Treatment of hypothalamic obesity

Abstract

The present disclosure relates to the treatment of hypothalamic obesity with tesofensine alone or in combination with a beta-blocker. In particular, the disclosure relates to treatments that result in weight loss, a reduction in fat mass, particularly visceral fat, and a reduction in pre-diabetic symptoms in patients with hypothalamic obesity.

Description

[Technical Field]

[0001] The present disclosure relates to the treatment of hypothalamic obesity, particularly to treatments that result in weight loss, a reduction in fat mass, particularly visceral fat, as well as the reduction of pre-diabetic symptoms in patients suffering from hypothalamic obesity. [Background technology]

[0002] Hypothalamic obesity (HO) is a rare disease characterized by constant food cravings that can have serious consequences for patients. Hypothalamic obesity can result from damage to the hypothalamus, for example, from the growth or surgical removal of rare brain tumors, and from other types of damage to the hypothalamus, including stroke, brain trauma, or radiation for cancer patients. The hypothalamus is a micronucleus in the brain that controls important biological functions, including body temperature, hunger, and weight. Rare brain tumors, craniopharyngiomas, or surgical removal of these tumors are the most common causes of hypothalamic obesity. Therefore, hypothalamic obesity is sometimes referred to as craniopharyngioma-associated obesity.

[0003] Craniopharyngiomas are benign tumors that most commonly affect children between the ages of 5 and 10, although they can also develop in adulthood. Craniopharyngiomas are also a rare disease with an estimated prevalence of 1:50,000 in the United States. Treatment involves surgical removal of the tumor in almost all patients. The procedure can result in complications, including damage to the hypothalamus, which can lead to loss of appetite control, insatiable hunger, and morbid obesity. A high incidence of hypothalamic obesity, ranging from 30% to 77%, has been reported after the procedure. Because of the Prader-Willi syndrome-like insatiable hunger, hypothalamic obesity is sometimes referred to as "acquired Prader-Willi syndrome."

[0004] To date, no viable long-term solution for HO has been found, either due to the need for an intact hypothalamic pathway or significant side effects (Abuzzahab et al, Hypothalamic Obesity: Prologue and Promise, Horm Res Paediatr. 2019;91(2):128-136. doi:10.1159 / 000496564. Epub 2019 Mar 18).

[0005] Tesofensine, or [(1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-2-(ethoxymethyl)-8-methyl-8-azabicyclo[3.2.1]octane], first described in WO 97 / 30997, is a triple monoamine reuptake inhibitor being developed for the treatment of obesity.

[0006] Tesofensine effectively induces approximately twice the weight loss seen with currently available anti-obesity drugs in obese individuals. Results from clinical studies using tesofensine also demonstrated that the compound has a favorable safety profile and is well tolerated. However, while no clinically relevant cardiovascular adverse events were observed, increased heart rate and small increases in blood pressure were also observed at high doses. While such small effects do not pose an immediate risk to patients, some medical and regulatory concerns have been raised based on observational studies, and even small changes in cardiovascular parameters may have long-term impacts on patients' benefit / risk assessments.

[0007] Preclinical and clinical data suggest that appetite suppression is an important mechanism by which tesofensine exerts its potent weight-loss effects. In particular, the strong anorectic response to tesofensine treatment (i.e., decreased appetite, reduced food intake, and decreased sweet and sugar cravings) is shown to be associated with central stimulation of serotonergic, noradrenergic, and dopaminergic neurotransmission. However, tesofensine's sympathomimetic mode of action may also be associated with the elevated heart rate and blood pressure observed in the clinical setting.

[0008] Beta-blockers (β-blockers, beta-adrenergic blockers, beta antagonists, beta-adrenergic antagonists, beta-adrenergic receptor antagonists, or beta-adrenergic receptor antagonists) are a class of drugs typically used in the management of arrhythmias, to protect the heart from a second heart attack (myocardial infarction) after a first heart attack (secondary protection), and, in certain cases, to protect against hypertension. Beta-blockers are also known for their reducing effect on heart rate.

[0009] Metoprolol, or 1-(isopropylamino)-3-[4-(2-methoxyethyl)-phenoxy]-propan-2-ol, branded under various trade names, is a selective β1 (adrenergic) receptor blocker commonly used to treat various diseases of the cardiovascular system, especially hypertension.

[0010] Carvedilol ((±)-[3-(9H-carbazol-4-yloxy)-2-hydroxypropyl][2-(2-methoxyphenoxy)ethyl]amine) is a mixed, or nonselective, alpha and beta blocker. It is sold under various brand names and is traditionally used to treat mild to severe congestive heart failure (CHF) and hypertension.

[0011] WO 2013 / 120935 describes the treatment of obesity by co-administration of tesofensine and metoprolol to ameliorate drug-induced increases in blood pressure or heart rate.

[0012] The serum half-life of tesofensine is 9 days (Bara-Jimenez W, Dimitrova T, Sherzai A, Favit A, Mouradian MM, Chase TN (2004). "Effect of monoamine reuptake inhibitor NS 2330 in advanced Parkinson's disease." Mov Disord 19(10):1183-6). In comparison, the half-lives of beta-blockers are very short: 3-4 hours for metoprolol and approximately 7-10 hours for carvedilol. Therefore, simultaneous daily administration of these two drugs likely induces large fluctuations in beta-blocker serum levels and potentially recurs a temporary lack of beta-blocker therapeutic effect. Summary of the Invention

[0013] The present invention relates to a method for the treatment of hypothalamic obesity comprising the daily administration to a patient suffering from hypothalamic obesity of a pharmaceutical composition comprising 0.01 mg to 1.5 mg of tesofensine or a pharmaceutically acceptable salt thereof.

[0014] We conducted a phase 2 clinical trial in patients with hypothalamic obesity using low-dose tesofensine, demonstrating statistically significant and clinically relevant reductions in body weight, waist circumference, fat mass, and HbA1c levels. Tesofensine was co-administered with a sustained-release formulation of metoprolol, which counteracted the effects of tesofensine on heart rate and blood pressure.

