Novel dosing regimen for preventing or treating obsessive-compulsive disorder using low doses of donepezil or derivatives thereof

Abstract

The present invention relates to a novel daily low dosage regimen of donepezil and its derivatives or pharmaceutically acceptable salts and / or solvates for use in the prevention and / or treatment of obsessive-compulsive disorders, in particular eating disorders. The invention also relates to a unit dosage form comprising from 0.25 mg to 2.5 mg of donepezil, derivatives or pharmaceutically acceptable salts and / or solvates thereof, in particular for use in the prevention and / or treatment of obsessive-compulsive disorders, in particular eating disorders.

Description

Technical Field

[0001] The present invention relates to a novel daily low-dose regimen of donepezil and its derivatives for the prevention and / or treatment of obsessive-compulsive disorders, in particular eating disorders. Background Art

[0002] Acetylcholine (ACh) is a major neuromodulator in the striatal network and a key transmitter at the neuromuscular junction. Following exocytic release of ACh, its effects are rapidly terminated by hydrolysis catalyzed by an enzyme called acetylcholinesterase (AChE). AChE inhibitors (AChEIs) inhibit this reaction, preventing the breakdown of ACh into choline and acetate. Consequently, AChEIs can increase the extracellular levels and duration of ACh action in the central nervous system and at the neuromuscular junction.

[0003] The present inventors recently discovered that striatal ACh also plays an important role in eating disorders (Favier et al., The Journal of Clinical Investigation, 2020, 130, 12, pp6616-6630).

[0004] Full-blown syndromic and subthreshold forms of eating disorders, such as anorexia nervosa and bulimia nervosa, affect up to 10% of the population. Anorexia nervosa has the highest mortality rate of all psychiatric disorders (approximately 5% per decade). However, our understanding of the neural basis of anorexia nervosa is very limited, and as a result, there are no clear biological treatments for this severe condition.

[0005] The inventors have demonstrated that cholinergic interneurons are key regulators of the striatum and habit formation. To study the role of ACh in habitual behavior, the inventors specifically silenced ACh signaling in the striatum in a mouse model and then determined that reduced ACh transmission would make mice more susceptible to excessive habits. To understand whether these excessive habits could lead to eating disorders, the inventors then used a pathological diet model in a second rodent model: the activity-based anorexia model (ABA, a model of anorexia nervosa (Klenotich and Dulawa, 2012)). In the ABA model, mutant mice lacking ACh in the striatum were more prone to self-starvation than control mice.

[0006] Based on these unexpected findings, the present inventors hypothesize that acetylcholinesterase inhibitors may be useful in preventing and / or treating obsessive compulsive disorders, in particular eating disorders such as anorexia.

[0007] Donepezil is a reversible and selective inhibitor of AChE. It is an off-label compound produced by pharmaceutical companies Eisai and Pfizer under the trade name Aricept. Aricept has been widely used to treat Alzheimer's disease at a dose of 5 to 10 mg / day. However, the efficacy of this treatment is still unclear, and serious side effects (dizziness, nausea, vomiting, heart problems, etc.) have been reported after years of use of Aricept for Alzheimer's disease. See Dunn NR et al. Journal of Psychopharmacology, 2000, 14(4), p. 406-408.

[0008] Therefore, there is a need for an effective treatment for obsessive compulsive disorders, particularly eating disorders, with limited or no side effects, particularly peripheral side effects, and improved treatment compliance. Summary of the Invention

[0009] Against this background, the present inventors unexpectedly discovered that a well-known and available acetylcholinesterase inhibitor, i.e., donepezil or its derivatives, can be used to effectively prevent and / or treat obsessive-compulsive disorders, in particular eating disorders, at a dose that is 4 to 10 times lower than that used for treating Alzheimer's disease, and without causing any serious side effects.

[0010] According to a first aspect, the present invention relates to a compound of formula (I):

[0011]

[0012] Wherein X is an oxygen atom or a group N-OH,

[0013] Or a pharmaceutically acceptable salt and / or solvate thereof for use in preventing and / or treating obsessive-compulsive disorder, especially eating disorders, in particular anorexia, in a subject in need thereof, characterized in that the compound of formula (I) is administered to the subject at a daily dose of 0.25 mg to 2.5 mg, preferably 0.5 mg to 2.5 mg.

[0014] The present invention also relates to a method for preventing and / or treating obsessive-compulsive disorder, especially eating disorders, in particular anorexia, in a subject in need thereof, comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof at a daily dose of 0.25 mg to 2.5 mg, preferably 0.5 mg to 2.5 mg.

