Compositions suitable for administering creatine esters

Abstract

The present invention provides - at least one creatine ester or creatine ester salt in particulate form; - 50% (w / w) to 80% (w / w) of aqueous solvent; - 10% (w / w) to 40% (w / w) of lipids, The present invention relates to a composition in the form of a microparticle emulsion comprising:

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to compositions useful for the administration of creatine esters or creatine ester salts. [Background technology]

[0002] Technical background Creatine is an endogenous nutrient provided by diet and is also produced naturally by the liver and kidneys of most vertebrates. Creatine is also known as 2-[carbamimidoyl(methyl)amino]acetic acid. It has the nominal formula NH2-C(NH)-N(CH3)-CH2-COOH and the following structure: TIFF2026507848000001.tif24170

[0003] Creatine's primary use is as a supplement to increase muscle mass and enhance muscle performance.

[0004] Creatine is found primarily in muscle, but also in the brain, eyes, testes, and kidneys. In particular, creatine is essential for proper brain function, playing a key role in energy storage and transmission, with additional roles as an anti-apoptotic, antioxidant, neuroprotective, and neuromodulator.

[0005] However, when given as oral supplementation as creatine monohydrate, brain concentration is poor, primarily due to creatine transporters limiting its transfer from blood to the brain and due to high inter-individual variability. Therefore, creatine supplementation to neuronal cells remains a challenge.

[0006] Creatine deficiency involves defects in its biosynthesis by enzymes such as arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT), as well as defects in its intercellular transport, particularly at the brain level. The latter, known as creatine transporter deficiency (CTD), is a neurological disorder caused by defects in the cellular creatine transporter (CrT), encoded by SLC6A8. This disorder is inherited in 70% of cases. It significantly affects brain function, and the primary phenotypic consequences are mental retardation, severe language delay, autistic-like behavior, and seizures. However, other symptoms, such as growth failure, hypotonia, neurological and psychiatric complications, and cardiac and intestinal symptoms, can also be observed. CTD is a rare disease; approximately 20,000 cases are believed to exist, but only a few hundred have been reported in the medical literature to date.

[0007] Various therapeutic approaches have been tested worldwide to address the serious problem of creatine deficiency in the brain cells of CTD patients. To date, none of these approaches have provided significant benefit to CTD patients. In fact, oral administration of creatine monohydrate does not lead to any improvement because this compound cannot penetrate the brain cells of CTD patients. Administration of creatine precursors has also failed, indicating that this therapeutic approach, while effective for other creatine deficiency disorders (e.g., AGAT and GAMT), is not suitable for treating CTD patients.

[0008] Creatine prodrugs, such as creatine fatty esters, have shown promising results in vitro in animals and patient cells, including dodecylcreatine ester (DCE), which may be a good therapeutic option for patients with CTD (Trotier-Faurion et al. (2013) J. Med. Chem. 56:5173-81; Ullio-Gamboa et al. (2019) Nanomedicine 14:1579-12593).

[0009] However, in biological fluids such as plasma or extracellular fluids, creatine esters are rapidly degraded to creatinine by both esterases and by highly efficient non-enzymatic cyclization via intramolecular nucleophilic reactions, which prevents the use of creatine esters, such as creatine ethyl ester, as an effective supplement in CTDs.

[0010] Therefore, to address CTD and other brain energy deficiencies, an efficient delivery system that overcomes the rapid degradation of creatine prodrugs in plasma and extracellular fluids is needed.

[0011] Thus, in International Publication WO 2020 / 221780 it is proposed to formulate a creatine ester or a salt thereof for use in medicine in a composition comprising at least one omega-3 fatty acid or a salt thereof and at least one glyceride, said composition not comprising a non-ionic surfactant.

[0012] However, the amount of creatine ester that can be loaded into this composition and its stability are insufficient, the latter due to inefficient cyclization to creatinine, preventing this formulation from being used as a medicine. Furthermore, this composition is not particularly suitable for administration by spray, which would be the most practical form of nasal administration of creatine ester.

[0013] Therefore, there remains a need for formulations of creatine esters in which the creatine esters are stabilized and can be loaded in large amounts. Summary of the Invention

[0014] Summary of the Invention The present invention is based on the unexpected discovery by the inventors that a lipid-in-water microemulsion containing particulate dodecylcreatine ester (DCE) allows for high stability and high loading of DCE. Furthermore, the microemulsion is suitable for nebulization administration, and efficiently delivers creatine or creatine ester into the brain via the nose-to-brain pathway.