[0015] In this treatment-resistant patient population, treatment was effective and well tolerated with few side effects. Notably, there were no clinically meaningful differences in heart rate and blood pressure between treatment groups, demonstrating that the doses of tesofensine and metoprolol were well matched.

[0016] In an embodiment of the present disclosure, the patient's weight is reduced by at least 3%, for example, 5% to 10%, or 6% to 8% after 6 months of treatment.

[0017] In other embodiments, the patient's waist circumference is reduced by at least 4 cm, e.g., 4 cm to 6 cm, or 6 cm to 10 cm, 6 months after treatment. The reduction in waist circumference reflects the loss of visceral fat.

[0018] In a further embodiment, the patient's fat mass is reduced by at least 2 kg, e.g., 2 kg to 8 kg, or 3 kg to 6 kg, after 6 months of treatment. After long-term treatment (6 to 12 months), lean body mass tends to increase, suggesting muscle gain after the initial loss of fat mass.

[0019] A reduction in HbA1c is evidence that the symptoms of prediabetes or diabetes can be reduced in a patient. In a further embodiment, the treatment reduces one or more symptoms of prediabetes, diabetes, metabolic syndrome, dyslipidemia, atherosclerosis, overeating, bulimia nervosa, binge eating disorder, compulsive overeating, impaired appetite control, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH).

[0020] In one aspect, the present invention relates to a method for reducing weight in a patient suffering from hypothalamic obesity, the method comprising daily administration to said patient of a pharmaceutical composition comprising 0.01 mg to 1.5 mg of tesofensine or a pharmaceutically acceptable salt thereof.

[0021] In one aspect, the present invention relates to a method for reducing waist circumference in a patient suffering from hypothalamic obesity, the method comprising daily administration to said patient of a pharmaceutical composition comprising 0.01 mg to 1.5 mg of tesofensine or a pharmaceutically acceptable salt thereof.

[0022] In one aspect, the present invention relates to a method for reducing body fat in a patient suffering from hypothalamic obesity, the method comprising daily administration to the patient of a pharmaceutical composition comprising 0.01 mg to 1.5 mg of tesofensine or a pharmaceutically acceptable salt thereof. The body fat may be visceral fat.

[0023] In one aspect, the present invention relates to a method for reducing liver fat in a patient suffering from hypothalamic obesity, the method comprising daily administration to the patient of a pharmaceutical composition comprising 0.01 mg to 1.5 mg of tesofensine or a pharmaceutically acceptable salt thereof.

[0024] In one aspect, the present invention relates to a method for reducing serum HbA1c levels in a patient suffering from hypothalamic obesity, the method comprising daily administration of a pharmaceutical composition comprising 0.01 mg to 1.5 mg of tesofensine or a pharmaceutically acceptable salt thereof to the patient. Preferably, the patient suffers from type 2 diabetes, prediabetes, metabolic syndrome, insulin resistance, or glucose intolerance, preferably type 2 diabetes.

[0025] In one aspect, the present invention relates to a pharmaceutical composition comprising 0.01 mg to 1.5 mg of tesofensine, or a pharmaceutically acceptable salt thereof, for use in treating hypothalamic obesity in a subject suffering from hypothalamic obesity.

[0026] In one aspect, the invention relates to the use of a pharmaceutical composition comprising 0.01 mg to 1.5 mg of tesofensine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of hypothalamic obesity. [Brief explanation of the drawings]

[0027] [Figure 1]Comparison of weight loss in Tesomet (a combination of tesofensine and metoprolol) and placebo-treated subjects in Example 1. Changes in weight are given as percentages compared to baseline (mITT population). Data points for treatment and placebo were recorded on the same day during clinic visits. Solid line: placebo; dashed line (treatment): Tesomet. [Figure 2] Comparison of changes in waist circumference in Tesomet and placebo-treated subjects in Example 1. Changes in body waist circumference are given as percentages compared to baseline (mITT population). Data points for treatment and placebo were recorded on the same day during clinic visits. Solid line: placebo; dashed line (treatment): Tesomet. [Figure 3a] Treatment with Tesomet compared with placebo resulted in a statistically significant difference in the number of responders with a ≥ 5% weight loss from baseline at 24 weeks during the double-blind treatment period, and this effect was maintained after an additional 24 weeks of open-label Tesomet treatment. Patients treated with placebo during the initial 24-week double-blind period of the study and then receiving 24 weeks of Tesomet treatment during the open-label extension period also showed a significant improvement in the number of responders with a ≥ 5% weight loss from baseline. [Figure 3b] Treatment with Tesomet compared with placebo resulted in a significant difference in the number of responders with a ≥10% weight loss from baseline at 24 weeks during the double-blind treatment period, and this effect remained high after an additional 24 weeks of open-label Tesomet treatment. Patients treated with placebo during the initial 24-week double-blind period of the study and then receiving 24 weeks of Tesomet treatment during the open-label extension period also showed a significant improvement in the number of responders with a ≥10% weight loss from baseline. [Figure 4] Tesomet treatment resulted in clinically meaningful reductions in HbA1c levels in patients with type 2 diabetes after 24 to 48 weeks of treatment, while no effect was seen in normoglycemic patients. [Figure 5]Compared with placebo, treatment with Tesomet resulted in statistically significant and clinically meaningful weight loss from baseline through 24 weeks of treatment, and this effect was maintained after an additional 24 weeks of open-label Tesomet treatment. Patients treated with placebo during the first 24 weeks of the study, followed by 24 weeks of open-label Tesomet treatment, also demonstrated clinically meaningful weight loss from baseline. [Figure 6] Compared to placebo, treatment with Tesomet resulted in clinically meaningful reductions in fat mass from baseline through 24 weeks of treatment, and this effect was maintained after an additional 24 weeks of open-label Tesomet treatment. Patients treated with placebo during the first 24 weeks of the study, followed by 24 weeks of open-label Tesomet treatment, also demonstrated clinically meaningful reductions in fat mass from baseline. [Figure 7] Patients treated with Tesomet during the 24-week double-blind phase, followed by an additional 24 weeks of open-label Tesomet treatment, showed evidence of increased lean tissue mass during the open-label extension. During the double-blind phase, Tesomet-treated patients lost lean mass. In contrast, patients who received a placebo during the 24-week double-blind phase, followed by an additional 24 weeks of open-label Tesomet treatment, showed evidence of decreased lean tissue mass. DETAILED DESCRIPTION OF THE INVENTION

[0028] HO typically occurs in patients with tumors and lesions in the medial hypothalamic region. Hypothalamic dysfunction can lead to hyperinsulinemia and leptin resistance. These patients often have damage to the hypothalamus. Damage to the hypothalamus has long been known to promote excessive eating (hyperphagia) and weight gain, termed "hypothalamic obesity." This form of weight gain often does not respond to diet and exercise.

