Solid Formulations of 1,2,4-Oxadiazole Derivatives

Abstract

The present invention provides At least one 1,2,4-oxadiazole derivative of formula (I): [Formula 1] TIFF2022541554000011.tif65162 (in the formula, R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 thioalkyl, and Citric acid and / or saccharin A solid formulation comprising: the molar ratio between the total amount of citric acid and / or saccharin and the amount of the 1,2,4-oxadiazole derivative in the solid formulation is in the range of about 2 to about 20; Concerning solid formulations. The present invention also relates to a process for producing the solid compositions according to the invention and to a process for increasing the physical stability of the 1,2,4-oxadiazole derivatives of formula (I).

Description

[Technical field]

[0001] The present invention relates to solid formulations of 1,2,4-oxadiazole derivatives containing only two monocyclic tertiary amine groups in association with citric acid and / or saccharin.

[0002] The present invention also relates to a process for producing a solid composition according to the invention, comprising a step of mixing a 1,2,4-oxadiazole derivative containing only two monocyclic tertiary amine groups with citric acid and / or saccharin, as well as to solid formulations obtainable from said process.

[0003] The present invention also relates to a method for increasing the physical stability of a 1,2,4-oxadiazole derivative containing only two monocyclic tertiary amine groups, comprising the step of mixing the 1,2,4-oxadiazole derivative with citric acid and / or saccharin. [Background technology]

[0004] Cardiometabolic diseases are the most common cause of death worldwide. They account for 32% of all causes of death before cancer and chronic respiratory diseases, affecting over 100 million people. It is projected to result in over 25 million deaths in 2030, compared to 17.5 million deaths in 2005. It is estimated that in the United States, one in four adults is affected, and in Europe, 15% of adults are affected.

[0005] A widespread cardiometabolic disorder is type 2 diabetes or non-insulin-dependent diabetes mellitus. This diabetes is the most common form, since it affects about 90% of diabetic patients. The disease affects all age groups, but its frequency increases with age. For example, the incidence of the disease is 25% in the United States over 65 years old and in France over 75 years old. On a global basis, the incidence of diabetes in adults has increased from 4.7% in 1980 to 8.5% in 2015. Mortality directly related to diabetes is estimated at 1.6 million deaths / year. Moreover, recent studies have shown that diabetes is associated in 60% of cases with the emergence of many other cardiometabolic risks, such as hypertension, overweight, and even obesity and dyslipidemia. Thus, the search for a treatment for type 2 diabetes remains a major challenge to this day.

[0006] It is known that GLP-1 peptide receptor is related to cardiovascular disease and eating disorders such as diabetes, obesity or anorexia.In addition, GLP-1 receptor is also directly and indirectly related to brain disorders, especially neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and psychiatric disorders such as schizophrenia and mood disorders.Therefore, patent application WO 2012 / 101292 (VIVIABIOTECH SL) discloses 1,2,4-oxadiazole derivatives for preventing and / or treating diseases involving or mediated by GLP-1 receptor, which may be beneficial for the treatment of diabetes.

[0007] However, the disclosed 1,2,4-oxadiazole derivatives are not convenient for widespread medical use because they exist in the form of oils or deliquescent solids. Such physical forms are a significant limitation for the industrial manufacturing process of drugs derived from these active ingredients, since oils or deliquescent solids are not convenient in terms of handling (transfer, mixing, washing) and quality control (e.g. in-line automated analysis), especially compared to homogeneous and stable liquids or powders. Storage between the manufacture of the active ingredient and the further manufacture of the pharmaceutical composition containing it is also more difficult with oils or deliquescent solids.

[0008] It would therefore be advantageous to obtain the 1,2,4-oxadiazole derivatives disclosed in WO 2012 / 101292 in a more convenient physical form.

[0009] The applicant has carried out thorough research to solve the technical problem of the physical stability of 1,2,4-oxadiazole derivatives. In particular, it has been attempted to utilize the presence of tertiary amine functional groups of 1,2,4-oxadiazole derivatives to prepare mono- or di-addition salts that may be required to stabilize the intramolecular structure of 1,2,4-oxadiazole derivatives. Unfortunately, contacting organic or inorganic acids with 1,2,4-oxadiazole derivatives often results in another sticky oil or a hygroscopic solid that leads to rapid deliquescence (as shown in the comparative example below). Thus, it was thought that physically stable addition salts of 1,2,4-oxadiazole derivatives could not be easily formed.

[0010] Surprisingly, however, the Applicant has found that solid formulations can be obtained by mixing citric acid and / or saccharin with a 1,2,4-oxadiazole derivative containing two monocyclic tertiary amine groups, and that the solid formulations thus formulated remain physically stable over time beyond expectation. Summary of the Invention

[0011] The present invention relates to Approximately 75(w / w)% to approximately 100(w / w)% At least one 1,2,4-oxadiazole derivative of formula (I): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , and R 5are each independently selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 thioalkyl; and Citric acid and / or saccharin A solid formulation comprising: the molar ratio between the total amount of citric acid and / or saccharin and the amount of 1,2,4-oxadiazole derivative in the solid formulation is in the range of about 2 to about 20; Concerning solid formulations.

[0012] The present invention also relates to a solid formulation obtainable by mixing at least one 1,2,4-oxadiazole derivative as defined herein above with citric acid and / or saccharin, in which the initial molar ratio between the total amount of citric acid and / or saccharin and the amount of 1,2,4-oxadiazole derivative ranges from about 2 to about 20, and the solid formulation comprises a total amount of 1,2,4-oxadiazole derivative and citric acid and / or saccharin ranging from about 75 (w / w)% to about 100 (w / w)%, Concerning solid formulations.

[0013] In one embodiment, R 1 , R 2 , R 4 , and R 5 is hydrogen and R 3 is C1-C3 haloalkyl, preferably C1-C3 fluoroalkyl.

[0014] In one embodiment, the 1,2,4-oxadiazole derivative has the formula (A): [ka] It is a compound of the formula:

[0015] In one embodiment, the molar ratio is in the range of about 2 to about 10. In one embodiment, the molar ratio is in the range of about 2 to about 5. In one particular embodiment, the molar ratio is about 2.

[0016] The present invention also relates to a process for producing a solid composition according to the invention, comprising a step of mixing at least one 1,2,4-oxadiazole derivative as defined hereinabove with citric acid and / or saccharin, wherein the initial molar ratio between the total amount of citric acid and / or saccharin and the amount of 1,2,4-oxadiazole derivative is in the range of about 2 to about 20, preferably in the range of about 2 to about 5.