[0015] In another aspect, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof in the preparation of a medicament for preventing and / or treating obsessive-compulsive disorder, especially eating disorders, particularly anorexia, in a subject by administering the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof to the subject at a daily dose of 0.25 mg to 2.5 mg, preferably 0.5 mg to 2.5 mg.

[0016] According to another aspect, the present invention relates to a unit dosage form comprising 0.25 mg to 2.5 mg, preferably 0.5 mg to 2.5 mg of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

[0017] Detailed description

[0018] definition

[0019] As used herein, the term "stereoisomer" refers to configurational stereoisomers, more specifically optical isomers. Thus, optical isomers that are not mirror images of one another are termed "diastereomers," and optical isomers that are non-superimposable mirror images are termed "enantiomers." An equimolar mixture of two enantiomers of a chiral compound is termed a racemic mixture or racemate.

[0020] For the purposes of the present invention, the term "pharmaceutically acceptable" is intended to mean useful for preparing pharmaceutical compositions and generally safe and non-toxic for pharmaceutical use.

[0021] Within the framework of the present invention, the term "pharmaceutically acceptable salts and / or solvates" is intended to mean salts and / or solvates of pharmaceutically acceptable compounds as defined above, which possess the pharmacological activity of the corresponding compounds.

[0022] Pharmaceutically acceptable salts include:

[0023] (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; or acid addition salts formed with organic acids such as acetic acid, benzenesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, succinic acid, dibenzoyl-L25 tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid and trifluoroacetic acid, and

[0024] (2) Base addition salts formed by replacing acidic protons in the compound with metal ions (e.g., alkali metal ions, alkaline earth metal ions, or aluminum ions), or by coordination with organic or inorganic bases. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.

[0025] Acceptable solvates for therapeutic use of the compounds of the present invention include conventional solvates, such as solvates formed in the last step of the preparation of the compounds of the present invention due to the presence of a solvent. For example, solvates formed due to the presence of water (these solvates are also referred to as hydrates) or solvates formed due to the presence of ethanol can be mentioned.

[0026] Within the framework of the present invention, the term "pharmaceutical composition" refers to a composition having both prophylactic and therapeutic properties.

[0027] As used herein, the term "treatment compliance" is understood as the degree to which a patient's behavior corresponds to the prescribed treatment (ie, the prescribed dosage regimen, including time, dosage, and intervals between doses).

[0028] By dividing the individual's weight (in kg) by their height (in m 2 The term "body mass index" (BMI) is calculated using the weight of the body (units of weight). BMI is often used to assess whether an individual is malnourished or, conversely, overweight or obese.

[0029] Compound of formula (I)

[0030] The compounds of formula (I) for use according to the present invention may be in the form of stereoisomers or mixtures of stereoisomers, such as mixtures of enantiomers, diastereomers or tautomers, in particular racemic mixtures.

[0031] When X is an oxygen atom, the compound of formula (I) for use according to the present invention corresponds to the compound of formula (IA), ie donepezil:

[0032]

[0033] When X is an N-OH group, the compound of formula (I) for the use according to the invention corresponds to the compound of formula (IB):

[0034]

[0035] According to a preferred embodiment, the compound of formula (I) is donepezil. According to a preferred embodiment, the compounds of formulae IA and IB are in the form of the hydrochloride salt.

[0036] obsessive-compulsive disorder

[0037] The compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof as described herein is used in a daily dose of 0.25 mg to 2.5 mg, preferably 0.5 mg to 2.5 mg, for the prevention and / or treatment of obsessive-compulsive disorder.

[0038] The term "compulsive disorder" includes, but is not limited to, addiction, obsessive-compulsive disorder, eating disorders and related behaviors, particularly eating disorders. The term "eating disorder" includes, but is not limited to, anorexia nervosa, bulimia nervosa, and obesity.

[0039] The term "anorexia" in this disclosure refers only to "anorexia nervosa." Medical anorexia, which is caused by digestive system pathology and results in the patient being unable to eat, is not within the scope of the present invention.

[0040] According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), to be diagnosed with anorexia nervosa, the following criteria must be met:

[0041] - Energy intake is restricted relative to requirements, resulting in significantly low body weight, for age, sex, developmental trajectory, and physical health;

[0042] -Problems with the perception of one's own weight or body shape, where weight or body shape has an inappropriate impact on self-evaluation, or the patient denies the severity of their current low weight.