[0029] Body mass index (BMI) is a value derived from a person's weight and height. BMI is defined as weight divided by height squared, expressed in kg / m 2In one aspect, the present disclosure relates to a method for reducing or maintaining BMI in a patient with hypothalamic obesity.

[0030] The terms "subject" and "patient" are used interchangeably herein.

[0031] People are generally considered overweight or pre-obese if their BMI is between 25 and 30, and obese if their BMI is above 30. Morbidly obese subjects have a BMI above 35.

[0032] In one embodiment, the subject is 2 More than, for example, 30 kg / m 2 More than, for example, 35 kg / m 2 More than, for example, 40 kg / m 2 Have a BMI above .

[0033] In one embodiment, the subject is 2 Have a BMI above .

[0034] In one embodiment, the subject is 2 Have a BMI above .

[0035] Tesofensine is preferably administered to the subject who needs it once a day.However, in certain embodiments, Tesofensine can be administered more than once a day, such as twice a day, or alternatively less than once a day, such as once every two or three days, depending on the concentration of each component of the specific formulation and composition.The subject to be treated is preferably a human, such as an adult over 18 years old.

[0036] To approve a regular weight loss product, the FDA requires the following: A statistically significant difference of ≥ 5% in weight loss from baseline between actively treated and placebo treated patients At least 35% of patients in the active treatment group will achieve a weight loss of ≥ 5% from baseline The proportion of patients with a weight loss of ≥ 5% in the active group is at least twice that of the placebo group It has.

[0037] These requirements do not necessarily apply to rare diseases such as hypothalamic obesity, which involves intractable obesity that is resistant to lifestyle changes and standard weight loss treatments.

[0038] As shown in Figure 3a, approximately two-thirds of patients experienced at least a 5% weight loss after 24 weeks of treatment. 33% to 41% of patients experienced at least a 10% weight loss, thus significantly exceeding FDA requirements (Figure 3b). It is also shown that weight loss is maintained after the first six months of tesofensine therapy (Figure 5). It is very common for weight loss therapies to have temporary effects.

[0039] In one embodiment, treatment as described herein results in the alleviation or amelioration of pre-diabetes or diabetic complications.

[0040] Type 2 diabetes is a metabolic disease characterized by hyperglycemia due to the association of insulin resistance and relative insulin deficiency. Type 2 diabetes accounts for approximately 90% of diabetes cases, with the remaining 10% being primarily due to type 1 diabetes and gestational diabetes. Obesity is thought to be a major cause of type 2 diabetes in people genetically predisposed to it.

[0041] Prediabetes is used interchangeably herein with moderate hyperglycemia. Moderate hyperglycemia is a biochemical state in which a person has blood glucose levels above the normal range but has not yet met the diagnostic criteria for diabetes. The primary goal of managing moderate hyperglycemia is to prevent progression to diabetes.

[0042] Prediabetic subjects were defined as those with impaired fasting glucose (IFG) and / or impaired glucose tolerance (IGT) and / or elevated glycosylated hemoglobin (HbA 1c ) levels.

[0043] Weight loss can prevent the progression of prediabetes to diabetes and can also significantly improve the clinical symptoms of type 2 diabetes, making it an attractive treatment strategy for subjects with prediabetes and type 2 diabetes.

[0044] In one embodiment, the patient suffering from hypothalamic obesity is obese and may be pre-diabetic, hi one embodiment, the patient suffers from type 2 diabetes.

[0045] The WHO criteria for diagnosing diabetes are shown in the table below.

[0046] [Table 1]

[0047] HO patients who would benefit from treatment with the compositions of the present disclosure may also suffer from an obesity-related disease or condition, such as those selected from the group consisting of prediabetes, diabetes, metabolic syndrome, dyslipidemia, atherosclerosis, drug-induced obesity, binge eating disorder, bulimia nervosa, binge eating disorder, compulsive overeating, impaired appetite regulation, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH).

[0048] In still further embodiments, HbA1c in the patient is reduced by at least 3 mmol / mol, eg, 3 mmol / mol to 9 mmol / mol, or 4 mmol / mol to 8 mmol / mol, after 6 months of treatment.

[0049] In particular, it is expected that treatment may result in the treatment of fatty liver diseases such as non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

[0050] Nonalcoholic fatty liver disease (NAFLD) is a cause of fatty liver disease that occurs when fat accumulates in the liver (steatosis) due to causes other than excessive alcohol consumption. NAFLD is the most common liver disorder in Western developed countries. NAFLD is associated with insulin resistance and metabolic syndrome (obesity, combined hyperlipidemia, diabetes mellitus (type 2), and hypertension). Nonalcoholic steatohepatitis (NASH) is the most extreme form of NAFLD and the leading cause of cirrhosis of the liver. NASH is a condition in which fatty liver is accompanied by a combination of inflammation and fibrosis (steatohepatitis).

[0051] In one embodiment, the treatment of the present disclosure results in a reduction in liver fat and / or visceral fat, which has been shown to be effective in treating fatty liver disorders.

[0052] Tesofensine The methods described herein involve the administration of an active ingredient (API) selected from tesofensine or a pharmaceutically acceptable salt thereof.

[0053] Tesofensine [(1R,2R,3S,5S)-3-(3,4-dichlorophenyl)-2-(ethoxymethyl)-8-methyl-8-azabicyclo[3.2.1]octane] is a centrally acting triple monoamine reuptake inhibitor (MRI) with intrinsic inhibitory activity against norepinephrine, serotonin, and dopamine transporter function. After correcting for placebo and diet effects, chronic tesofensine treatment produces approximately 10% weight loss in obese patients, which is typically double that achieved with currently marketed anti-obesity medications.