[0015] Therefore, the present invention provides - at least one creatine ester or creatine ester salt in particulate form; - 50% (w / w) to 80% (w / w) of aqueous solvent; - 10% (w / w) to 40% (w / w) of lipids The present invention relates to a composition in the form of a microparticle emulsion comprising:

[0016] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: - at least one creatine ester or creatine ester salt in particulate form; - 50% (w / w) to 80% (w / w) of aqueous solvent; - 10% (w / w) to 40% (w / w) of lipids; - at least one surfactant, wherein the at least one surfactant is present at a concentration of less than 15% (w / w), i.e. the total amount of one or more surfactants present in the composition is present at a concentration of less than 15% (w / w); The present invention relates to a composition in the form of a microparticle emulsion comprising:

[0017] Advantageously, the compositions according to the present invention can contain more creatine ester or creatine ester salt than prior art nasal creatine-containing compositions, i.e., the loading capacity of the compositions according to the present invention is increased. Furthermore, the compositions according to the present invention allow for improved stability of creatine ester or creatine ester salt. Furthermore, the compositions according to the present invention are suitable for aerosol administration and can deliver more creatine or creatine ester to the brain via the nasal route than prior art nasal creatine-containing compositions.

[0018] The present invention also provides a method for preparing a composition in the form of a microparticulate emulsion comprising at least one creatine ester or creatine ester salt in particulate form, comprising the steps of: - adding a solution of at least one surfactant to a first mixture of at least one creatine ester or creatine ester salt and lipid to form a second mixture; - agitating the second mixture to form a particulate emulsion comprising at least one creatine ester or creatine ester salt in particulate form. Including, wherein the at least one surfactant is at a concentration of less than 15% (w / w) in the composition in the form of a microemulsion. [Brief explanation of the drawings]

[0019] [Figure 1] FIG. 1 shows the measured plume (spray) angle in degrees (vertical axis) (RT: room temperature) for four test pumps containing a composition in the form of a microparticle emulsion according to the present invention. [Figure 2] FIG. 2 shows the ellipticity of the spray (ordinate) measured for four test pumps containing a composition in the form of a microparticle emulsion according to the invention (RT: room temperature). [Figure 3] FIG. 3 shows the brain concentration of DCE (vertical axis, units: ng / g) in SLC6A8 KO mice intranasally administered vehicle (KO-Vehicle), a non-particulate DCE formulation (KO-4.4s), or a DCE composition in the form of a particulate emulsion according to the present invention (KO-510). [Figure 4] FIG. 4 shows the brain concentration of creatine (vertical axis, units: ng / g) in SLC6A8 KO mice administered intranasally with vehicle (KO-Vehicle), a non-particulate DCE formulation (KO-4.4s), or a DCE composition in the form of a particulate emulsion according to the present invention (KO-510). [Figure 5] FIG. 5 shows a micrograph (top, polarized light) of a composition in the form of a microparticle emulsion according to the invention, with a DCE concentration of 40 mg / g. DETAILED DESCRIPTION OF THE INVENTION

[0020] Detailed Description of the Invention As intended herein, the word "comprising" is synonymous with "include" or "contain." When a subject matter is said to comprise one or more features, it means that features other than the mentioned features may also be included in the subject matter. Conversely, the phrase "constituted of" is synonymous with "consisting of." When a subject matter is said to consist of one or more features, it means that features other than the mentioned features are not included in the subject matter.

[0021] composition Emulsions, in particular nano- or microemulsions, are well known to those skilled in the art and are described in particular in Ullio-Gamboa et al. (2019) Nanomedicine 14:1579-1593, which is incorporated herein by reference.

[0022] Preferably, the composition according to the present invention does not contain omega-3 fatty acids such as DHA.

[0023] Preferably, the composition according to the present invention further comprises at least one humectant. More preferably, the humectant is selected from the group consisting of talc, silica, vegetable stearin, magnesium stearate, glycerin, stearic acid, and hyaluronic acid (e.g., sodium hyaluronate), and in particular, the humectant is glycerin and / or sodium hyaluronate. Most preferably, the composition comprises 1% (w / w) to 10% (w / w), 2% (w / w) to 7% (w / w), 2.5% (w / w) to 5.5% (w / w), or 3% (w / w) to 5% (w / w) of the humectant.

[0024] Preferably, the composition according to the invention further comprises at least one stabilizer. As will be apparent to those skilled in the art, the term stabilizer relates to emulsion stabilizers. More preferably, the stabilizer is selected from the group consisting of β-lactoglobulin, gum arabic and xanthan gum, in particular the stabilizer is xanthan gum. Most preferably, the composition comprises 0.05% (w / w) to 1% (w / w), 0.1% (w / w) to 0.5% (w / w), or 0.2% (w / w) to 0.4% (w / w) of the stabilizer.