[0043] Anorexia nervosa (AN) consists of two major subtypes: restricting-type and binge-eating / purging-type. The restricting-type (AN-R) is characterized by dieting, fasting, and / or excessive exercise. The binge-eating / purging-type (AN-BP) involves recurrent episodes of binge eating (i.e., eating large amounts of food over a period of time without feeling physically hungry and without control) and / or purging behaviors (i.e., self-induced vomiting, or the misuse of laxatives, diuretics, or enemas).

[0044] The DSM diagnostic criteria for bulimia are:

[0045] - Recurring episodes of uncontrolled binge eating that occur at least twice a week for at least three months,

[0046] - Recurrent inappropriate compensatory behaviors, such as vomiting, to prevent weight gain and

[0047] -Self-evaluation that is overly influenced by body shape and weight.

[0048] According to a preferred embodiment, the obsessive-compulsive disorder treated in the context of the present invention is anorexia.

[0049] Dosage regimen

[0050] In the present invention, the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is administered to a subject in need thereof to prevent and / or treat obsessive-compulsive disorder, especially eating disorders, in particular anorexia, in an amount of 0.25 mg to 2.5 mg per day, preferably 0.5 mg to 2.5 mg.

[0051] The subject in need according to the present invention is a mammal, especially a human. In the case of anorexia, the subject in need is especially a person who has a very strict restrictive eating pattern (usually resulting in significant weight loss), extreme weight control (through a lot of exercise, forcing oneself to vomit, etc.), and always thinks that he is too fat and has a wrong perception of weight. In particular, the subject in need with anorexia usually has a body mass index (BMI) below 17.5 kg / m 2 For subjects with severe anorexia, a BMI of 15 to 17 kg / m 2 For subjects with extreme anorexia, BMI less than 15 kg / m 2 .

[0052] The daily dose of the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate is 0.25 mg to 2.5 mg, preferably 0.5 mg to 2.5 mg, which is equivalent to a therapeutically effective amount. "Therapeutically effective amount", "therapeutically effective dose" or "effective amount" refers to the amount of the compound of formula (I) that effectively and measurably improves one or more symptoms of obsessive-compulsive disorder to be treated. A therapeutically effective dose further refers to the amount of the compound of formula (I) that is sufficient to at least partially improve the symptoms (e.g., treat, cure, prevent or improve related medical conditions), or increase the speed of treating, curing, preventing or improving such conditions.

[0053] In the case of treatment of anorexia, improvement in symptoms typically results in a reduction in weight gain, a decrease in the need to control weight and eat, and a reduction in compulsive behaviors (particularly eating compulsions), as measured by the Yale-Brown OCD Scale (YBOCS), the Eating Disorders Diagnostic Questionnaire (Q-EED), and the Eating Disorder Inventory 2 (EDI). In particular, improvement in symptoms results in a return to baseline weight, i.e., a healthy weight for the subject, particularly an increase in BMI, particularly greater than 17.5 kg / m 2 , preferably greater than 18.5kg / m 2 , more preferably greater than 19 and less than 23 kg / m 2 .

[0054] In a particular aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof for use in improving BMI, in particular to at least 17.5 kg / m 2 , preferably 18.5kg / m 2 , more preferably 19kg / m 2 Up to 23kg / m 2 The invention relates to a method for treating BMI of a subject, characterized in that the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is administered to a subject in need thereof at a daily dosage regimen of 0.25 mg to 2.5 mg, preferably 0.5 mg to 2.5 mg.

[0055] In other words, the present invention relates to a method for improving the BMI of a subject in need thereof, in particular to at least 17.5 kg / m 2 , preferably 18.5kg / m 2 , more preferably 19kg / m 2 Up to 23kg / m 2 A method for reducing BMI of a subject comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof at a daily dose of 0.25 mg to 2.5 mg, preferably 0.5 mg to 2.5 mg.

[0056] In some embodiments, the daily dose of the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate is 0.25 mg to 2 mg, preferably 0.5 mg to 2.5 mg, more preferably 0.5 mg to 1.5 mg. In other words, the compound of formula (I) can be advantageously administered to a subject in need thereof at a daily dose of 0.5 mg to 2 mg, more preferably 0.5 mg to 1.5 mg, to prevent and / or treat obsessive-compulsive disorder.

[0057] The daily dose of formula (I) compound according to the present invention or its pharmaceutically acceptable salt and / or solvate can be administered once or multiple times a day, for example, once a day, twice, three times or four times a day in a manner to be administered to a subject in need. In the case of multiple daily administrations, the daily dose is separated so that the dosage administered to the subject during each administration is identical or different. Advantageously, the daily dose is administered once a day.