[0017] The present invention also relates to a method for increasing the physical stability of at least one 1,2,4-oxadiazole derivative as defined herein above, comprising a step of mixing the 1,2,4-oxadiazole derivative with citric acid and / or saccharin, wherein the initial molar ratio between the total amount of citric acid and / or saccharin and the amount of the 1,2,4-oxadiazole derivative is in the range of about 2 to about 20, preferably in the range of about 2 to about 5, and no solvent is present during the mixing step. In one embodiment, the mixing is stirring and / or grinding.

[0018] The present invention also relates to a pharmaceutical composition comprising the solid formulation according to the present invention and at least one pharma- ceutically acceptable excipient. In one embodiment, the at least one pharma- ceutically acceptable excipient does not comprise citric acid and saccharin. The present invention also relates to the solid formulation according to the present invention or the pharmaceutical composition according to the present invention for use as a medicament.

[0019] The present invention also relates to a solid formulation according to the invention or a pharmaceutical composition according to the invention for use in the treatment and / or prevention of a disease in which the GLP-1 receptor is involved or mediated. In one embodiment, the disease is metabolic disorders, e.g. diabetes or obesity; Diseases induced by or associated with metabolic disorders, such as diabetic neuropathy, diabetic retinopathy, glaucoma, cataracts, diabetic nephropathy, or diabetic foot ulcers; cardiovascular disease, such as coronary artery disease, stroke, heart failure, hypertensive heart disease, or congenital heart disease; Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple system atrophy, Huntington's disease, optic nerve degeneration, and movement disorders, neuromuscular diseases, or cognitive deficiencies; and Neurological or neuropsychiatric disorders, such as epilepsy, schizophrenia, bipolar disorder, depression, or pain is selected from.

[0020] definition For the purposes of the present invention, the following terms have the following meanings.

[0021] The word "about" preceding a number means plus or minus 10% of that number.

[0022] "Alkoxy" refers to a radical of the formula -O-alkyl.

[0023] "Alkyl" refers to any saturated straight or branched hydrocarbon chain having 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl and its isomers (e.g., n-pentyl or i-pentyl), or hexyl and its isomers (e.g., n-hexyl or i-hexyl). Preferably, the alkyl is ethyl or methyl, more preferably methyl.

[0024] "Amine" refers to a group containing the functional groups -NH2 (primary amine), -NHR (secondary amine), or -NRR' (tertiary amine), where R and R' are each different from hydrogen. Preferably, R and R' are independently alkyl groups. Amines can be linear or branched, alicyclic or cyclic (monocyclic or polycyclic).

[0025] "Deliquescence" describes the process by which a solid absorbs ambient humidity (H2O present in the air) until it dissolves in the absorbed liquid to form a solution. Deliquescence occurs when the vapor pressure of the solution formed by absorption is lower than the partial pressure of water vapor in the air. Substances that absorb moisture from the air up to their melting point are called "deliquescent." Substances that absorb moisture from the air, but not necessarily to their melting point, are called "hygroscopic."

[0026] "Haloalkyl" refers to an alkyl group as defined hereinabove in which at least one hydrogen atom is replaced by a halogen atom selected from fluoride, chloride, bromide, and iodine. Preferably, each halogen atom in the haloalkyl is a fluoride, i.e., the haloalkyl is a "fluoroalkyl."

[0027] "Hygroscopy" describes the process by which a solid absorbs ambient humidity (H2O present in the air). If the material eventually dissolves in the absorbed liquid to form a solution, the hygroscopy is called "deliquescence". Substances that absorb moisture from the air, but not necessarily to the point of dissolution, are called "hygroscopic".

[0028] "Pharmaceutically acceptable" as used in conjunction with components of a composition means that the components of a pharmaceutical composition are compatible with each other and not deleterious to a subject to which the pharmaceutical composition is administered.

[0029] A "pharmaceutically acceptable excipient" refers to an excipient or vehicle that does not produce adverse, allergic, or other undesirable reactions when administered to a subject, preferably a human. This includes any solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. For human administration, preparations must meet sterility, pyrogenicity, general safety, and purity standards as required by regulatory agencies, such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA).

[0030] "Pharmaceutical composition" refers to a composition comprising at least one pharma- ceutical active agent in association with at least one pharma- ceutical acceptable excipient. The pharmaceutical composition is for therapeutic use and is related to health. In particular, the pharmaceutical composition may be for treating a disease selected from eating disorders, such as obesity.

[0031] "Physical stability" of a solid refers to the absence of deliquescence and melting of a substance at room temperature (about 20°C) in air. Melting of a solid substance is avoided if the melting point of the substance is higher than the atmospheric temperature. Physical stability is considered to be achieved when at least 90 (w / w)%, preferably at least 95 (w / w)%, more preferably at least 99 (w / w)%, and even more preferably at least 99.9 (w / w)% of the substance shows no deliquescence or melting. Preferably, a physically stable substance should have low moisture absorption.

[0032] "Solid" refers to a substance whose melting point is greater than 25° C. at atmospheric pressure (1 atm, ie 101325 Pa).

[0033] "Specific surface area" is the total surface area of ​​a substance per unit mass (m 2 / g), which can be measured, for example, by BET (Brunauer, Emmett and Teller) analysis.

[0034] "Subject" refers to a warm-blooded animal, preferably a mammal, more preferably a human.Preferably, the subject is a patient, i.e., a subject who is waiting for medical treatment, or is receiving medical treatment, or is / may be a subject of medical treatment now / in the future.For example, the subject may be treated for an eating disorder, such as obesity.

[0035] "Therapeutic agent," "active agent," and "pharmacologically active agent" are synonymous and refer to compounds for therapeutic use and are health related. In particular, therapeutic agents may be designated for treating eating disorders, such as obesity.

[0036] "Thioalkyl" refers to a radical of the formula -S-alkyl.

[0037] "Treating" or "treatment" or "alleviation" refers to both therapeutic treatment and preventative or prophylactic measures, the purpose of which is to prevent or delay (attenuate) the disease or condition of interest in a subject in need thereof. Those in need of treatment include those who already have the disease or condition, and those who are prone to have the disorder, or those in whom the disorder is to be prevented. A subject is successfully "treated" with a disease if, after administration of a therapeutic amount of a compound or composition according to the present invention, the subject shows an observable and / or measurable reduction or absence of one or more of the following: a reduction in the number of pathogenic cells; a reduction in the percentage of total cells that are pathogenic; an alleviation to some extent of one or more of the symptoms associated with a particular disease or condition; a reduction in morbidity and mortality; and / or an improvement in quality of life. The above parameters for assessing the success of treatment and improvement of the disease are easily measurable by routine methods familiar to physicians. For example, the disease can be selected from eating disorders, such as obesity.