[0025] Preferably, the composition according to the invention further comprises at least one surfactant, in particular at least one non-ionic surfactant. More preferably, the surfactant is selected from the group consisting of polysorbates (e.g., polysorbate 20 or polysorbate 80), cocoglycosides, sugar esters, polyol esters such as sorbitan esters (e.g., Span 80), lecithin, cholesterol, polyethylene glycol and its derivatives, polyglycerol, and creatine dodecyl ester, in particular the surfactant is polysorbate 80. More preferably, the composition according to the invention comprises at least one surfactant in a concentration of less than 15% (w / w), 10% (w / w), 9% (w / w), 8% (w / w), 7% (w / w), 6% (w / w), 5% (w / w), 4% (w / w), 3% (w / w), 2% (w / w), 1% (w / w), 0.5% (w / w), or 0.2% (w / w). (i.e., the total amount of one or more surfactants present in the composition is at a concentration of less than 15% (w / w), 10% (w / w), 9% (w / w), 8% (w / w), 7% (w / w), 6% (w / w), 5% (w / w), 4% (w / w), 3% (w / w), 2% (w / w), 1% (w / w), 0.5% (w / w), or 0.2% (w / w).) Most preferably, the composition comprises between 0.01% (w / w) and 1% (w / w), between 0.05% (w / w) and 0.2% (w / w), or between 0.09% (w / w) and 0.11% (w / w) of surfactant.

[0026] Preferably, the composition according to the present invention further comprises sodium chloride (NaCl), more preferably 0.1% (w / w) to 2% (w / w), 0.5% (w / w) to 1.5% (w / w), or 0.7% (w / w) to 1.0% (w / w) of NaCl.

[0027] Preferably, the aqueous solvent as defined above is water. More preferably, the water is purified water, distilled water, or deionized water. Most preferably, the composition comprises 55% (w / w) to 75% (w / w), 60% (w / w) to 70% (w / w), or 64% (w / w) to 66% (w / w) of water.

[0028] "Lipid" is well known to those skilled in the art and refers to small hydrophobic or amphiphilic molecules, including, among others, fats, waxes, sterols, fat-soluble vitamins, fatty acids, their salts and esters, monoglycerides, diglycerides, triglycerides, phospholipids.

[0029] Preferably, the lipid as defined above is a triglyceride, in particular a medium chain triglyceride, and / or isopropyl myristate. More preferably, the lipid is a medium chain triglyceride. More preferably, the lipid is isopropyl myristate.

[0030] Medium-chain triglycerides are well known to those skilled in the art. Preferably, the medium-chain triglyceride is a triglyceride containing two or three fatty acids having a linear or branched, saturated or unsaturated aliphatic chain of 6 to 12 carbon atoms. Preferably, the fatty acid is selected from the group consisting of caproic acid, caprylic acid, capric acid, and lauric acid.

[0031] Preferably, the composition contains 15% (w / w) to 35% (w / w), 20% (w / w) to 30% (w / w), or 24% (w / w) to 26% (w / w) of medium-chain triglycerides and / or isopropyl myristate. More preferably, the composition contains 15% (w / w) to 35% (w / w), 20% (w / w) to 30% (w / w), or 24% (w / w) to 26% (w / w) of medium-chain triglycerides. More preferably, the composition contains 15% (w / w) to 35% (w / w), 20% (w / w) to 30% (w / w), or 24% (w / w) to 26% (w / w) of isopropyl myristate.

[0032] At least one preservative, such as benzalkonium chloride, may also be included in the pharmaceutical composition defined above.

[0033] Pharmaceutical compositions according to the invention may also include flavoring agents (e.g., to impart strawberry, banana, vanilla, or neroli flavors), taste maskers, or taste enhancers, particularly in concentrations of 0.001% to 0.01%, more particularly 0.002% to 0.003%.

[0034] Preferably, the composition according to the invention is in the form of a microparticle emulsion, - 0.1% (w / w) to 10% (w / w) of creatine esters or creatine ester salts in particulate form; - 64% (w / w) to 66% (w / w) water; - 24%(w / w) to 26%(w / w) of medium-chain triglycerides Includes:

[0035] Creatine esters Preferably, the creatine ester defined above has the following formula (I): (NH2)-C(NH)-N(CH3)-CH2-COOR(I) [Wherein R is - hexosyl groups, in particular glucosyl groups, which may be substituted by at least one group selected from the group consisting of an alkyl group containing 1 to 5 carbon atoms, an aryl group containing 5 to 10 carbon atoms, an alkoxy group containing 1 to 5 carbon atoms, a halogen atom, a cyano group, a trifluoromethyl group or a nitro group; - an alkyl group having 1 to 30 carbon atoms, which may be substituted by at least one group selected from the group consisting of an alkyl group having 1 to 5 carbon atoms, an aryl group having 5 to 10 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, a halogen atom, a cyano group, a trifluoromethyl group, or a nitro group; an alkenyl group containing 2 to 30 carbon atoms, which may be substituted by at least one group selected from the list consisting of an alkyl group containing 1 to 5 carbon atoms, an aryl group containing 5 to 10 carbon atoms, an alkoxy group containing 1 to 5 carbon atoms, a halogen atom, a cyano group, a trifluoromethyl group, or a nitro group; or - an aryl group containing 5 to 30 carbon atoms, which may be substituted with at least one group selected from the list consisting of an alkyl group containing 1 to 5 carbon atoms, an aryl group containing 5 to 10 carbon atoms, an alkoxy group containing 1 to 5 carbon atoms, a halogen atom, a cyano group, a trifluoromethyl group, or a nitro group. represents] It is expressed as:

[0036] Preferably, R represents an alkyl group containing from 6 to 20, more preferably from 8 to 15, carbon atoms.

[0037] Preferably, the creatine ester as defined above is selected from the group consisting of nonyl creatine ester (NCE), decyl creatine ester, undecyl creatine ester, dodecyl creatine ester (DCE), tridecyl creatine ester and tetradecyl creatine ester.

[0038] Preferably, the creatine ester defined above is dodecyl creatine ester (DCE) and / or nonyl creatine ester (NCE). More preferably, the creatine ester defined above is dodecyl creatine ester (DCE). More preferably, the creatine ester defined above is nonyl creatine ester (NCE).

[0039] Preferably, the creatine ester salt is selected from the group consisting of salts of alkali metals, in particular sodium or potassium salts, salts of alkaline earth metals, in particular magnesium or calcium salts, salts of organic amides, more particularly salts of amino acids such as arginine or lysine, salts of inorganic acids, for example salts of hydrochloric acid, sulfuric acid, or hydrobromic acid, and salts of organic acids, for example salts of acetic acid, formic acid, fumaric acid, triflic acid, tartaric acid, oxalic acid, citric acid, trifluoroacetic acid, or methanesulfonic acid.

[0040] As intended herein, the creatine ester or creatine ester salt is in particulate form, i.e., the creatine ester or creatine ester salt is suspended as particles in the emulsion.

[0041] Preferably, the creatine ester or creatine ester salt as defined above is micronized.

[0042] Preferably, the volume average diameter (Dv) of the particles of the creatine ester or creatine ester salt is from about 0.1 μm to about 100 μm.

[0043] Preferably, at least 90% of the particles of creatine ester or creatine ester salt have a mean diameter by volume (Dv) of 1 μm or more, 2 μm or more, 3 μm or more, 4 μm or more, or 5 μm or more.

[0044] Preferably, less than 10% of the particles of the creatine ester or creatine ester salt have a mean diameter by volume (Dv) of 1 μm or less, 2 μm or less, 3 μm or less, 4 μm or less, or 5 μm or less.

[0045] Preferably, at least 90% of the particles of creatine ester or creatine ester salt have a volume mean diameter (Dv) of 50 μm or less, 30 μm or less, or 25 μm or less.

[0046] Preferably, less than 10% of the particles of creatine ester or creatine ester salt have a volume mean diameter (Dv) of 50 μm or more, 30 μm or more, or 25 μm or more.

[0047] Preferably, at least 50% of the particles of the creatine ester or creatine ester salt have a volume mean diameter (Dv) of 5 μm or more, 6 μm or more, 7 μm or more, 8 μm or more, 9 μm or more, 10 μm or more, 11 μm or more, 12 μm or more, 13 μm or more, 14 μm or more, or 15 μm or more.

[0048] Preferably, less than 50% of the particles of the creatine ester or creatine ester salt have a mean diameter by volume (Dv) of 5 μm or less, 6 μm or less, 7 μm or less, 8 μm or less, 9 μm or less, 10 μm or less, 11 μm or less, 12 μm or less, 13 μm or less, 14 μm or less, or 15 μm or less.

[0049] Preferably, the volume mean diameter (Dv) distribution of the particles of the creatine ester or creatine ester salt is as follows:

[0050] Dv(10) is 2 to 6 μm, preferably 2 to 4 μm, more preferably 2 to 3 μm;

[0051] Dv(50) is 7 to 13 μm, preferably 7 to 10 μm, more preferably 7 to 9 μm; and

[0052] Dv(90) is 20 to 30 μm.

[0053] Preferably, the average width (W) of the particles of the creatine ester or creatine ester salt is from about 0.1 μm to about 100 μm.

[0054] Preferably, at least 90% of the particles of creatine ester or creatine ester salt have an average width (W) of 0.5 μm or greater, 2.5 μm or greater, or 8 μm or greater.

[0055] Preferably, less than 10% of the particles of creatine ester or creatine ester salt have an average width (W) of 0.5 μm or less, 2.5 μm or less, or 8 μm or less.

