 (a CFTR modulator currently used in treatment), and R08 (a synthetic composition with antioxidant properties). The results clearly show that VX445 (a drug currently used clinically) is effective in restoring band C (approximately 180 kDa), but also show positive effects from MIPV and DIPV at concentrations of 100 nM and 500 nM for the former composition, and at 500 nM and 1 μM for the latter composition. Furthermore, the increase in band B is noteworthy, indicating that MIPV and DIPV intervention reduced CFTR degradation and increased the proportion of CFTR in the endoplasmic reticulum. This is a very interesting result, as compositions already in clinical use can indeed induce the maturation of band B, paving the way for the combined use of VX445 or similar agents in clinical MIPV and DIPV. As a result, increased accumulation of band B can enhance the effectiveness of treatments currently in use in clinical practice.

[0065] In conclusion, in the cystic fibrosis models examined, MIPV and DIPV were already active at low concentrations. In particular, MIPV and DIPV at concentrations of 100-500 nM to 1 μM were able to restore band C of the delF508 CFTR channel in Western blotting, thus enabling the localization of the channel within the cell membrane.

[0066] Example 3. Representation of oxidation events involving DIPV and MIPV The in vivo actions of the two molecules, DIPV and MIPV, involve oxidation events that utilize the hydroxyl groups on the phenyl rings of both molecules. These oxidation events allow the equilibrium of the enol to change into its ketone body.

[0067] In particular, the schematization of the oxidation of the hydroxyl group of DIPV to the orthoquinone type via an orthodiphenol intermediate is straightforward (Figure 4A). This oxidation is very common in polyhydrophenols. The oxidation of MIPV that provides only one hydroxyl group (Figure 4B) is far more complex. In this event, one electron of the phenyl anion is oxidized, resulting in the generation of a phenoxy radical, which subsequently reacts with molecular oxygen to produce a paraperoxycycloexadienone derivative. Finally, the parabenzoquinone derivative is produced by the loss of one water molecule.

[0068] Finally, Figure 5 shows MIPVa and DIPVa, two types of gamma-valerolactones, in which the lactone ring is open. Because the electron charge on the γ carbon atom is affected by the electron-withdrawing effect of the carboxyl group of the lactone ring, the lactone ring may exist in the body even in an open state. Since the active site of the molecule is the phenyl ring (see Figure 5), MIPVa and DIPVa, even in which the lactone ring is open, may be able to maintain clinical activity in the body.

[0069] In this regard, the ring-opening MIPVa (CAS number 31129-95-0) and DIPVa (CAS number 31129-94-9), both shown in Figure 5, can also be administered in esterified form. The esters of MIPVa and DIPVa preferably include methyl esters or esters containing alkyl chains with 2 to 5 carbon atoms.

[0070] Example 4. Functional analysis of CFTR channels in the Wushing chamber To supplement the data obtained from the above-mentioned tests, a Ussing chamber experiment was conducted. The results are shown in Figure 6. In particular, A represents the short-circuit current (ΔIsc) of a single-layer polarization CFBE-delF treated for 24 hours using 25 μM or 50 μM MIPV or DIPV in combination with VX445 (2 μM) and VX661 (5 μM). Inh172 The following is a list of the results. Error bars represent the mean ± SD (number of tissues). Multiple comparisons were performed using one-way ANOVA with VX445+VX661 (*p<0.05; ***p<0.001). B shows representative traces of Ussing chamber measurements in CFBE-delF epithelial cells treated with VX445+VX661, compared to the case where a collector and 50 μM DIPV were used together.

[0071] In short, CFBE-delF508 cells were densely seeded on a porous membrane (Corning® Costar® Snapwell Insert, 3801) coated with type IV collagen (C7521, Sigma). The cells were cultured in liquid-liquid state in MEM complete medium (10% FBS, 1% PSG, 2 μg / ml puromycin). After 6-7 days, the resistance was 400 Ω·cm. 2 Polarized epithelial cells exceeding a certain value were used in the Ussing chamber experiment. 24 hours prior to analysis, the epithelial cells were treated with either collectors VX445 and VX661 alone, or in combination with MIPV and DIPV (25 μM or 50 μM).

[0072] The Snapwell insert was mounted in a Ussing chamber with the apical half-chamber filled with Ringer's solution (30 mM NaCl, 0.4 mM KH2PO4, 1.6 mM K2HPO4·3H2O, 5 mM glucose, 1 mM MgCl2·6H2O, 1.5 mM CaCl2·2H2O, 90 mM sodium gluconate, 25 mM NaHCO3). In the basal chamber, the NaCl concentration was increased to 120 mM. The solution was maintained at 37°C and continuously bubbling with a 5% CO2-95% O2 gas mixture. During the Ussing experiment, CFTR activity was induced by coating the apical half-chamber with the adenylyl cyclase activator forskolin (FSK, 2 μM) and the phosphodiesterase inhibitor IBMX (100 μM). Both agents promote the activation of PKA (protein kinase A) and subsequent CFTR phosphorylation, ultimately leading to channel opening. Next, a prolonged chloride ion flux passing through the activated CFTR channel was induced using the potentiser VX770 (1 μM). Finally, a selective CFTR inhibitor (CFTRinh-172) (10 μM) was added to inhibit the CFTR-mediated current. In each epithelial cell, the amplitude of the current reduction induced by Inh-172 was comparable to the total activity of the CFTR channels in the epithelium.

[0073] The function of CFTR channels was analyzed in bronchial epithelial cells permanently introduced with the delF508CFTR mutation (CFBE-delF508). This technique was performed in polarized epithelial cells expressing mature CFTR channels on the cell membrane surface, and allowed for the measurement of chloride ion flux from the basolateral to the apical side during CFTR activation within a Ussing chamber.

[0074] Data obtained from CFBE-delF508 epithelial cells treated with MIPV and DIPV for 24 hours demonstrate that these compositions, when used in combination with the collectors (VX445 and VX661) currently used in therapy, statistically significantly induce CFTR activity. In particular, an increase in current was observed after treatment with 50 μM DIPV, indicating an increase in the number of CFTR channels opened into the cell membrane. Therefore, combination therapy with DIPV and a collector enhances CFTR-delF508 channel activity compared to treatment with a collector alone.

Claims

1. A composition selected from (4R)-5-(3'-hydroxyphenyl)-γ-valerolactone (MIPV), (4R)-5-(3',4'-dihydroxyphenyl)-γ-valerolactone (DIPV), and mixtures thereof, for use in the treatment of cystic fibrosis.

2. The composition according to claim 1, wherein the composition is a racemate, an R enantiomer, an S enantiomer, or a salt thereof.

3. The composition according to claim 2, wherein the composition is an R-enantiomer.

4. The composition according to any one of claims 1 to 3, wherein the agent comprises a metabolite that releases the composition, preferably an extract of European grape seeds.

5. The composition according to any one of claims 1 to 4, which is administered as an adjunct to other drugs for the treatment of cystic fibrosis.

6. The composition according to claim 5, wherein the other agent is a CFTR modulator, particularly elexacaftol, tezacaftol, ibacaftol, or a combination thereof.

7. The composition has a ring-opened lactone ring, and optionally a ring-opened lactone ring that has been esterified. The composition according to any one of claims 1 to 6.

8. A food supplement comprising the composition described in claim 1 and a suitable food excipient.

9. A pharmaceutical composition or nutritional supplement composition comprising the composition according to any one of claims 1 to 8 and at least one physiologically acceptable excipient.

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