[0058] The daily dose of the compound of formula (I) according to the present invention or its pharmaceutically acceptable salt and / or solvate is usually administered to a subject in need thereof for a period of time that is necessary to assess a measurable improvement in one or more symptoms of the obsessive-compulsive disorder to be treated or to assess at least a partial improvement in the symptoms of the obsessive-compulsive disorder. In the case of preventing and / or treating anorexia, the daily dose of the compound of formula (I) according to the present invention or its pharmaceutically acceptable salt and / or solvate is usually administered to a subject in need thereof for a period of time that is necessary to assess weight gain, a reduction in the need to control weight and eat, a reduction in compulsive eating behavior, in particular an increase in BMI, preferably to a BMI of at least 17.5 kg / m 2 , preferably 18.5kg / m 2 , more preferably 19kg / m 2 Up to 23kg / m 2 It is necessary.

[0059] The daily dose according to formula (I) compound of the present invention or its pharmaceutically acceptable salt and / or solvate can remain unchanged during treatment, or can increase or decrease in one day, but it is required that it remain in the range of 0.25mg to 2.5mg. According to some embodiments, when treatment begins, daily dose starts with 0.25mg or 0.5mg. Then, during treatment, regularly (such as weekly) re-evaluate the patient's symptoms, and adjust daily dose according to the development of symptoms. If necessary, daily dose can be increased with an increment of 0.25mg or 0.5mg, but it is required that it remain in the range of 0.25mg to 2.5mg.

[0060] According to some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is administered to a subject in need thereof at a daily dose of 0.25 mg to 2.5 mg, preferably 0.5 mg to 2.5 mg, for at least one month, preferably at least two months, preferably at least five months, more preferably one month to one year, and especially two months to six months.

[0061] The daily dose of the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate according to the present invention can be administered to a subject in need by oral or parenteral (including but not limited to subcutaneous, intramuscular, intravenous), ocular, intravitreal, topical, sublingual administration, preferably by oral administration.

[0062] The daily dose of the compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof according to the present invention for preventing and / or treating obsessive-compulsive disorder is preferably administered to a subject in need thereof as a pharmaceutical composition comprising the compound of formula (I) as an active ingredient and a pharmaceutically acceptable excipient.

[0063] Pharmaceutical compositions comprising a dose of 0.25 mg to 2.5 mg, preferably 0.5 mg to 2.5 mg, of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof and a pharmaceutically acceptable excipient can be mixed with conventional pharmaceutical carriers and administered in a unit form for administration.

[0064] Preferably, especially in the case of oral administration, the pharmaceutical composition may be in solid or liquid (solution or suspension) dosage form.

[0065] Solid dosage form can be tablet, gelatin capsule, powder, granule etc.In tablet, active component can be mixed with pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talcum powder, gum arabic etc., then tabletting.Tablet can further be coated, especially with sucrose or other suitable material coating, or it can be processed so that it has the activity of extension or delay.In powder or granule, active component can be mixed or granulated with dispersant, wetting agent or suspending agent and flavoring or sweetener.In gelatin capsule, active component can be introduced in soft or hard gelatin capsule with the form of aforementioned powder or granule or the form of liquid dosage form described below.

[0066] Liquid dosage forms can contain the active ingredient with a sweetener, flavoring agent, or suitable coloring agent in a solvent such as water. Liquid dosage forms can also be obtained by suspending or dissolving the above-mentioned powder or granules in a liquid such as water, juice, milk, etc. For example, it can be an emulsion, suspension, syrup, or elixir.

[0067] For parenteral administration, the composition may be in the form of an aqueous suspension or solution, which may contain a suspending agent and / or a wetting agent. The composition is preferably sterile. It may be in the form of an isotonic solution (particularly compared to blood).

[0068] Solid and liquid dosage forms can be formulated so that they match the desired release profile, such as immediate release, delayed release, and extended or sustained release.

[0069] The daily dose of the compound of formula (I) or its pharmaceutically acceptable salt and / or solvate according to the present invention is preferably administered to a subject in need thereof in a dosage unit form, especially an oral dosage unit form, in particular an oral solid dosage unit form (eg tablet).

[0070] According to some embodiments, the pharmaceutical composition of the present invention comprising a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof and a pharmaceutically acceptable excipient in a dosage of 0.25 mg to 2.5 mg, preferably 0.5 mg to 2.5 mg, further comprises one or more other acetylcholinesterase inhibitors, such as galantamine or rivastigmine. In such embodiments, the one or more acetylcholinesterase inhibitors are preferably present in the pharmaceutical composition in a dosage lower than the above dosage.