[0038] Detailed Description Solid Formulations The present invention relates to a 1,2,4-oxadiazole derivative containing only two monocyclic tertiary amine groups; With citric acid and / or saccharin A solid formulation comprising: the molar ratio in the solid formulation between the total amount of citric acid and / or saccharin and the amount of 1,2,4-oxadiazole derivative is about 2 or more; Concerning solid formulations.

[0039] The present invention also provides A 1,2,4-oxadiazole derivative containing only two monocyclic tertiary amine groups is With citric acid and / or saccharin A solid formulation obtainable by mixing, the initial molar ratio between the total amount of citric acid and / or saccharin and the amount of 1,2,4-oxadiazole derivative is greater than or equal to about 2; Concerning solid formulations.

[0040] In one embodiment, no solvent is present during the mixing step.In one embodiment, no substances other than the 1,2,4-oxadiazole derivative and citric acid and / or saccharin are present during the mixing step.

[0041] In one embodiment, the 1,2,4-oxadiazole derivative has the formula (I-0): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, and C1-C3 thioalkyl. It is a compound of the formula:

[0042] In one embodiment, R 1 , R 2 , R 3 , R 4 , and R 5 are each independently selected from hydrogen and C1-C3 haloalkyl, preferably C1-C3 haloalkyl is C1-C3 fluoroalkyl; more preferably C1-C3 fluoroalkyl containing only three fluoride atoms, such as trifluoromethyl. In one embodiment, R 3 is C1-C3 haloalkyl; preferably C1-C3 fluoroalkyl; more preferably C1-C3 fluoroalkyl containing only three fluoride atoms, such as trifluoromethyl.

[0043] In one embodiment, R 1 , R 2 , R 3 , R 4, and R 5 At least two of R 1 and R 5 is hydrogen. In one embodiment, R 1 , R 2 , R 3 , R 4 , and R 5 At least four of R 1 , R 2 , R 4 , and R 5 is hydrogen.

[0044] In one preferred embodiment, the 1,2,4-oxadiazole derivative is Formula (A): [ka] The compound is 4-((1-((3-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-5-yl)methyl)piperidin-3-yl)methyl)morpholine (hereinafter referred to as "Compound A").

[0045] Compound A was named using ChemDraw® Professional 15.0 (PerkinElmer).

[0046] formula: [ka] Citric acid or "2-hydroxypropane-1,2,3-tricarboxylic acid" (CHO, CAS [77-92-9]) is a weak organic acid (pKa at the acid group of 5.2, 4.3, and 3.0 at 25 °C) that occurs naturally in citrus fruits.

[0047] formula: [ka] Saccharin or "benzoic acid sulfimide" or "1,1-dioxo-1,2-benzothiazol-3-one" (C7H5NO3S, CAS[81-07-2]) is a weak organic acid (pKa of 1.6 at 25 °C) produced by synthetic chemistry.

[0048] All references in this disclosure to "1,2,4-oxadiazole derivatives," "citric acid," or "saccharin" include all enantiomers and solvates thereof. All references in this disclosure to "1,2,4-oxadiazole derivatives," "citric acid," or "saccharin" include all salts thereof, preferably pharma-ceutically acceptable salts thereof. All references to "compounds" (e.g., "1,2,4-oxadiazole derivatives") should be construed to mean "at least one compound," and thus include mixtures of two or more 1,2,4-oxadiazole derivatives, any of their enantiomers, solvates, and / or salts.

[0049] In one embodiment, the solid formulation comprises 50% (w / w) or more of the 1,2,4-oxadiazole derivative and citric acid and / or saccharin (i.e., the total amount of the 1,2,4-oxadiazole derivative and citric acid and / or saccharin represents at least 50% of the total weight of the solid composition). In one embodiment, the solid formulation comprises a total amount of the 1,2,4-oxadiazole derivative and citric acid and / or saccharin in the range of about 75 to about 100% (w / w), preferably in the range of about 85 to 99% (w / w), more preferably in the range of about 90 to 98% (w / w), even more preferably in the range of about 95 to 97% (w / w), and even more preferably in the range of about 95 to 96% (w / w). In these embodiments, "w / w" means "weight relative to the total weight of the solid formulation". In one embodiment, the solid formulation consists of the 1,2,4-oxadiazole derivative and citric acid and / or saccharin.

[0050] In one embodiment, the solid formulation comprises a mono- or di-citrate salt of a 1,2,4-oxadiazole derivative. In one embodiment, the solid formulation comprises a di-citrate salt of a 1,2,4-oxadiazole derivative. In one embodiment, the solid formulation comprises a mono- or disaccharin salt of a 1,2,4-oxadiazole derivative. In one embodiment, the solid formulation comprises a disaccharin salt of a 1,2,4-oxadiazole derivative. In one embodiment, the solid formulation comprises a mono-citrate salt and a mono-saccharin salt of a 1,2,4-oxadiazole derivative.

[0051] In one embodiment, the solid formulation comprises: A 1,2,4-oxadiazole derivative and / or a salt thereof, (Citric acid and / or its salts) and / or (Saccharin and / or its salts) It comprises or consists of:

[0052] In one embodiment, the molar ratio in the solid formulation or the initial molar ratio between the total amount of citric acid and / or saccharin and the amount of 1,2,4-oxadiazole derivative is less than or equal to about 100. In one embodiment, the molar ratio is in the range of about 2 to about 20. In one particular embodiment, the molar ratio is in the range of about 2 to about 10. In one further particular embodiment, the molar ratio is in the range of about 2 to about 5. In one further particular embodiment, the molar ratio is about 2, about 3, about 4, or about 5. In one further particular embodiment, the molar ratio is about 2 to about 3. In one further particular embodiment, the molar ratio is about 2.

[0053] In one embodiment, the solid formulation retains its physical stability (as defined hereinabove) at 19±2° C. and 60±5% humidity for at least 7 days. In one embodiment, the solid formulation retains its physical stability for at least 12 days. In one particular embodiment, the solid formulation retains its physical stability for at least 2 weeks. In one further particular embodiment, the solid formulation retains its physical stability for at least 5 weeks. In one further particular embodiment, the solid formulation retains its physical stability for at least 10 weeks.

[0054] In one embodiment, the specific surface area (BET) of the solid formulation is higher than the specific surface area of ​​citric acid and / or saccharin when the citric acid and / or saccharin are not included in the solid formulation.