[0056] Preferably, at least 90% of the particles of creatine ester or creatine ester salt have an average width (W) of 6 μm or less, 8 μm or less, or 25 μm or less.

[0057] Preferably, less than 10% of the particles of creatine ester or creatine ester salt have an average width (W) of 6 μm or more, 8 μm or more, or 25 μm or more.

[0058] Preferably, at least 50% of the particles of creatine ester or creatine ester salt have an average width (W) of 2.75 μm or greater, 5 μm or greater, or 15 μm or greater.

[0059] Preferably, less than 50% of the particles of creatine ester or creatine ester salt have an average width (W) of 2.75 μm or less, 5 μm or less, or 15 μm or less.

[0060] Preferably, the average width (W) distribution of the particles of the creatine ester or creatine ester salt is as follows:

[0061] W(10) is 0.5 to 8 μm, preferably 2 to 7 μm, more preferably 0.5 to 2.5 μm;

[0062] W(50) is 2.75 to 15 μm, preferably 6 to 12 μm, more preferably 2.75 to 5 μm; and

[0063] W(90) is 6 to 25 μm, preferably 10 to 22 μm, and more preferably 6 to 8 μm.

[0064] Preferably, the average length (L) of the particles of the creatine ester or creatine ester salt is from about 0.1 μm to about 100 μm.

[0065] Preferably, at least 90% of the particles of creatine ester or creatine ester salt have an average length (L) of 0.5 μm or more, 2.5 μm or more, or 7 μm or more.

[0066] Preferably, less than 10% of the particles of creatine ester or creatine ester salt have an average length (L) of 0.5 μm or less, 2.5 μm or less, or 7 μm or less.

[0067] Preferably, at least 90% of the particles of creatine ester or creatine ester salt have an average length (L) of 18 μm or less, 22 μm or less, or 40 μm or less.

[0068] Preferably, less than 10% of the particles of creatine ester or creatine ester salt have an average length (L) of 18 μm or more, 22 μm or more, or 40 μm or more.

[0069] Preferably, at least 50% of the particles of creatine ester or creatine ester salt have an average length (L) of 5 μm or more, 9 μm or more, or 20 μm or more.

[0070] Preferably, less than 50% of the particles of creatine ester or creatine ester salt have an average length (L) of 5 μm or less, 9 μm or less, or 20 μm or less.

[0071] Preferably, the average length (L) distribution of the particles of the creatine ester or creatine ester salt is as follows: L(10) is 0.5 to 7 μm, preferably 0.5 to 2.5 μm; L(50) is 5 to 20 μm, preferably 5 to 9 μm; and L(90) is 18 to 40 μm, preferably 18 to 22 μm.

[0072] Methods for determining the volume mean diameter (Dv), mean width (W), mean length (L) of particles, and the Dv, W, and L distributions are well known to those skilled in the art and involve microscopy techniques, in particular using a Malvern Morphologi 4 or Morphology G3S instrument, or laser diffraction techniques, in particular using a Malvern Mastersizer 3000 Hydro MV instrument.

[0073] Preferably, the composition according to the invention comprises 0.1% (w / w) to 10% (w / w), 1% (w / w) to 8% (w / w), or 2% (w / w) to 6% (w / w) of creatine ester or creatine ester salt.

[0074] Preferably, the composition according to the invention comprises: - 3-5% (w / w) micronized DCE, hydrochloride; - 60-70% (w / w) purified water; - 0.5-1.0% (w / w) sodium chloride; - 1.0-6.0% (w / w) glycerin (4811); - 0.1-0.3% (w / w) sodium hyaluronate; - 20-30% (w / w) of triglyceride-based lipids (Kollisolv® MCT70, BASF); - 0.1-0.5% (w / w) xanthan gum; - 0.05 to 0.20% (w / w) of polysorbate 80, - Optionally 0.01-0.05% (w / w) neroli Includes:

[0075] Therapeutic Use Preferably, the composition according to the invention is a pharmaceutical composition or a medical device.

[0076] Preferably, the pharmaceutical composition or medical device as defined above further comprises at least one pharmaceutically acceptable vehicle, carrier or excipient, particularly suitable for administration by topical or nasal route.

[0077] Preferably, the compositions according to the invention are suitable for administration by nebulization. The nebulizer may be a single-dose, double-dose, or multi-dose device.

[0078] Preferably, the composition according to the invention is a dermatological composition.

[0079] Preferably, the compositions according to the invention, in particular the dermatological compositions, are suitable for topical administration, in particular by means of a spray, cream, ointment, gel or balm.

[0080] Preferably, the compositions according to the invention are administered in unit doses of 50 μL to 2 mL.

[0081] Preferably, the composition according to the invention is for pharmaceutical use.