[0071] In other words, the daily dose of the compound of formula (I) according to the present invention or its pharmaceutically acceptable salt and / or solvate for preventing and / or treating obsessive-compulsive disorder is preferably administered to a subject in need thereof as a pharmaceutical composition comprising a compound of formula (I), one or more other acetylcholinesterase inhibitors and a pharmaceutically acceptable excipient.

[0072] In an alternative embodiment, a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof is administered to a subject in need thereof at a daily dosage regimen of 0.25 mg to 10 mg, or 0.5 mg to 10 mg, or 0.5 mg to 5 mg, or 2.5 mg to 10 mg, or 5 mg to 10 mg, preferably 0.5 mg to 2.5 mg to prevent and / or treat a specific obsessive-compulsive disorder.

[0073] Unit dosage form

[0074] Other aspects of the present invention relate to a unit dosage form comprising 0.25 mg to 2.5 mg, preferably 0.5 mg to 2.5 mg of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof. Preferably, the unit dosage form of the present invention is an oral unit dosage form. In particular, the unit dosage form of the present invention is a solid unit dosage form.

[0075] In some other aspects, the present invention relates to the unit dosage form of the present invention for use as a medicament, in particular for the prevention and / or treatment of obsessive-compulsive disorders, such as eating disorders, in particular anorexia.

[0076] Advantageously, the unit dosage form of the invention is used once daily as a medicament, in particular for the prevention and / or treatment of obsessive-compulsive disorders, such as eating disorders, in particular anorexia.

[0077] According to another aspect of the present invention, the present invention relates to a method for preventing and / or treating obsessive-compulsive disorder, in particular eating disorders, such as anorexia, comprising administering the unit dosage form of the present invention to a subject in need thereof once a day. DETAILED DESCRIPTION

[0078] Example

[0079] Six anorexic patients were treated with donepezil: five patients were treated with a daily dose according to the invention and one patient was treated with a higher dose (comparison).

[0080] The studies were conducted in hospitals. Each case is described below.

[0081] Case 1 (comparison)

[0082] Patient description

[0083] Patient #1 was a 35-year-old woman who had suffered from restrictive anorexia nervosa for 21 years. She went into remission in late adolescence, which lasted approximately 4 to 5 years. However, she continued to struggle with the behavioral manifestations and cognitive ruminations that are characteristic of the disorder. She had a very restrictive diet, severely restricting her calorie intake and avoiding foods high in sugar, carbohydrates, or fat. She also exercised for at least an hour daily and had difficulty resting or sitting down. She also exhibited severe body image dissatisfaction, concerns about her weight and shape, and cognitions and ruminations that were characteristic of an eating disorder.

[0084] Treatment with a daily dose of 5 mg of donepezil

[0085] When she started taking donepezil at a daily dose of 5 mg, her condition stabilized. Within 5 days, she reported developing side effects of drowsiness and headaches, which responded to over-the-counter pain medication. Within a week, her blood pressure began to rise from a previously normal 120 / 70 mmHg to 175 / 120 mmHg. She also reported severe headaches that woke her from sleep and were unresponsive to over-the-counter pain medication. She also reported feeling groggy. She presented to a local emergency room with a blood pressure of 183 / 124 mmHg. After a comprehensive medical evaluation, no other cause for the hypertension was found, so she was instructed to discontinue donepezil. Over the next few weeks, her blood pressure slowly decreased but remained elevated at 140 / 95 mmHg.

[0086] Case 2 (the present invention)

[0087] Patient description

[0088] Patient #2 is a 21-year-old woman who developed restrictive anorexia nervosa during adolescence. She is very strict about the foods she eats and avoids processed foods or foods high in sugar or fat. She exercises three to four hours daily. Because of her constant anxiety, she cannot reduce her exercise even slightly. She is unable to eat enough to maintain a healthy weight. Her BMI is 18.5 kg / m2 , her condition stabilized when she started taking donepezil.

[0089] Treatment with donepezil at a daily dose of 0.5 to 2.5 mg

[0090] Patient #2 received donepezil with the following regimen:

[0091] Treatment began with a daily dose of donepezil of 0.5 mg for 10 days, then the daily dose was increased to 1 mg for 7 days, then to 1.5 mg for 71 days (2 months and 10 days), then to 2 mg for 22 days, then to 2.5 mg and maintained at this dose for 4 months and 18 days.

[0092] Benefits of donepezil for patient #2:

[0093] Her blood pressure was monitored and was not affected. She had no other side effects. Over the next five months, she reported a decrease in rumination and compulsive exercise. She was able to reduce her exercise to a goal of 90 minutes per day. She had more flexibility in her diet, incorporating a wider variety of foods, including sugary foods. She was also able to be more flexible with her eating and exercise schedules. Her BMI exceeded 20 kg / m for the first time. 2 She also stopped caring so much about her weight or appearance and was able to tolerate weight gain.