[0055] In one embodiment, the specific surface area (BET) of the solid formulation is less than 5 m 2 / g, preferably 10m 2 / g, more preferably 20m 2 In one particular embodiment, the specific surface area (BET) of the solid formulation is greater than about 25 m 2 In one particular embodiment, the specific surface area (BET) of the solid formulation is about 20 m 2 In one particular embodiment, the specific surface area (BET) of the solid formulation is about 6 m 2 / g

[0056] In one embodiment, the solid formulation is not a pharmaceutical composition. In one embodiment, the solid formulation is not an oral formulation, such as an oral powder. In one embodiment, the solid formulation is not a solid formulation, such as a solid tablet. In these embodiments, the solid formulation per se contains a very high concentration of the therapeutic agent (i.e., the 1,2,4-oxadiazole derivative), and is not suitable for direct administration to a subject for therapeutic purposes, since it would result in toxicity or significant side effects or would not provide an effective medical treatment. However, the solid formulation can be formulated into a pharmaceutical composition, as described herein below, as a therapeutic agent for therapeutic purposes, usually in very small amounts.

[0057] salt The present invention also relates to the citric acid and / or saccharin salts of 1,2,4-oxadiazole derivatives which contain only two monocyclic tertiary amine groups.

[0058] In one embodiment, the salt is a mono- or di-citrate salt of the 1,2,4-oxadiazole derivative, i.e., the 1,2,4-oxadiazole derivative is ionized via the transfer of at least one proton from one citrate salt to at least one of the tertiary amine groups. In one embodiment, the salt is a di-citrate salt of the 1,2,4-oxadiazole derivative, i.e., the 1,2,4-oxadiazole derivative is ionized via the transfer of two protons from one or two citrate salts to both tertiary amine groups.

[0059] In one embodiment, the salt is a mono- or disaccharin salt of a 1,2,4-oxadiazole derivative, i.e., the 1,2,4-oxadiazole derivative is ionized via the transfer of at least one proton from one saccharin to at least one of the tertiary amine groups. In one embodiment, the salt is a disaccharin salt of a 1,2,4-oxadiazole derivative, i.e., the 1,2,4-oxadiazole derivative is ionized via the transfer of two protons from two saccharins to both tertiary amine groups.

[0060] In one embodiment, the salts are monocitrate and monosaccharin salts of the 1,2,4-oxadiazole derivative, i.e., the 1,2,4-oxadiazole derivative is ionized via the transfer of one proton each from one citrate and one saccharin to both tertiary amine groups.

[0061] In one embodiment, the salt is a pharma- ceutically acceptable salt.

[0062] In one embodiment, the 1,2,4-oxadiazole derivative is a compound of formula (I-0) or compound A, as described herein above.

[0063] Processes and methods The present invention also relates to a process for producing a solid composition according to the invention as described herein above, comprising the step of mixing a 1,2,4-oxadiazole derivative containing only two monocyclic tertiary amine groups with citric acid and / or saccharin, the initial molar ratio between the total amount of citric acid and / or saccharin and the amount of 1,2,4-oxadiazole derivative is greater than or equal to about 2; Regarding the process.

[0064] The present invention also relates to a method for increasing the physical stability of a 1,2,4-oxadiazole derivative containing only two monocyclic tertiary amine groups, comprising the steps of mixing said 1,2,4-oxadiazole derivative with citric acid and / or saccharin, the initial molar ratio between the total amount of citric acid and / or saccharin and the amount of 1,2,4-oxadiazole derivative is greater than or equal to about 2; It concerns the method.

[0065] According to the definition of "physical stability" provided herein above, "improved physical stability" or "increased physical stability" of a substance in the present invention refers to the reduction (or suppression) of deliquescence and / or the reduction (or suppression) of moisture absorption of the substance, so that the substance is solid, the substance is not deliquescent and / or absorbs less water and / or the melting point of the substance is increased.

[0066] A reduction in the deliquescence of a material may possibly be characterized as a reduction in moisture absorption of the material. Moisture absorption may be measured, for example, by DVS (Dynamic Vapor Sorption), which measures the change in mass of a sample with respect to the vapor pressure of a solvent.

[0067] The melting point of a substance can be measured, for example, by DSC (differential scanning calorimetry) analysis, which measures the heat flow between a sample and a reference substance held at the same temperature, or by a melting point meter, which is an instrument in which a sample can be observed as it is gradually heated to detect the melting point.

[0068] In one embodiment, the 1,2,4-oxadiazole derivative is a compound of formula (I-0) or compound A as described herein above.

[0069] In one embodiment, the initial molar ratio between the total amount of citric acid and / or saccharin and the amount of 1,2,4-oxadiazole derivative is less than or equal to about 100. In one embodiment, the molar ratio is in the range of about 2 to about 20. In one particular embodiment, the molar ratio is in the range of about 2 to about 10. In one further particular embodiment, the molar ratio is in the range of about 2 to about 5. In one further particular embodiment, the molar ratio is about 2, about 3, about 4, or about 5. In one further particular embodiment, the molar ratio is in the range of about 2 to about 3. In one further particular embodiment, the molar ratio is about 2.

[0070] In one embodiment, the process or method comprises a first step of contacting the 1,2,4-oxadiazole derivative with citric acid and / or saccharin followed by a second step of mixing the 1,2,4-oxadiazole derivative and citric acid and / or saccharin.

[0071] In one embodiment, the mixing is stirring. In one embodiment, the mixing is grinding.

[0072] In one embodiment, no solvent is present during the mixing step.In one embodiment, no substances other than the 1,2,4-oxadiazole derivative and citric acid and / or saccharin are present during the mixing step.

[0073] Pharmaceutical Compositions The present invention also relates to a pharmaceutical composition comprising the solid formulation according to the invention as described herein above and at least one pharma- ceutically acceptable excipient.

[0074] In one embodiment, the solid formulation in the pharmaceutical composition is a therapeutic agent.

[0075] In one embodiment, the pharmaceutical composition contains the solid formulation in an amount ranging from about 0.0001 to about 20 (w / w)%, preferably from about 0.001 to about 10 (w / w)%, more preferably from about 0.01 to about 5 (w / w)%. In one embodiment, the pharmaceutical composition contains the solid formulation in an amount ranging from about 0.01 to about 5 (w / w)%, preferably from about 0.05 to about 2.5 (w / w)%, more preferably from about 0.1 to about 1 (w / w)%. In these embodiments, "w / w" means "weight relative to the total weight of the pharmaceutical composition."