[0082] Preferably, the dermatological composition according to the invention is for use as a dermatological medicine.

[0083] Preferably, the composition according to the invention is for use in the prevention or treatment of creatine deficiency, such as creatine transporter deficiency (CTD) syndrome, GAMT deficiency, or AGAT deficiency, mitochondrial diseases such as Leich Syndrome, Leber's Hereditary Optic Neuropathy or MELAS syndrome, neurodegenerative diseases, in particular Parkinson's disease and related disorders, or multiple system atrophy (MSA), neuromuscular disorders, hypoxia, ischemic brain diseases such as stroke, cardiovascular diseases, muscular dystrophies, skin disorders such as atopic dermatitis or skin damage, amyotrophic lateral sclerosis, adrenoleukodystrophy, leukodystrophy, Rett syndrome, Kabuki syndrome, or inflammation.

[0084] More preferably, the composition according to the invention is for use in the prevention or treatment of creatine transporter deficiency (CTD).

[0085] Cosmetic use Preferably, the composition according to the invention is a cosmetic composition.

[0086] The present invention also relates to the use of a composition according to the invention as a cosmetic or for cosmetic applications.

[0087] When used as a cosmetic composition, the composition according to the present invention is preferably applied topically to the skin of an individual, more preferably a human individual, in particular by spraying, cream, ointment, gel or balm. The cosmetic use of the composition according to the present invention is intended to improve the appearance of the skin to which it is applied. In this case, the individual is preferably not suffering from a disease, in particular a skin disease, that can be treated by the composition according to the present invention.

[0088] individual Preferably, the compositions according to the invention should be administered to individuals who are mammals, particularly humans.

[0089] method Preferably, the solution containing at least one surfactant further contains NaCl and / or at least one humectant. The solvent of the solution is an aqueous solvent, preferably water.

[0090] Preferably, a solution of at least one stabilizer is mixed with the microparticle emulsion.

[0091] The present invention is further illustrated by the following non-limiting figures and examples. [Example]

[0092] Example 1. Preparation of microparticle emulsion of dodecylcreatine ester (DCE) A composition is prepared comprising the following ingredients: TIFF2026507848000002.tif52170

[0093] Briefly, a first mixture (Mixture 1) is prepared as follows: In a beaker, dissolve NaCl in water. Add glycerol and polysorbate 80 and stir using a magnetic stir bar until completely dissolved and a homogeneous mixture is obtained.

[0094] A second mixture (Mixture 2) is prepared as follows: In a beaker, dissolve the DCE hydrochloride in the medium-chain triglyceride using a magnetic stir bar until completely dissolved and a homogeneous mixture is obtained.

[0095] Mixture 1 is mixed with Mixture 2 while stirring (magnetic stir bar) to obtain a third mixture (Mixture 3) while stirring as follows: Place the Ultraturax in the beaker containing the water phase (mixture 1) and slowly pour in the oil phase (mixture 2) while stirring with the Ultraturax. Mix until a white emulsion phase is obtained. Then gradually reduce the speed of the Ultraturax and stop it.

[0096] A fourth mixture (Mix 4) is made as follows: Dissolve the xanthan gum in the water in a beaker using a magnetic stir bar until completely dissolved.

[0097] Finally, Mixture 3 is mixed with Mixture 4 to obtain a uniform emulsion as follows: Slowly pour Mixture 4 into Mixture 3 while stirring with the Ultraturax. Add the taste masker. Mix until a completely homogeneous emulsion is achieved. Allow to stand and check the emulsion homogeneity under a microscope (Figure 5).

[0098] Alternatively, the first mixture (Mixture 1) is prepared as follows: In a beaker, dissolve NaCl in water. Then, using a magnetic stir bar, dissolve the xanthan gum in the water until it is completely dissolved. Add the glycerol and polysorbate 80 and stir using a magnetic stir bar until completely dissolved, resulting in a homogeneous mixture.

[0099] A second mixture (Mixture 2) is prepared as follows: In a beaker, dissolve the DCE hydrochloride in the medium-chain triglyceride using a magnetic stir bar until completely dissolved and a homogeneous mixture is obtained.

[0100] Mixture 1 is mixed with Mixture 2 while stirring (magnetic stir bar) to obtain a third mixture (Mixture 3) while stirring as follows: Place the Ultraturax into the beaker containing the water phase (Mixture 1) and slowly incorporate the oil phase (Mixture 2) while stirring with the Ultraturax. Mix until a uniform white microemulsion is obtained. Then gradually reduce the speed of the Ultraturax to a stop. Add the taste masker. Mix until a completely uniform emulsion is obtained. Let stand and check the uniformity of the microemulsion under a microscope (Figure 5).