[0054] The chemical structure of tesofensine is:

[0055] [ka]

[0056] is.

[0057] Preclinical and clinical data suggest that appetite suppression is an important mechanism by which tesofensine exerts its potent weight-loss effects. Additionally, tesofensine has also been shown to increase nocturnal energy expenditure in human subjects. These findings have recently been corroborated and expanded in a preclinical setting, suggesting that tesofensine induces potent and sustained weight loss in a rat model of diet-induced obesity (DIO), with the prolonged weight loss driven by appetite suppression accompanied by a gradual increase in energy expenditure. Notably, the anorectic effect of tesofensine in DIO rats is highly dependent on stimulated α1-adrenergic receptor activity and, to a lesser extent, on dopamine D1 receptor function, suggesting that enhanced central noradrenergic and dopaminergic neurotransmission constitutes an important mechanism underlying tesofensine's potent appetite-suppressing effects.

[0058] Overall, chronic tesofensine treatment was associated with mild adverse events and minimal cardiovascular effects, suggesting that tesofensine may generally be a well-tolerated long-term treatment for obesity. However, dose-dependent increases in heart rate and significant increases in blood pressure have been reported in obese individuals. The long-term consequences of such tesofensine-induced cardiovascular effects are unknown and could potentially play a role in the benefit / risk assessment of patients treated with tesofensine.

[0059] The dose preferably results in a steady-state plasma or serum concentration of tesofensine of 5 ng / mL to 15 ng / mL, e.g., 7 ng / mL to 13 ng / mL, which is expected to result in weight loss, body fat loss, or waist circumference loss.

[0060] For weight maintenance, the dose preferably results in a steady state plasma concentration of tesofensine of 3 ng / mL to 6 ng / mL.

[0061] Beta-blockers In certain embodiments, the present disclosure includes the use of a beta-blocker. The beta-blocker can be any conventional beta-blocker known in the art. Preferably, the beta-blocker is selected from the following compounds, which are known in the art and may be commercially available under different trade names or may be obtained as described in the literature:

[0062] In one embodiment, the pharmaceutical composition comprises an extended release (ER) composition of a beta-blocker. In one embodiment, the pharmaceutical composition comprises an extended release (ER) composition of a beta-blocker and an immediate release (IR) composition of a beta-blocker.

[0063] In one embodiment, the beta-blocker in the ER composition is the same beta-blocker as in the IR composition.

[0064] In one embodiment, the pharmaceutical composition comprises ER metoprolol and IR metoprolol.

[0065] As used herein, the term "ER metoprolol" refers to an extended release (ER) composition of metoprolol, or a pharmaceutically acceptable salt thereof.

[0066] As used herein, the term "IR metoprolol" refers to an immediate release (IR) composition of metoprolol, or a pharmaceutically acceptable salt thereof.

[0067] Nonselective beta-blockers In one embodiment, the beta blocker is a non-selective beta blocker. Examples of non-selective beta blockers include alprenolol, amosulalol, bucindolol, carteolol, levobunolol, mepindolol, metipranolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, and timolol.

[0068] In one embodiment, the beta blocker is selected from the group consisting of alprenolol, amosulalol, bucindolol, carteolol, levobunolol, mepindolol, metipranolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, timolol, and pharmaceutically acceptable salts thereof.

[0069] Beta-1-selective beta-blockers In another embodiment, the beta blocker is a beta 1 selective beta blocker.

[0070] Examples of beta 1 selective beta blockers include acebutolol, atenolol, betaxolol, bisoprolol, esmolol, landiolol, metoprolol and nebivolol.

[0071] In one embodiment, the beta blocker is selected from the group consisting of acebutolol, atenolol, betaxolol, bisoprolol, esmolol, landiolol, metoprolol, nebivolol, and pharmaceutically acceptable salts thereof.

[0072] In certain embodiments, the beta blocker is metoprolol or a pharmaceutically acceptable salt thereof.

[0073] Combined alpha- and beta-blockers In still further embodiments, the beta blocker is a mixed alpha and beta blocker.

[0074] Examples of combined alpha and beta blockers include carvedilol, celiprolol, and labetalol.

[0075] In one embodiment, the beta blocker is selected from the group consisting of carvedilol, celiprolol, labetalol, and pharmaceutically acceptable salts thereof.

[0076] In certain embodiments, the beta blocker is carvedilol or a pharmaceutically acceptable salt thereof.

[0077] Beta-2-selective beta-blockers In still further embodiments, the beta blocker is a beta2 selective beta blocker.

[0078] An example of a beta2 selective beta blocker is butaxamine.

[0079] In one embodiment, the beta blocker is butaxamine or a pharmaceutically acceptable salt thereof.

[0080] Pharmaceutically acceptable salts Examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic inorganic and organic acid addition salts such as hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconitate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, p-toluenesulfonate, etc. Such salts may be formed by procedures well known and described in the art.

[0081] Examples of pharmaceutically acceptable cationic salts of an API include, but are not limited to, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, choline, lysinium, and ammonium salts of an API containing an anionic group, etc. Such cationic salts may be formed by procedures well known and described in the art.

[0082] In the context of this disclosure, the "onium salts" of N-containing compounds are also considered to be pharmaceutically acceptable salts. Preferred "onium salts" include alkyl-onium salts, cycloalkyl-onium salts, and cycloalkylalkyl-onium salts.

[0083] In one embodiment of the present disclosure, tesofensine is selected from the free base, citrate, and tartrate salts.

[0084] Suitable pharmaceutically acceptable salts of metoprolol include any of the salts described herein, preferably the tartrate, succinate, fumarate, or benzoate, especially the succinate. The S enantiomer of metoprolol or its salts, especially the benzoate or sorbate, can also be used.

[0085] Pharmaceutical Composition The dose of tesofensine, optionally in combination with a beta-blocker, is 0.1 mg to 1.5 mg. When administered with a beta-blocker, the two active ingredients can be formulated in a single formulation or given as two separate entities.