[0076] In one embodiment, at least one pharma- ceutically acceptable excipient does not include citric acid. In one embodiment, at least one pharma-ceutically acceptable excipient does not include saccharin. In one embodiment, at least one pharma-ceutically acceptable excipient does not include citric acid and saccharin, i.e., each pharma-ceutically acceptable excipient included in the pharmaceutical composition does not include citric acid or saccharin.

[0077] use The present invention also relates to a solid formulation or a pharmaceutical composition according to the invention as described herein above for use as a medicament.

[0078] In one embodiment, the solid formulation or the pharmaceutical composition is for use in the treatment and / or prevention of a disease in which the GLP-1 receptor is involved or mediated.

[0079] In one embodiment, the solid formulation or the pharmaceutical composition is for use in the treatment and / or prevention of diseases in which the GLP-1 receptor is involved or mediated, as disclosed in patent application WO 2012 / 101292 (VIVIABIOTECH SL).

[0080] In one embodiment, the disease that GLP-1 receptor is involved in or mediated by is selected from obesity, anorexia, lipid dysfunction, diabetes, hyperinsulinemia, and metabolic syndrome.In one embodiment, the disease that GLP-1 receptor is involved in or mediated by is obesity.In another embodiment, the disease that GLP-1 receptor is involved in or mediated by is diabetes.In one embodiment, the diabetes is type 2 diabetes mellitus.

[0081] In one embodiment, the disease involving or mediated by the GLP-1 receptor is selected from obesity, anorexia, lipid dysfunction, diabetes, hyperinsulinemia, and diseases induced by or associated with metabolic syndrome ("GLP-1 related diseases"). In one embodiment, the disease is induced by or associated with diabetes ("diabetes related diseases"), such as diabetic neuropathy, diabetic retinopathy, glaucoma, cataracts, diabetic nephropathy, or diabetic foot ulcers.

[0082] In one embodiment, the solid formulation or the pharmaceutical composition is for use in the treatment and / or prevention of an eating disorder, hi one embodiment, the eating disorder is selected from obesity, anorexia, lipid dysfunction, diabetes, hyperinsulinism, and metabolic syndrome.

[0083] In one embodiment, the solid formulation or the pharmaceutical composition is for use in the treatment and / or prevention of a metabolic disorder, such as diabetes or obesity. In one embodiment, the metabolic disorder is selected from diabetes and obesity.

[0084] In one embodiment, the solid formulation or pharmaceutical composition is for use in the treatment and / or prevention of cardiovascular disease. In one embodiment, the cardiovascular disease is selected from coronary artery disease, stroke, heart failure, hypertensive heart disease, and congenital heart disease.

[0085] In one embodiment, the solid formulation or pharmaceutical composition is for use in the treatment and / or prevention of a neurodegenerative disease, in one embodiment, the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, multiple system atrophy, Huntington's disease, optic nerve degeneration, and movement disorders, neuromuscular diseases, and cognitive deficiencies.

[0086] In one embodiment, the solid formulation or the pharmaceutical composition is for use in the treatment and / or prevention of a neurological or neuropsychiatric disorder, in one embodiment, the neurological or neuropsychiatric disorder is selected from epilepsy, schizophrenia, bipolar disorder, depression, and pain.

[0087] The present invention therefore relates to a method for the treatment and / or prevention of a disease, comprising the administration to a subject in need thereof of a therapeutically effective amount of a solid formulation or a pharmaceutical composition according to the invention as described hereinabove. The present invention therefore also relates to the use of a solid formulation or a pharmaceutical composition according to the invention as described hereinabove in the manufacture of a medicament.

[0088] The present invention also relates to a non-therapeutic method of preventing weight gain in a subject, comprising administering to said subject a solid formulation or a pharmaceutical composition according to the invention as described herein above, in one embodiment, the prevention of weight gain is the prevention of fat gain.

[0089] The present invention also relates to a non-therapeutic method for controlling weight gain in a subject, comprising administering to said subject a solid formulation or a pharmaceutical composition according to the invention as described herein above, in one embodiment, the control of weight gain is the control of fat gain.

[0090] The present invention also relates to a non-therapeutic method of stimulating weight loss in a subject, comprising administering to said subject a solid formulation or a pharmaceutical composition according to the invention as described herein above, in one embodiment, the stimulation of weight loss is the stimulation of fat loss. [Brief description of the drawings]

[0091] [Figure 1] FIG. 1 is a photograph showing A-2CA as a physically stable white powder obtained by grinding Compound A with 2.0 equivalents of citric acid. [Diagram 2] FIG. 2 is a photograph showing A-2SA as a physically stable white powder obtained by grinding Compound A with 2.0 equivalents of saccharin. [Diagram 3] FIG. 3 is a photograph showing A-1CA-1SA as a physically stable white powder obtained by grinding Compound A with 1.0 equivalent of saccharin and 1.0 equivalent of citric acid. [Figure 4] FIG. 4 is a graph showing overlaid powder X-ray diffraction of an A-2CA solid formulation (top black curve) and citric acid (bottom grey curve). [Diagram 5] FIG. 5 is a photograph showing an SEM micrograph of an A-2CA solid formulation. [Figure 6] FIG. 6 is a graph showing overlaid powder X-ray diffraction of an A-2SA solid formulation (top black curve) and saccharin (bottom grey curve). [Figure 7] FIG. 7 is a photograph showing an SEM micrograph of an A-2SA solid formulation. [Figure 8] FIG. 8 is a graph showing overlaid powder X-ray diffraction of an A-1CA-1SA solid formulation (top black curve), saccharin (bottom dark grey curve), and citric acid (bottom light grey curve). [Figure 9] FIG. 9 is a photograph showing an SEM micrograph of an A-1CA-1SA solid formulation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0092] Working Example The invention is further illustrated by the following examples.