[0094] The results of anxiety

[0095] Patient #2's anxiety was also assessed before and after treatment using the Generalized Anxiety Disorders Assessment (GAD-7) questionnaire (available at https: / / adaa.org / sites / default / files / GAD-7_Anxiety-updated_0.pdf). The scores were as follows:

[0096]

[0097]

[0098] The scores obtained with the questionnaire GAD-7 are categorized as follows:

[0099] 5-9: Mild anxiety; 10-14: Moderate anxiety; 15-21: Severe anxiety

[0100] Therefore, after treatment with donepezil, patient #2 also experienced a decrease in anxiety.

[0101] Results for depression

[0102] Patient #2's depressive symptoms were also assessed before and after treatment using the Patient Health Questionnaire (PHQ-9) (available at https: / / med.stanford.edu / fastlab / research / imapp / msrs / _jcr_content / main / accordion / accordion_content3 / download_256324296 / file.res / PHQ9%20id%20date%2008.03.pdf). The scores were as follows:

[0103]

[0104] The scores obtained with the questionnaire PHQ-9 are categorized as follows:

[0105] 5-9: Mild depression; 10-14: Moderate depression; 15-19: Moderate to severe depression; 20-27: Severe depression Therefore, after treatment with donepezil, patient #2's depressive symptoms also decreased.

[0106] Results for obsessive-compulsive disorder

[0107] Patient #2's obsessive-compulsive disorder (OCD) symptoms were also assessed before and after treatment using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) questionnaire (available at https: / / pcl.psychiatry.uw.edu / wp-content / uploads / 2021 / 12 / YBOCS.pdf). The scores were as follows:

[0108]

[0109] The scores obtained with the questionnaire Y-BOCS are categorized as follows:

[0110] 0-7: subclinical; 8-15: mild symptoms; 16-23: moderate symptoms; 24-31: severe symptoms; 32-40: extreme symptoms

[0111] Therefore, after treatment with donepezil, patient #2 also experienced a reduction in his OCD symptoms.

[0112] Case 3 (present invention)

[0113] Patient description

[0114] Patient #3 was a 36-year-old woman who had suffered from anorexia nervosa (bulimia nervosa) for 20 years. She had been in recovery for two years before relapsing following a relationship trauma. She had been slowly losing weight, bingeing every night and inducing vomiting multiple times. She would wake up at 4 a.m. every morning and exercise frantically for hours. She spent all her disposable income on binge eating, and her savings were gradually depleted. She would sometimes steal food to support her binge eating.

[0115] Treatment with donepezil at a daily dose of 0.5 to 2.5 mg

[0116] Patient #3 received donepezil with the following regimen:

[0117] Treatment was initiated with a daily dose of donepezil of 0.5 mg for 10 days, then the daily dose was increased to 1 mg for 9 days, then to 1.5 mg for 17 days, then to 2 mg for 7 days, then to 2.5 mg for 16 days, and then discontinued.

[0118] Benefits of donepezil for patient #3:

[0119] A month after starting the medication, she was able to significantly reduce her binge eating (and the vomiting that came with it). She only spent $5 on binge eating and stopped stealing food altogether. She no longer had to use her savings to fund her binge eating. She is still receiving treatment.

[0120] Case 4 (the present invention)

[0121] Patient #4 is a 19-year-old girl who has had restrictive anorexia nervosa for 10 years and has had difficulty gaining weight. She does not exercise excessively but has a very restrictive diet. She has struggled with weight gain and has struggled with severe body image distortion, eating disorder cognitions, and ruminations. Despite a BMI below 15 kg / m 2 , but she still felt that she was too heavy. In one year, she gained weight and her BMI went from 11kg / m 2 The low point rebounded to 15kg / m 2 However, over the next seven months, she continued to gain no weight and her BMI stagnated.

[0122] Treatment with donepezil at a daily dose of 0.5 to 1.5 mg

[0123] Patient #4 received donepezil with the following regimen:

[0124] Treatment started with a daily dose of donepezil of 0.5 mg for 13 days, then the daily dose was increased to 0.75 mg for 9 days, then to 1 mg for 17 days, then to 1.5 mg and maintained at this dose for one month, then stopped for two months, then restarted at a daily dose of 1.5 mg, maintained for one month, and then stopped.