[0086] In one embodiment, the pharmaceutical composition comprises: a. a first composition comprising an extended release (ER) composition of an active ingredient (API) selected from a beta-blocker or a pharmaceutically acceptable salt thereof; and b. A second composition comprising an active ingredient (API) selected from tesofensine or a pharmaceutically acceptable salt thereof. Includes:

[0087] Optionally, the pharmaceutical composition comprises: c. A third composition comprising an immediate release (IR) composition of an active ingredient (API) selected from a beta-blocker or a pharmaceutically acceptable salt thereof. It may further include:

[0088] In one aspect, the present disclosure relates to a pharmaceutical composition comprising the first, second, and third compositions. In one embodiment, the pharmaceutical composition comprises 1.5 mg or less, e.g., 1 mg or less, of tesofensine or a pharmaceutically acceptable salt thereof; 5 mg to 100 mg of an ER beta-blocker, e.g., metoprolol; and 1 mg to 25 mg of an IR beta-blocker, e.g., metoprolol.

[0089] The beta-blocker can be, for example, metoprolol or carvedilol or a pharmaceutically acceptable salt thereof, including phosphate, succinate, maleate, sulfate, glutarate, lactate, benzoate, and mandelate salts.

[0090] The in vitro biodissolution profile (measured with a USP Type II apparatus using rotating paddles at 37°C and 500 mL of pH 7.4 phosphate buffer set at a rotation speed of 50 rpm) of the beta-blocker is preferably as shown in Table 1.

[0091] [Table 2]

[0092] It is desirable that release from a sustained release formulation commence without delay and that the release rate for a once-daily formulation be substantially linear over a period of 16 to 24 hours, for example about 20 hours.

[0093] For example, the composite in vitro biodissolution profile of metoprolol preferably has a dissolution profile within one or more release ranges in Table 2 for different metoprolol IR:ER ratios at various time points (measured using a USP Type II apparatus with a rotating paddle set at a rotation speed of 75 rpm, 37°C, and 900 mL of phosphate buffer, pH 7.4).

[0094] [Table 3]

[0095] [Table 4]

[0096] Generally, the tesofensine in the composition dissolves within ½ to 1 hour. The in vitro dissolution profile of tesofensine under the above conditions is at least 80% of the API within 45 minutes.

[0097] Many physiological factors affect both the gastrointestinal transit time and the release of the drug from a controlled-release dosage form, and therefore the uptake of the drug into the systemic circulation. A sustained-release dosage form should release the beta-blocker at a controlled rate so that the amount of active ingredient available in the body to treat the condition is maintained at a relatively constant level over an extended period of time. The release of the active ingredient from a controlled-release dosage form is generally controlled by diffusion through a coating.

[0098] It is equally important that a portion of the beta-blocker be released rapidly so that therapeutically effective levels of the beta-blocker are reached quickly.

[0099] In one embodiment, the pharmaceutical composition is in the form of a pharmaceutical dosage form, such as a tablet or capsule. In one embodiment, the pharmaceutical composition is formulated as a dosage unit. In one embodiment, the pharmaceutical composition is formulated as a once-daily dosage unit.

[0100] In one aspect, the present invention relates to a kit-of-parts for use in treating hypothalamic obesity in a subject, said kit-of-parts comprising at least two separate unit dosage forms (A) and (B); (A) comprises tesofensine or a pharmaceutically acceptable salt thereof; and (B) comprises a beta-blocker, or a pharmaceutically acceptable salt thereof; (A) and (B) are administered to a subject simultaneously, sequentially, or separately. In one embodiment, the beta-blocker in (B) is metoprolol or a pharmaceutically acceptable salt thereof.

[0101] Similarity Functions The similarity function (f2) is a recognized method for determining the similarity between the dissolution profiles of a reference compound and a test compound. The similarity function (f2) is the logarithmic transformation of the sum of squared errors. The similarity function (f2) is 100 when the test profile and the reference profile are identical and approaches zero as the dissimilarity increases. The similarity function has also been adapted for application in determining the similarity between the dissolution profiles of a reference compound and a test compound as they relate to modified-release formulations, such as those exemplified herein.

[0102] The f2 similarity function has been adopted in the SUP AC guidelines for dissolution testing of immediate release dosage forms and by FDA guidance (FDA Guidance for Industry, Dissolution Testing of Immediate Release Solid Oral Dosage Forms, FDA, (CDER), August 1997 (Dissolution Tech. 4, 15-22, 1997)).

[0103] Preferably, the pharmaceutical composition has a beta-blocker in vitro dissolution profile generated using a USP Type II apparatus, rotating paddle method as described herein, having a similarity function (f) of 50-100 when calculated using one of the examples in Figure 1 or Figure 3 in WO 2016 / 138908 as the reference behavior.

[0104] Amounts and ratios of API in the pharmaceutical composition Beta-blocker dose In one embodiment, a pharmaceutical composition as used herein comprises a beta-blocker, or a pharmaceutically acceptable salt thereof, hi one embodiment, a pharmaceutical composition as used herein is administered in combination with a beta-blocker, or a pharmaceutically acceptable salt thereof.

[0105] The ratio of sustained-release beta-blocker, such as metoprolol, to immediate-release beta-blocker can be 75-95:25-5. Suitably, the beta-blocker, such as metoprolol, in the pharmaceutical composition is present in a sustained-release to immediate-release ratio of about 80:20, i.e., the ratio of ER metoprolol / IR metoprolol is about 4:1 by weight. In another embodiment, the beta-blocker, such as metoprolol, is present in a sustained-release to immediate-release ratio of about 90:10 or 100:10. In one embodiment, the ratio of ER / IR beta-blocker, such as ER metoprolol / IR metoprolol, is about 95:5. In yet another embodiment, the ratio is about 80:20 or 75:25. Expressed differently, for a unit dosage form, such as a tablet, containing 40 mg of a beta-blocker, such as metoprolol, the beta-blocker may be present in an amount of about 30 mg in the sustained-release phase and 10 mg in the immediate-release phase. For a unit dosage form containing 22 mg of a beta-blocker, such as metoprolol, the beta-blocker ER may be present in an amount of 20 mg, and the beta-blocker IR may be present in an amount of 2 mg. For example, in one embodiment, the ratio of the sustained-release phase to the immediate-release phase represents the proportional amount of each layer in a bilayer dosage form. In another embodiment, the ratio represents the amount of metoprolol in the sustained-release intragranular component versus the immediate-release extragranular component of a single-layer dosage form. The ratios and amounts described in this paragraph fully apply to metoprolol as a beta-blocker.