[0093] Example 1: Synthesis of a solid formulation material Compound A was synthesized by methods known in the art.13 C-NMR(CDCl3): δ 24.5 (CH 2pip ), 28.3 (CH 2pip ), 32.6 (CH), 52.7 (CH 2pip ), 53.2 (CH2N pip ), 53.7 (2CH2N morph ), 57.6 (CH2N pip ), 62.3 (CH 2morph ), 66.2 (2CH2O morph ), 122.4 (q, CF3), 125.2 (q, C) 126.2 (2CH), 127.9 (2CH), 130.9 (q, C)166.5 (C(N)=N), 177.8 (C(O)=N). 1 H-NMR (CDCl3): δ 0.88-1.01 (m, 1H, 1 / 2CH 2pip ), 1.58-1.80 (m, 3H, 1 / 2CH 2pip , C.H. 2pip ), 1.87-2.02 (m, 2H, 1 / 2 CH2N pip , CH), 2.13-2.28 (m, 3H, CH 2morph , 1 / 2 CH2N pip ), 2.32-2.54 (m, 4H, 2CH2N morph ), 2.92 (d, 1H, 1 / 2 CH2N pip ), 3.09 (d, 1H, 1 / 2CH2N pip ), 3.62-3.78 (m, 4H, 2CH2O morph ), 3.94 (q, 2H, CH 2pip ), 7.75 (d, 2H, 2CH Ar ), 8.23 ​​(d, 2H, 2CH Ar ). Rf: 0.67 (eluent: thin layer chromatography (TLC) on silica plates (silica gel 60 F254 Merck on 2 mm thick aluminum foil) with dichloromethane / methanol (9 / 1), developed with UV and KMnO4 solution).

[0094] All other reactants and all solvents were purchased from commercial suppliers. All reactants and solvents used were reagent grade.

[0095] Example 1-1: Mix A with liquid acid General Methodology In a round bottom flask, to a solution of A in anhydrous Et2O (6 mL / mmol) under an argon atmosphere, the acid was added dropwise, either as a neat liquid or in anhydrous Et2O (3 mL / mmol). The mixture was allowed to stand for 3 h. The product was then isolated by evaporation of the solvent and dried under vacuum.

[0096] Acetic acid The reaction between A and acetic acid was carried out with 2.0 equivalents of acid. After drying under vacuum, a sticky oil was obtained.

[0097] Hydrobromic Acid The reaction between A and hydrobromic acid was carried out with 2.0 equivalents of acid. After drying under vacuum, a deliquescent solid was obtained.

[0098] hydrochloric acid The reaction between A and hydrochloric acid was carried out with a significant excess of acid. After drying under vacuum, a deliquescent solid was obtained.

[0099] Methanesulfonic acid The reaction between A and methanesulfonic acid was carried out several times with 1.0, 1.3, 2.3, and 3.2 equivalents of acid.

[0100] After drying under vacuum, a sticky oil was obtained except for the product formed at 3.2 equivalents which was instead a deliquescent solid.

[0101] sulfuric acid The reaction between A and sulfuric acid was carried out with 2.0 equivalents of acid. After drying under vacuum, a sticky oil was obtained.

[0102] Example 1-2: Mixing solid acid with A General Methodology Mechanochemistry can be used for the efficient production of salts of organic compounds from solid acids or bases. It is a solvent-free process that includes a mixing step, such as a grinding step. The grinding step can be performed either by net grinding or by "Liquid Assisted Grinding (LAG)" (where a very small amount of solvent can be added to increase molecular mobility). This is aimed at accelerating and / or completing the reaction.

[0103] In the present case, neat milling was used because compound A was an oil and therefore molecular mobility was presumably sufficient. Two different neat milling approaches were used: Solid Mixture 1: To an Eppendorf, A (200 mg, 0.5 mmol) and acid were added. The Eppendorf was then placed in a grinding apparatus (Retsch MM400) and stirred at 30 Hz for 90 min. Mixing of solids 2: In a mortar, A (200 mg, 0.5 mmol) and acid were added, then manually ground with a pestle.

[0104] Citric acid The reaction between A and citric acid was carried out with 2.0 equivalents of acid. After grinding, a white powder was obtained ("A-2CA" shown in Figure 1).

[0105] The reaction between A and citric acid was also carried out with 1.0 equivalent of acid. After trituration, a sticky oil was obtained ("A-1CA").

[0106] Fumaric acid The reaction between A and fumaric acid was carried out twice with 1.0 or 2.0 equivalents of the acid. In both cases, a sticky oil was obtained.

[0107] saccharin The reaction between A and saccharin was carried out twice with 1.0 or 2.0 equivalents of acid. When only 1 equivalent of saccharin was used, a sticky oil was obtained. On the other hand, when 2 equivalents were used, a white powder was obtained ("A-2SA" shown in Figure 2).

[0108] Saccharin and Citric Acid The reaction between A and saccharin and citric acid was carried out with 1.0 equivalent of each acid. After grinding, a white powder was obtained ("A-1CA-1SA" shown in Figure 3).

[0109] Sodium bicarbonate The reaction between A and sodium bicarbonate was carried out twice with 1.0 or 2.0 equivalents of acid. In both cases, a sticky oil was obtained.

[0110] Succinic acid The reaction between A and succinic acid was carried out twice with 1.0 or 2.0 equivalents of acid. In both cases, a sticky oil was obtained.

[0111] Example 2: Analysis of solid formulations material and method Nuclear magnetic resonance (NMR) analysis NMR spectra were recorded on a JEOL JNM EX-400 400Hz or a JEOL JNM-ECZ 500Hz. Samples were prepared in standard quartz tubes (5mm) in deuterated DMSO at room temperature. Spectra were analyzed using the Delta program.

[0112] BET (Brunauer, Emmett and Teller) analysis The specific surface area was measured by nitrogen adsorption-desorption analysis using a volumetric adsorption analyzer (Micromeritics 3Flex physisorption apparatus) at 77 K. The BET (Brunauer, Emmett and Teller) method was applied in the range of P / P0 from 0.05 to 0.20 to calculate the specific surface area.

[0113] X-Ray Powder Diffraction (PXRD) Powder X-ray diffraction (PXRD) data were collected on a Panalytical X'Pert Pro diffractometer (Bragg-Brentano geometry, X'Celerator detector) using Cu Kα radiation (λ=1.54184 Å) at 45 kV and 30 mA.

[0114] Scanning electron microscope (SEM) photograph Photographs of the samples were taken using a SEM microscope Jeol JSM-6010LV equipped with a SEI detector.

[0115] Example 2-1: Analysis of A-2CA 2-1-1) Preparation of A-2CA analysis sample To a 2 mL Eppendorf tube was added A (201 mg, 0.490 mmol, 1.0 eq), citric acid (188 mg, 0.976 mmol, 2.0 eq), two 3 mm stainless steel grinding balls, and five 2 mm stainless steel grinding balls. The Eppendorf was then placed in a grinding machine (Retsch Mixer Mill 400) equipped with two grinding jars. Dry grinding was then performed at 30 Hz for 90 min. Similar results were obtained by decreasing the grinding time to 30 min. To improve mixing, the reaction mixture was placed in a mortar and manually ground with a pestle until A-2CA was obtained as a white powder.