[0125] Benefits of donepezil for patient #4:

[0126] After one month of daily dosing at 1.5 mg, she reported greater flexibility in her diet, less obsession with her eating disorder cognitions, and no longer having a strong desire to diet and lose weight. Her weight also increased to 15.6 kg / m 2 However, after the first month, she discontinued medication, and over the next two months, her beliefs about her eating disorder and her obsession with weight restriction and weight loss became increasingly persistent. She decided to restart donepezil at a daily dose of 1.5 mg for one month. Her diet became more flexible, and she began to slowly gain weight, and she continued to improve even after discontinuing treatment.

[0127] Patient #4 was assessed for eating disorders before and after treatment using the Eating Disorder Examination Questionnaire (EDE-q) (available at https: / / www.corc.uk.net / outcome-experience-measures / eating-disorder-examination-questionnaire-ede-q / ), with the following results:

[0128]

[0129] The scores obtained with the questionnaire EDE-q are categorized as follows:

[0130] Scores of 4 or higher indicate the clinical range, while scores above 2.8 indicate the possibility of clinically significant pathology (Jennings KM, Phillips KE. Arch Psychiatr Nurs. 2017(6):578-581. doi:10.1016 / j.apnu.2017.08.002; and Velkoff EA et al. Eat Disord. 2023;31(5):464-478. doi:10.1080 / 10640266.2023.2191488).

[0131] The results of anxiety

[0132] Patient #4's anxiety was also assessed using the GAD-7 questionnaire before and after treatment. The scores were as follows:

[0133]

[0134] The scores obtained with the questionnaire GAD-7 are categorized as follows:

[0135] 5-9: Mild anxiety; 10-14: Moderate anxiety; 15-21: Severe anxiety

[0136] Thus, a reduction in anxiety was also observed in patient #4 after treatment with donepezil.

[0137] Results for depression

[0138] Patient #4's depressive symptoms were also assessed using the PHQ-9 questionnaire before and after treatment. The scores were as follows:

[0139]

[0140] The scores obtained with the questionnaire PHQ-9 are categorized as follows:

[0141] 5-9: Mild depression; 10-14: Moderate depression; 15-19: Moderate to severe depression; 20-27: Severe depression

[0142] Thus, a reduction in depressive symptoms was also observed in patient #4 after receiving donepezil treatment.

[0143] Results for obsessive-compulsive disorder

[0144] Patient #4 was also evaluated for obsessive-compulsive disorder (OCD) symptoms using the Y-BOCS questionnaire before and after treatment. The scores were as follows:

[0145]

[0146] The scores obtained with the questionnaire Y-BOCS are categorized as follows:

[0147] 0-7: subclinical; 8-15: mild symptoms; 16-23: moderate symptoms; 24-31: severe symptoms; 32-40: extreme symptoms

[0148] Thus, a reduction in OCD symptoms was also observed in patient #4 after receiving donepezil treatment.

[0149] Case 5 (present invention)

[0150] A 43-year-old patient presented with anorexia nervosa during her second pregnancy at age 36. She had been concerned about her calorie intake and body image since adolescence. She also had recurrent depression, treated with venlafaxine 75 mg daily, and generalized anxiety disorder. At age 41, her malnutrition had worsened significantly, with a minimum BMI of 11 kg / m2.2 Except for pregnancy, the patient's highest BMI in her life was 19.8 kg / m 2 Symptoms primarily consist of qualitative and quantitative food restriction and excessive physical activity. Patients experience months of excessive eating and vomiting. Neurocognitive executive function is adequate, with patients demonstrating a high tolerance for delayed rewards as measured by the Delay Discounting Task.

[0151] Treatment with donepezil at a daily dose of 2.5 mg

[0152] Donepezil was taken at 2.5 mg per day for 2 months.

[0153] Benefits of donepezil for patient #5:

[0154] At the end of the treatment period, patient #5 started eating more easily, had lunch every day with relatives, and increased her weight from 27 kg to 36 kg in three months.

[0155] Case 6 (present invention)

[0156] A 34-year-old woman presented with a 20-year history of anorexia nervosa (binge / purging subtype) and a comorbid obsessive-compulsive disorder. Her symptoms were prominent throughout adolescence, with partial remission in early adulthood. Over the next 10 years, her symptoms waxed and waned, with two severe relapses, both of which gradually resolved. She had regained her weight, but relapsed under the influence of environmental stressors. She struggled with increasing disordered eating ruminations and cognitions, as well as a distorted and dissatisfied body image. She became more rigid and restrictive in her eating habits. Her obsessive-compulsive disorder symptoms also worsened.