[0106] In one embodiment, one dosage form contains an amount of beta-blocker, such as metoprolol, of up to 100 mg, such as about 75 mg, such as about 50 mg, such as about 25 mg, such as about 12.5 mg of beta-blocker.

[0107] Preferably, one dosage form contains an amount of beta-blocker such as metoprolol, ER, e.g., 25 mg to 200 mg, for example, 5 mg to 100 mg API, for example, 15 mg to 100 mg API, preferably 15 mg to 50 mg, for example, 15 mg to 40 mg, for example, 5 mg to 50 mg, for example, 5 mg to 20 mg, for example, about 8 mg, about 20 mg or about 40 mg. In one embodiment, one dosage form contains an amount of beta-blocker such as metoprolol, ER, e.g., 200 mg or less API, for example, 150 mg or less, for example, 100 mg or less, for example, 50 mg or less, for example, 20 mg or less.

[0108] In one embodiment, one dosage form comprises an amount of beta blocker, such as metoprolol, ER, of up to 80 mg, such as about 60 mg, for example about 40 mg, for example about 20 mg, for example about 10 mg.

[0109] Other beta-blockers may require lower doses, in which case one dosage form may contain, for example, 10 mg to 20 mg API, preferably 12 to 20, e.g., about 15 mg, of beta-blocker, such as carvedilol, ER, or the like, 5 mg to 40 mg API.

[0110] The amount of beta blocker, such as metoprolol, IR, per dosage form can be 1 mg to 25 mg API, for example 1 mg to 15 mg, for example 3 mg to 15 mg, for example 4 mg to 10 mg, for example 5 mg to 10 mg, for example 1 mg to 10 mg, for example 1 mg to 5 mg, for example 2 mg to 5 mg, for example about 2 mg, about 5 mg, about 10 mg, about 6 mg, or about 8 mg. In one embodiment, the amount of beta blocker, such as metoprolol, IR, per dosage form is 25 mg or less API, for example 20 mg or less, for example 15 mg or less, for example 10 mg or less, for example 5 mg or less.

[0111] In one embodiment, one dosage form comprises an amount of beta blocker, such as metoprolol, IR, of 20 mg, such as about 15 mg, such as about 10 mg, such as about 5 mg, such as about 2.5 mg.

[0112] The amount of beta-blocker specified herein is based on the amount of metoprolol tartrate. Other beta-blockers, or pharmaceutically acceptable salts thereof, as well as other pharmaceutically relevant salts of metoprolol, or the free base, may also be used in amounts equivalent to the doses of metoprolol tartrate disclosed herein.

[0113] In one embodiment, the amount of ER metoprolol in the pharmaceutical composition ranges from 1 mg to 20 mg. In one embodiment, the amount of ER metoprolol ranges from 5 mg to 15 mg. In one embodiment, the amount of ER metoprolol is 10 mg.

[0114] In one embodiment, the amount of IR metoprolol in the pharmaceutical composition ranges from 1 mg to 10 mg. In one embodiment, the amount of IR metoprolol ranges from 1 mg to 5 mg. In one embodiment, the amount of IR metoprolol is 2.5 mg.

[0115] In one embodiment, the total daily dose of the beta-blocker is less than 125 mg, for example, 5 mg to 50 mg, 10 mg to 30 mg, for example, 25 mg, or 12.5 mg. In one embodiment, the total daily dose of metoprolol is less than 25 mg.

[0116] Tesofensine dosage The amount of tesofensine per dosage form (e.g., in the second composition) is generally 0.01 mg to 1 mg of API, 0.125 mg to 0.75 mg, e.g., 0.25 mg to 0.5. In one embodiment, the amount of tesofensine per dosage form is 0.75 mg or less of API, e.g., 0.50 mg or less, e.g., 0.250 mg or less, e.g., 0.150 mg or less, e.g., 0.125 mg or less. Doses of tesofensine are based on the amount of the free base, although pharmaceutically relevant salts of tesofensine may also be used in amounts equivalent to the doses of the free base disclosed herein.

[0117] Tesofensine and beta-blocker doses In one embodiment, the ratio of the amount of beta-blocker, such as metoprolol, to tesofensine is about 200:1. In one embodiment, the ratio of the amount of beta-blocker, such as metoprolol, to tesofensine is about 100:1. In one embodiment, the ratio of tesofensine to metoprolol is about 1:100 by weight. The amount of beta-blocker as specified herein is based on the amount of metoprolol tartrate. Other beta-blockers, or pharmaceutically acceptable salts thereof, as well as pharmaceutically relevant salts or the free base of metoprolol, may also be used in amounts equivalent to the doses of metoprolol tartrate disclosed herein. The amount of tesofensine is based on the amount of the free base, but pharmaceutically relevant salts of tesofensine may also be used in amounts equivalent to the doses of the free base disclosed herein.

[0118] One dosage form, such as a tablet or capsule, may contain 10 mg to 100 mg ER metoprolol, 2.5 mg to 25 mg IR metoprolol, and 0.125 mg to 1 mg tesofensine, for example 10 mg to 80 mg ER metoprolol, 2.5 mg to 20 mg IR metoprolol, and 0.125 mg to 1 mg tesofensine, for example 10 mg to 60 mg ER metoprolol, 0.25 mg to 15 mg IR metoprolol, and 0.125 mg to 0.75 mg tesofensine.

[0119] One dosage form, such as a tablet or capsule, may contain 10 mg to 125 mg ER metoprolol and 0.125 mg to 1.5 mg tesofensine, for example 10 mg to 100 mg ER metoprolol and 0.125 mg to 1 mg tesofensine, for example 12.5 mg to 75 mg ER metoprolol and 0.125 mg to 0.75 mg tesofensine.