[0101] 2. Administration of the composition by spraying The composition was sprayed using multiple pumps as follows: TIFF2026507848000003.tif27170

[0102] Atomization was evaluated by calculating plume angle, plume ellipticity, and uniformity of delivery.

[0103] 2.1. Spray angle The spray angle is determined from the tangent to the spray cone at a position 60 mm from the tip of the spray nozzle.

[0104] The plume angle measurements (in degrees) for the four pumps using fine particle emulsion are shown in Figure 1 and Table 1 below: TIFF2026507848000004.tif47170

[0105] A large spray angle is required. In this example, the fine emulsion for spraying allows all pumps to obtain a large spray angle, the pump PFP N from SILGAN shows a larger spray angle, and the VP7 CB18 pump from APTAR is also efficient for spraying fine emulsion.

[0106] 2.2.Spray ellipticity The spray ovality is obtained from the spray pattern calculated at a position 6 cm from the tip of the pump. The spray ovality is calculated by the formula: Dmax / Dmin.

[0107] The spray ellipticity of the four pumps using fine particle emulsions was measured for spraying at different temperatures and the results are shown in Figure 2 and Table 2 below: TIFF2026507848000005.tif42170

[0108] An ovality close to 1 is required. In this example, all tested pumps produced good quality spray ovality, with the APTAR VP7-CB18 pump being slightly better.

[0109] 2.3. Uniformity of delivery - Uniformity of delivered dose due to complete emptying of the pump The delivered dose was weighted over the pump's life cycle. Each set of experiments was performed by two different researchers to account for potential interindividual variability. Some experiments were performed at room temperature or after storing the device at 4°C for at least 24 hours.

[0110] CPS (APTAR), VP7 CB18 (APTAR), and 3K (URSATEC) delivered consistent doses during the first 70 actuations.

[0111] - Uniformity of delivered dose according to the European Pharmacopoeia The uniformity of the delivered DCE dose was measured in association with the microemulsion and three pumps: APTAR CPS, APTAR VP7 CB18, and APTAR CPS. The study was performed according to the European Pharmacopoeia for nasal formulations.

[0112] DCE content was quantified in the delivery formulation for 10 pump actuations (3 at the beginning, 4 in the middle, and 3 at the end of pump life). The results are shown in Tables 3-5 below: TIFF2026507848000006.tif69170

[0113] TIFF2026507848000007.tif70170

[0114] TIFF2026507848000008.tif70170

[0115] The European Pharmacopoeia's approval criteria for nasal preparations are as follows: - The average delivered dose is 85-115% of the target dose; - Activation will occur a maximum of 1 time outside the range of 75% to 125% of the target, and no activation will occur outside the range of 65% to 135%.

[0116] All criteria were met for the three pump / microemulsion combinations tested.

[0117] 4. Stability of DCE in microemulsions The chemical stability of DCE in the microemulsions was monitored using an HPLC / UV method at 4° C. and room temperature, and the results are shown in Tables 6-7 below: TIFF2026507848000009.tif45170

[0118] DCE is stable for more than 3 months when stored in a refrigerator (4°C), and extrapolation using the slope of the decay indicates that more than 95% should remain over 18 months. TIFF2026507848000010.tif48170

[0119] DCE is stable for over 20 days when stored at room temperature (20-25°C), with extrapolation using the decay slope indicating that over 99% remains over one month.

[0120] From the above, the microparticle emulsion of the present invention is suitable for long-term storage in a refrigerator. The good short-term stability at room temperature allows the microparticle emulsion to be stored outside the refrigerator for at least one month.

[0121] 5. Effectiveness of Creatine Delivery to the Brain Three groups of SLC6A8 knockout (KO) mice were administered intranasally with vehicle (the same emulsion without DCE), a DCE emulsion (KO-4.4s) in which the formation of DCE particles was limited by a high concentration of surfactant (polysorbate 80) and dissolution was also promoted, and a composition of the present invention in the form of a microparticle emulsion of DCE (KO-510). TIFF2026507848000011.tif39170

[0122] Briefly, formulations KO-4.4s and KO-510 contained 40 mg / ml and 38 mg / ml DCE, respectively, and 10 μL of formulation was delivered to each nostril once daily for one month.

[0123] DCE and its active metabolite, creatine, were then detected by LC / MS / MS in one brain hemisphere of each mouse. The results are reported in Figures 3-4.

[0124] The brain concentrations of DCE and creatine were higher in the group of mice administered the nebulizable microemulsion of the present invention (i.e., KO-510), demonstrating that the composition in the form of a microemulsion of the present invention is more efficient in delivering DCE and its active metabolite, creatine, to the brain, particularly via the nasal route by nebulization.