[0116] 2-1-2) NMR analysis A-2CA 1 H NMR showed a spectrum similar to the superposition of the spectra of A and citric acid, thus the molecular structures of A and citric acid are maintained and no degradation of the reactants is observed.

[0117] A-2CA 13 C NMR did not show any significant shifts for the carbon atoms near the nitrogen atom (tertiary amine) compared to A. Therefore, it could not be assessed from RMN whether a salt was formed.

[0118] 2-1-3) Deliquescence test A-2CA was left in air at normal humidity (relative humidity 60±5%) and room temperature (19°C±2°C) for 12 days.

[0119] During this period no liquid phase appears and therefore the A-2CA solid composition is physically stable.

[0120] After 7 days, the particles of the A-2CA powder became slightly sticky, thus making this solid composition moderately hygroscopic.

[0121] 2-1-4) Powder XRD The diffractograms of A-2CA and citric acid are shown in Figure 4. Citric acid is detected with A-2CA since both diffractograms display the same pattern of peaks. Furthermore, the diffractogram of A-2CA shows the presence of an amorphous phase.

[0122] 2-1-5) Specific surface area (BET) The specific surface area of ​​A-2CA is: BET surface A-2CA =26.6m 2 / g was measured by BET analysis.

[0123] 2-1-6) SEM Photos SEM pictures of many samples of A-2CA were recorded and a representative example is shown in Figure 5. SEM pictures can be useful for characterizing the particle size distribution of solid formulations.

[0124] Example 2-2: A-2SA Analysis 2-2-1) Preparation of A-2SA analysis sample To a 2 mL Eppendorf tube was added A (150 mg, 0.365 mmol, 1.0 eq), saccharin (135 mg, 0.737 mmol, 2.0 eq), two 3 mm stainless steel grinding balls, and five 2 mm stainless steel grinding balls. The Eppendorf was then placed in a grinding machine (Retsch Mixer Mill 400) equipped with two grinding jars. Dry grinding was then performed at 30 Hz for 35-90 min to yield A-2SA as a white powder.

[0125] It was found that the grinding time did not affect the results. The following analyses were performed on the solid formulations obtained after 35 minutes of grinding.

[0126] 2-2-2) NMR analysis A-2SA 1 H NMR showed a spectrum similar to the superposition of the spectra of A and saccharin, thus indicating that the molecular structures of A and saccharin were maintained and no degradation of the reactants was observed.

[0127] A-2SA 13 C NMR did not show any significant shifts for the carbon atoms near the nitrogen atom (tertiary amine) compared to A. Therefore, it could not be assessed from RMN whether a salt was formed.

[0128] 2-2-3) Deliquescence test A-2SA was left in air at normal humidity (relative humidity 60±5%) and room temperature (19±2°C) for 12 days.

[0129] During this period no liquid phase appears and therefore the A-2SA solid composition is physically stable.

[0130] After 7 days, the particles of the A-2SA powder became slightly sticky, thus making this solid composition moderately hygroscopic.

[0131] 2-2-4) Powder XRD Comparative Analysis-Saccharin Powder XRD and SEM Photos For comparison, it is important to look at the effect of milling on saccharin: commercial saccharin was milled for 35 minutes at 30 Hz and compared to unmilled powder from the same batch of commercial saccharin.

[0132] Diffraction patterns (PXRD) of saccharin before and after milling were obtained and compared: they are identical. Thus, milling does not result in amorphization of saccharin under the experimental conditions.

[0133] Furthermore, scanning electron microscope (SEM) images of saccharin before and after milling confirmed that the particles were smaller than those of commercially available saccharin, but the crystal structure of the milled saccharin did not change.

[0134] Powder XRD of A-2SA The diffractograms of A-2SA and saccharin are shown in Figure 6. In A-2CA, saccharin is detected in A-2SA since both diffractograms present the same peak pattern. Furthermore, the diffractogram of A-2SA shows the presence of an amorphous phase.

[0135] 2-2-5) Specific surface area Comparative Analysis – Specific Surface Area of ​​Saccharin For comparison, it is important to look at the effect of milling on saccharin: commercial saccharin was milled for 35 minutes at 30 Hz and compared to unmilled powder from the same batch of commercial saccharin.

[0136] The specific surface areas of the two saccharin samples are Saccharin (commercially available): BET surface SA(c) =9.9m 2 / g Saccharin (after grinding) BET surface SA(g) =6.7m 2 / g was measured by BET analysis.

[0137] This experiment demonstrates that although a moderate decrease (approximately -30%), no significant change is observed regarding the specific surface area (BET) of saccharin after grinding.

[0138] Specific surface area of ​​A-2SA The specific surface area of ​​A-2SA is BET surface A-2SA =21.6m 2 / g The results were measured by BET analysis.

[0139] With the same grinding procedure, a significant change was observed regarding the specific surface area (BET) of saccharin mixed with A-2SA, which was three times higher than the one of saccharin alone (about +220%).

[0140] Thus, the presence of A in the solid formulation significantly modifies the specific surface area of ​​the solid, thus demonstrating an interaction between the two compounds in the solid formulation. Thus, the solid formulation is not simply a mixture.

[0141] 2-2-6) SEM Photos A number of SEM photographs of the A-2SA samples were recorded and a representative example is shown in Figure 7.

[0142] Example 2-3: Analysis of A-1CA-1SA 2-3-1) Preparation of A-1CA-1SA analysis sample To a grinding jar was added A (302 mg, 0.735 mmol, 1.0 eq), citric acid (142 mg, 0.742 mmol, 1.0 eq), saccharin (13 mg, 0.737 mmol, 1.0 eq), and grinding balls made of agate. The jar was then placed in a grinding machine (Retsch Mixer Mill 400) equipped with another grinding jar. Dry grinding was carried out at 30 Hz for 60 minutes to give A-1CA-1SA as a white solid.

[0143] 2-3-2) NMR analysis A-1CA-1SA 1H NMR showed a spectrum similar to the superposition of the spectra of A, citric acid, and saccharin, thus the molecular structures of A, citric acid, and saccharin were maintained and no degradation of the reactants was observed.

[0144] A-1CA-1SA 13 C NMR did not show any significant shifts for the carbon atoms near the nitrogen atom (tertiary amine) compared to A. Therefore, it could not be assessed from RMN whether a salt was formed.

[0145] 2-3-3) Deliquescence test A-1CA-1SA was left in air at normal humidity (relative humidity 60±5%) and room temperature (19±2° C.) for 30 days.