[0120] In one embodiment, the beta blocker is metoprolol, and the amounts of the two APIs in the two or three phases of the current dosage form are present in the absolute amounts in Table 3.

[0121] [Table 5]

[0122] [Table 6]

[0123] Multilayer dosage form The sustained release phase can be part of a multi-layer tablet, such as a bi-layer or tri-layer dosage form.

[0124] In one embodiment, the dosage form comprises a tri-layer dosage form having an extended-release (ER) phase layer with a beta-blocker such as metoprolol or carvedilol, one immediate-release phase layer with a beta-blocker such as metoprolol or carvedilol, and another immediate-release layer with tesofensine. The ER phase contains a therapeutically effective amount of the beta-blocker, such as metoprolol or carvedilol, suitably in the form of granules.

[0125] In other embodiments, the dosage form is a bilayer tablet having an ER phase layer with a beta-blocker such as metoprolol or carvedilol and one immediate release layer with both a beta-blocker (such as metoprolol or carvedilol) and tesofensine.

[0126] In other embodiments, the dosage form is a bilayer tablet with an ER phase layer having a beta-blocker such as metoprolol or carvedilol and one immediate release layer having tesofensine.

[0127] Sustained-release phase Sustained release compositions of beta-blockers, such as metoprolol or pharmaceutically acceptable salts of metoprolol, are known in the art. Non-limiting examples of disclosures of such compositions can be found in WO 2015 / 004617, WO 2013 / 084089, WO 2013 / 030725, WO 2012 / 052834, WO 2011 / 143420, WO 2007 / 09770, WO 2004 / 069234, WO 2007 / 110753, WO 2007 / 029070, WO 2008 / 012346, and WO 2007 / 048233. Such sustained release compositions typically involve coating an API with a sustained release phase that provides a near zero order dissolution rate of the API.

[0128] In one embodiment, a sustained-release beta-blocker such as metoprolol is formulated as pellets with pharmaceutically acceptable excipients such as binders, film coating polymers, plasticizers, starches, lubricants, and disintegrants.

[0129] Sustained release formulations of carvedilol are also known from US Pat. No. 8,101,209 (Flamel Technologies).

[0130] Inert Core In some embodiments, the pellets comprise an initial core (an inactive core) coated with a layer of a beta-blocker, such as metoprolol or a metoprolol salt, and further coated with a sustained-release layer.

[0131] As used herein, the term initial core refers to a pharmaceutically acceptable core for use in a pharmaceutical formulation, where the core is inactive.

[0132] In one embodiment, a pharmaceutical composition for sustained release is provided comprising pellets coated with a beta-blocker, such as metoprolol or a metoprolol salt, each coated pellet comprising: a) an inert core comprising at least 50% (w / w) soluble material; b) a drug layer comprising a beta-blocker, such as metoprolol, which is a layer covering the inert core; and c) a controlled-release layer thereon.

[0133] In another embodiment, there is provided a pharmaceutical composition comprising a tableted or encapsulated composition of multiple pellets, wherein the release rate of a drug from the pellet portion is controlled by the amount or proportion of the initial cores / spheres in the pellets. Preferably, the amount of initial cores is about 15% to about 35%, e.g., 20% to 30%, by weight of the control-release coated pellets before tableting or filling into capsules.

[0134] In another embodiment, the inert core is strengthened by applying a subcoat to the initial core / sphere. In pharmaceutical compositions in which drug-containing pellets are compressed into tablets, the drug pellets are mixed with powdered excipients to form a tableting blend. However, the size of the drug-coated pellets, which is often larger than the particle size of the powdered excipients, can cause a lack of uniformity in the tableting blend. Preferred uniformity of the tableting blend is such that the average assay of a sample of the tableting blend, each equivalent in weight to one tablet, is within 90% to 110% of the labeled dose, with a relative standard deviation of 5% or less for individual assays. The size of the drug pellets is therefore preferably small. When a large amount of drug is layered on a small initial core, high stress is placed on the initial core. This stress can cause wear, especially when the inert core contains sugar spheres. A subcoat may be applied to the initial core / sphere to provide high physical strength to the inert core without altering the dissolution rate of the drug-coated pellets. Preferably, the amount of subcoat is about 10% to about 40% of the total weight of the subcoated inert core, more preferably, the amount of subcoat is about 15% to about 30% of the total weight of the subcoated inert core, and most preferably, the amount of subcoat is about 16% to about 20% of the total weight of the subcoated inert core.

[0135] The inert core of each pellet in the pharmaceutical composition may contain about 50% to about 100% (by weight) of soluble material. Preferably, the inert core contains about 70% to about 90% (by weight) of soluble material. A preferred initial core comprises a sugar sphere. Sugar spheres are used in the pharmaceutical industry as excipients. Such sugar spheres used in pharmaceutical compositions generally contain 92% or less sucrose, calculated on a dry basis, with the remainder consisting of corn starch. Sugar spheres with a core size of more than 500 μm are generally used. The core size of the inert core, preferably the sugar sphere, is about 50 μm to about 500 μm, preferably about 100 μm to about 400 μm, and more preferably about 250 μm to about 350 μm.

[0136] The inert core may comprise an initial core / sphere subcoated with a layer of a plasticizing film-coating polymer. This subcoating of the initial core / sphere provides physical strength to the inert core. The film-coating polymer may be a hydrophobic or hydrophilic polymer, or a combination of the two. Suitable film-coating polymers may be cellulosic polymers or polymethacrylate polymers. Additionally, a hydrophobic polymer or a hydrophilic plasticizer, or a combination of several plasticizers, may be used to plasticize the film-coating polymer. These polymer subcoat compounds are mixed with a solvent prior to their application to the initial core / sphere. Suitable solvents for use in mixing the polymer subcoat compounds are selected from ethanol, isopropyl alcohol, acetone, and purified water. For example, a mixture of ethanol, acetone, and water is preferred for use in mixing the preferred subcoat compound, ethyl cellulose (as the film-coating polymer), and the plasticizers, dibutyl sebacate and polyethylene glycol (EC, DBS, and PEG).