[0125] Furthermore, safety studies carried out in animals have shown that the microparticle emulsion according to the invention administered via the nasal route is safe, i.e. well tolerated by the nasal mucosa (rats at 6 mg / kg / day and dogs at 1 mg / kg / day, both via the nasal route for 30 days), but that formulation KO-4.4s induces local toxicity in the nasal cavity (cynomolgus monkeys at 0.9-2.3 mg / kg / day for 30 days), as histopathological studies show cellular inflammation, necrosis, and the presence of cellular debris and / or exudates.

Claims

1. A composition in the form of a microemulsion, comprising: at least one creatine ester or creatine ester salt in particulate form; - 50% (w / w) to 80% (w / w) of an aqueous solvent; 10% (w / w) to 40% (w / w) of lipids A composition comprising:

2. The composition of claim 1 , which is free of omega-3 fatty acids.

3. 3. The composition of claim 1, further comprising at least one humectant.

4. 4. The composition of claim 1, further comprising at least one stabilizer.

5. 5. The composition according to claim 1, further comprising at least one surfactant, in particular at least one non-ionic surfactant, more particularly at a concentration of less than 15% (w / w).

6. 6. The composition of claim 1, further comprising sodium chloride (NaCl).

7. 7. The composition of claim 1, wherein the aqueous solvent is water.

8. 8. A composition according to any one of claims 1 to 7, wherein the lipid comprises or consists of a triglyceride, in particular a medium chain triglyceride.

9. The creatine ester has the following formula (I): NH ２ -C(NH)-N(CH) ３ )-CH ２ -COOL(I) wherein R is a hexosyl group, optionally substituted by at least one group selected from the list consisting of an alkyl group containing 1 to 5 carbon atoms, an aryl group containing 5 to 10 carbon atoms, an alkoxy group containing 1 to 5 carbon atoms, a halogen atom, a cyano group, a trifluoromethyl group or a nitro group; - alkyl groups containing 1 to 30 carbon atoms, which may be substituted by at least one group selected from the list consisting of alkyl groups containing 1 to 5 carbon atoms, aryl groups containing 5 to 10 carbon atoms, alkoxy groups containing 1 to 5 carbon atoms, halogen atoms, cyano groups, trifluoromethyl groups or nitro groups; an alkenyl group containing 2 to 30 carbon atoms, which may be substituted by at least one group selected from the list consisting of an alkyl group containing 1 to 5 carbon atoms, an aryl group containing 5 to 10 carbon atoms, an alkoxy group containing 1 to 5 carbon atoms, a halogen atom, a cyano group, a trifluoromethyl group or a nitro group; or an aryl group containing 5 to 30 carbon atoms, which may be substituted by at least one group selected from the list consisting of an alkyl group containing 1 to 5 carbon atoms, an aryl group containing 5 to 10 carbon atoms, an alkoxy group containing 1 to 5 carbon atoms, a halogen atom, a cyano group, a trifluoromethyl group or a nitro group; represents The composition according to any one of claims 1 to 8, wherein

10. 10. The composition of claim 1, wherein the creatine ester is dodecyl creatine ester (DCE) and / or nonyl creatine ester (NCE).

11. 11. The composition of claim 1, wherein the creatine ester or creatine ester salt is micronized.

12. 12. A composition according to any one of claims 1 to 11, comprising from 0.1% (w / w) to 10% (w / w) of a creatine ester or creatine ester salt.

13. 13. A composition according to any one of claims 1 to 12, which is suitable for administration by aerosol.

14. 14. The composition of any one of claims 1 to 13, which is a pharmaceutical composition or a medical device.

15. 15. A composition according to any one of claims 1 to 14 for use as a medicine.

16. 15. A composition according to any one of claims 1 to 14, for use in the prevention or treatment of creatine deficiency; mitochondrial diseases such as Leigh syndrome, Leber's hereditary optic neuropathy or MELAS syndrome; neurodegenerative diseases, in particular Parkinson's disease and related diseases, or multiple system atrophy (MSA); neuromuscular disorders; hypoxia; ischemic brain diseases, such as stroke; cardiovascular diseases; muscular dystrophy; skin disorders, such as atopic dermatitis or skin damage; amyotrophic lateral sclerosis; adrenoleukodystrophy; leukodystrophy; Rett syndrome; Kabuki syndrome; or inflammation.

17. 17. The composition of claim 16, for use in the prevention or treatment of creatine transporter deficiency (CTD).

18. 1. A method for preparing a composition in the form of a microparticulate emulsion comprising at least one creatine ester or creatine ester salt in particulate form, comprising: - adding a solution of at least one surfactant to a first mixture of at least one creatine ester or creatine ester salt and lipid to form a second mixture; agitating the second mixture to form a particulate emulsion comprising at least one creatine ester or creatine ester salt in particulate form; Including, wherein the at least one surfactant is at a concentration of less than 15% (w / w) in the composition in the form of a microparticle emulsion.

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