[0157] Treatment with donepezil at a daily dose of 0.5 mg to 2.5 mg

[0158] Patient #6 received donepezil with the following regimen:

[0159] Treatment was initiated with a daily dose of donepezil of 0.5 mg for 8 days, then the daily dose was increased to 1 mg for 9 days, then to 1.67 mg for 62 days, and then to 2.5 mg.

[0160] She continued to take a higher dose (5 mg daily) of donepezil for treatment of her obsessive-compulsive disorder.

[0161] Benefits of donepezil for patient #6:

[0162] Over a three-month period, she experienced a significant decrease in her eating disorder cognitions and ruminations, as well as a reduction in the intensity of her body image distress.

[0163] Patient #6 was evaluated for eating disorders using the EDE-q questionnaire before and after treatment, with the following results:

[0164]

[0165] The scores obtained with the questionnaire EDE-q are categorized as follows:

[0166] Scores of 4 or higher indicate clinical range, while scores above 2.8 indicate the possibility of clinically significant pathology.

[0167] The results of anxiety

[0168] Patient #6's anxiety was also assessed using the GAD-7 questionnaire before and after treatment. The scores were as follows:

[0169]

[0170] The scores obtained with the questionnaire GAD-7 are categorized as follows:

[0171] 5-9: Mild anxiety; 10-14: Moderate anxiety; 15-21: Severe anxiety

[0172] Thus, a significant reduction in anxiety was also observed in Patient #6 after receiving donepezil treatment.

[0173] Results for depression

[0174] Patient #6 was also evaluated for depressive symptoms using the PHQ-9 questionnaire before and after treatment. The scores were as follows:

[0175]

[0176] The scores obtained with the questionnaire PHQ-9 are categorized as follows:

[0177] 5-9: Mild depression; 10-14: Moderate depression; 15-19: Moderate to severe depression; 20-27: Severe depression

[0178] Thus, a reduction in depressive symptoms was also observed in patient #6 after receiving donepezil treatment.

[0179] Results for obsessive-compulsive disorder

[0180] Patient #6 was also evaluated for obsessive-compulsive disorder (OCD) symptoms using the Y-BOCS questionnaire before and after treatment. The scores were as follows:

[0181]

[0182] The scores obtained with the questionnaire Y-BOCS are categorized as follows:

[0183] 0-7: subclinical; 8-15: mild symptoms; 16-23: moderate symptoms; 24-31: severe symptoms; 32-40: extreme symptoms

[0184] Thus, a reduction in OCD symptoms was also observed in patient #6 after receiving donepezil treatment.

[0185] in conclusion

[0186] Patient #1 treated with 5 mg PO OD experienced severe side effects (high blood pressure and severe headache). Other patients treated with lower doses (0.5 to 2.5 mg PO OD) improved without experiencing severe side effects.

[0187] These clinical cases demonstrate that low doses of donepezil, ranging from 0.5 to 2.5 mg / day, can be used to treat anorexia and associated compulsive behaviors without any side effects, thereby improving patient compliance with treatment.

Claims

1. A compound of the following formula (I): Wherein X is an oxygen atom or a group N-OH, or a pharmaceutically acceptable salt and / or solvate thereof for use in preventing and / or treating obsessive-compulsive disorder in a subject in need thereof, characterized in that The compound of formula (I) is administered to the subject at a daily dose of 0.25 mg to 2.5 mg.

2. The compound for use according to claim 1, characterized in that The daily dosage is 0.5 mg to 2 mg, preferably 0.5 mg to 1.5 mg.

3. The compound for use according to claim 1 or 2, characterized in that X is an oxygen atom, and the compound of formula (I) is donepezil.

4. The compound for use according to any one of claims 1 to 3, characterized in that Obsessive compulsive disorder is an eating disorder, preferably anorexia.

5. The compound for use according to any one of claims 1 to 4, which is administered as a pharmaceutical composition comprising a compound of formula (I) as an active ingredient and a pharmaceutically acceptable excipient.

6. The compound for use according to any one of claims 1 to 5, for oral administration.

7. The compound for use according to any one of claims 1 to 6, which is administered in a solid unit dosage form.

8. The compound for use according to any one of claims 1 to 7, characterized in that The daily dose is a single administration.

9. A unit dosage form comprising 0.25 mg to 2.5 mg of a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof.

10. The unit dosage form according to claim 9, for use as a medicament.

11. The unit dosage form according to claim 10, for use in the prevention and / or treatment of obsessive compulsive disorders, such as eating disorders, in particular anorexia.

12. The unit dosage form according to claim 11, characterized in that Obsessive compulsive disorder is an eating disorder, especially anorexia.

13. The unit dosage form according to any one of claims 10 to 12, which is administered once daily to a subject in need thereof.

Images