[0146] During this period no liquid phase appears and therefore A-1CA-1SA is physically stable.

[0147] 3-3-4) Powder XRD The diffractograms of A-1CA-1SA, citric acid, and saccharin are shown in Figure 8. As for A-2CA and A-2SA, citric acid and saccharin are detected in A-1CA-1SA since both diffractograms show the same peak pattern. Furthermore, the diffractogram of A-1CA-1SA shows the presence of an amorphous phase.

[0148] 3-3-5) Specific surface area The specific surface area of ​​the A-1CA-1SA sample is BET surface A-1CA-1SA =6.5m 2 / g The results were measured by BET analysis.

[0149] 3-3-6) SEM Photos Many SEM photographs of A-1CA-1SA were recorded, and a representative example is shown in Figure 9.

[0150] conclusion Due to the presence of two tertiary amine functional groups in the 1,2,4-oxadiazole derivative A, the preparation of mono- or di-addition salts was considered in order to obtain a physically stable form of the active ingredient.

[0151] The results of detailed formulation testing carried out by the applicant (Example 1) can be summarised as shown in Table 1 below. [Table 1]

[0152] Most of the acids used as liquids or solids in various relative amounts to A result in the formation of sticky oils or deliquescent (hygroscopic) compounds. Thus, physically stable addition salts of compound A were not thought to be readily available.

[0153] However, the use of certain acids, namely citric acid and / or saccharin, unexpectedly resulted in stable solid formulations of Compound A. Also, citric acid and / or saccharin must be used in an amount of at least 2 equivalents to achieve a stabilizing effect: it has been found that if only 1 equivalent of citric acid or saccharin is added to Compound A, the resulting mixture is sticky.

[0154] Analytical tests (Example 2) confirmed that the solid formulation according to the invention is physically stable.

[0155] It has also been demonstrated that the primary structure of Compound A in the solid formulation of the present invention is not affected, and therefore its biological activity can reasonably be expected to be equivalent to that of "free" Compound A.

[0156] The significant increase in surface specific area observed for A-2SA further indicates that the solid composition is not simply a mixture, but that A and saccharin have a chemical interaction within the solid formulation.

[0157] Without wishing to be bound by theory, the applicant believes that compound A may bind to citric acid and / or saccharin through non-covalent ("weak") bonds, such as hydrogen bonds or van der Waals forces, and thus the solid formulation is a complex of multiple components (A and citric acid and / or saccharin would be weakly bound without actual proton transfer, although the interaction would be sufficient to significantly increase the physical stability of compound A).

[0158] In conclusion, the experimental results provided herein clearly demonstrate that the present invention allows for fast and easy physical stabilization of 1,2,4-oxadiazole derivatives by mixing them with citric acid and / or saccharin. Thus, citric acid and / or saccharin, alone or in combination, are powerful stabilizers for 1,2,4-oxadiazole derivatives bearing two tertiary amine functional groups. The resulting physically stable solid powders make the 1,2,4-oxadiazole derivatives more useful for industrial applications and / or as pharmaceutical ingredients.

Claims

1. About 75% to about 100% (w / w), 1,2,4-Oxadiazole Derivatives of Formula (A) 【Chemistry 1】 And Citric acid and / or saccharin A solid formulation comprising: the molar ratio of the total amount of citric acid and / or saccharin to the amount of the 1,2,4-oxadiazole derivative in the solid formulation is in the range of about 2 to about 20; Solid formulations.

2. A 1,2,4-oxadiazole derivative of formula (A): 【Chemistry 2】 of, Citric acid and / or saccharin A solid formulation obtainable by mixing, the molar ratio of the total amount of citric acid and / or saccharin to the amount of said 1,2,4-oxadiazole derivative is in the range of about 2 to about 20; the solid formulation comprises a total amount of 1,2,4-oxadiazole derivative and citric acid and / or saccharin ranging from about 75% (w / w) to about 100% (w / w); Solid formulations.

3. 3. The solid formulation of claim 1 or claim 2, wherein the molar ratio is in the range of about 2 to about 10.

4. 4. The solid formulation of claim 3, wherein the molar ratio is in the range of about 2 to about 5.

5. 5. The solid formulation of claim 4, wherein the molar ratio is about 2.

6. A process for producing a solid composition according to any one of claims 1 to 5, comprising the steps of: mixing said 1,2,4-oxadiazole derivative of formula (A) with citric acid and / or saccharin, the molar ratio of the total amount of citric acid and / or saccharin to the amount of the 1,2,4-oxadiazole derivative is in the range of about 2 to about 20; process.

7. A 1,2,4-oxadiazole derivative of the formula (A): 【Chemistry 3】 1. A method for increasing the physical stability of mixing the 1,2,4-oxadiazole derivative with citric acid and / or saccharin; the molar ratio of the total amount of citric acid and / or saccharin to the amount of said 1,2,4-oxadiazole derivative is in the range of about 2 to about 20; no solvent is present during said mixing step; method.

8. The process of claim 6 or the method of claim 7, wherein the molar ratio is in the range of about 2 to about 10.

9. The process or method of claim 8, wherein the molar ratio is in the range of about 2 to about 5.

10. The process or method of claim 9, wherein the molar ratio is about 2.

11. 8. The process of claim 6 or the method of claim 7, wherein the mixing is stirring and / or grinding.

12. A pharmaceutical composition comprising the solid formulation according to any one of claims 1 to 5 and at least one pharma- ceutically acceptable excipient.

13. 13. The pharmaceutical composition of claim 12, wherein the at least one pharma- ceutically acceptable excipient does not include citric acid and saccharin.

14. A pharmaceutical composition according to claim 12 or claim 13 for use in the treatment and / or prevention of a disease in which the GLP-1 receptor is involved or mediated.

15. The disease, Metabolic disorders; Diseases induced by or associated with metabolic disorders; cardiovascular disease; Neurodegenerative diseases; and Neurological or neuropsychiatric disorders 15. The pharmaceutical composition for use according to claim 14, selected from:

16. The disease, diabetes or obesity; diabetic neuropathy, diabetic retinopathy, glaucoma, cataracts, diabetic nephropathy, or diabetic foot ulcers; coronary artery disease, stroke, heart failure, hypertensive heart disease, or congenital heart disease; Alzheimer's disease, Parkinson's disease, multiple system atrophy, Huntington's disease, optic nerve degeneration and movement disorders, neuromuscular diseases, or cognitive deficiencies; and Epilepsy, schizophrenia, bipolar disorder, depression, or pain 16. The pharmaceutical composition for use according to claim 15, selected from:

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