[0137] Preferably, the initial cores / spheres are sugar spheres subcoated with a mixture of cellulose derivatives, such as ethyl cellulose, and polymers such as triethyl citrate, polyethylene glycol, dibutyl sebacate, and dibutyl phthalate, and the subcoating layer on the initial cores / spheres does not alter the release rate of the drug from the pharmaceutical composition. A preferred subcoat on the sugar spheres contains ethyl cellulose as the hydrophobic film-coating polymer and a combination of two or more plasticizers, at least one hydrophilic and at least one hydrophobic plasticizer. Suitable plasticizers may include, for example, polyethylene glycol, citrate esters, dibutyl sebacate, diethyl phthalate, and triacetin. Preferred plasticizers are polyethylene glycol and dibutyl sebacate as the hydrophilic and hydrophobic plasticizers, respectively. Preferably, the subcoat contains, by weight of the subcoat, about 75% to about 85% ethyl cellulose, about 10% to about 20% polyethylene glycol, and about 3% to about 7% dibutyl sebacate. More preferably, the subcoat comprises, by weight of the subcoat, 80% ethyl cellulose, 15% polyethylene glycol, and 5% dibutyl sebacate.

[0138] Alternatively, the core may be an insoluble core on which the active ingredient is deposited, for example, by spraying. It may be made of silicon dioxide, glass, or plastic resin particles. Suitable types of plastic materials are pharmaceutically acceptable plastics such as polypropylene or polyethylene, preferably polypropylene. Such insoluble cores may have a diameter in the range of 0.01 mm to 2 mm, preferably in the range of 0.05 mm to 1.0 mm, and more preferably in the range of 0.1 mm to 0.7 mm.

[0139] Beta-blockers for sustained release In one embodiment, a beta-blocker, such as metoprolol or a pharmaceutically acceptable salt thereof, can be applied to the inert core. The use of "Class 2" solvents (as defined by the FDA) is not required to apply the active ingredient (API) drug onto the inert core to form the drug-coated pellet. The FDA defines "Class 2" solvents as inherently toxic. The active ingredient is preferably dispersed in water with an acceptable binder excipient, such as, but not limited to, polyvinylpyrrolidone, a cellulose derivative polymer, or starch.

[0140] Beta-blockers such as metoprolol may be applied as a dispersion rather than a solution. Therefore, it is preferable that the drug substance have physical properties that allow for high yields when preparing drug-coated pellets. Therefore, the drug substance preferably has a particle size distribution with a d(0.9) value of less than about 80 μm. Preferably, the d(0.9) value for the particle size distribution of the drug substance is less than about 50 μm, more preferably less than about 30 μm. As a result, a concentrated dispersion for application can be produced, which can shorten manufacturing time.

[0141] The drug-coated pellets may comprise about 40% to about 90% (by weight), preferably about 50% to about 80% (by weight), and more preferably about 55% to about 75% (by weight) of the drug layer.

[0142] Other beta-blockers such as carvedilol or its salts are applicable in a similar manner as indicated for metoprolol.

[0143] Controlled Release Layer The final layer applied to the pellets is a layer that controls the release of the active ingredient. The controlled-release layer-coated pellets may have a size of about 200 μm to about 800 μm. Preferably, the controlled-release layer-coated pellets have a size ranging from about 300 μm to about 700 μm, more preferably from about 400 μm to about 600 μm. In addition, the controlled-release layer may contain water-soluble and water-insoluble components. Such components may be film-forming polymers and plasticizers. For example, a film containing a polymer layer can be applied to the drug-coated pellets.

[0144] Three different types of sustained release coatings are described below.

[0145] First sustained-release coating In one embodiment, the sustained release film coat comprises i) an acrylic polymer, ii) a surfactant, and iii) sodium stearyl fumarate, wherein the film coat is deposited from a water-containing liquid.

[0146] Typically, the film coating composition comprises: a) 25% to 35% by weight of an acrylic polymer dispersion b) 0.1% to 4% by weight of surfactant c) 0.1% to 4% sodium stearyl fumarate and d) 100% water-containing liquid Includes:

[0147] In one embodiment, a film coating suitable for providing sustained release is provided. Preferably, the acrylic polymer used in this case comprises homogeneous particles, and the polymer or copolymer is in aqueous dispersion at a temperature of 1000°C. g < room temperature, but in dry conditions T g>room temperature. Suitable polymers include acrylic acid and its esters, particularly the methyl, ethyl, propyl, and butyl esters; and methacrylic acid and its esters, particularly the methyl, ethyl, propyl, and butyl esters. Particularly preferred polymers are those offered under the trade names Eudragit L30D® (Rohm Pharma) or Eudragit FS30D® (Rohm Pharma). Optionally, an additional anti-sticking agent may be required.

[0148] Suitably, the amount of acrylic polymer in the film coating composition is in the range of 15% to 50% by weight. Preferably, the amount of acrylic polymer in the film coating composition is in the range of 20% to 40% by weight. More preferably, the amount of acrylic polymer in the film coating composition is in the range of 25% to 35% by weight.

[0149] Preferably, the surfactant is a nonionic surfactant such as sorbitan esters (Span series); polysorbates (Tween series); polyoxyethylated glycol monoethers (such as the Brij series); polyoxyethylated alkylphenols (such as the Triton series or Igepal series); alkyl glucosides (e.g., dodecyl maltoside); sugar fatty acid esters (e.g., sucrose laurate); saponins; or mixtures thereof; amphoteric surfactants such as betaine; anionic surfactants such as sulfated fatty alcohols, e.g., sodium dodecyl sulfate SDS; sulfated polyoxyethylated alcohols; dioctyl sulfonates. Other surfactants such as succinates; bile salts (e.g., dihydroxy bile salts such as sodium deoxycholate, trihydroxy bile salts such as sodium glycocholate, etc.); fusidic acids (e.g., sodium dihydrofusidate); cationic surfactants such as ammonium compounds; soaps, fatty acids, and lipids and their salts, alkanoic acids (e.g., octanoic acid, oleic acid); monoglycerides (e.g., monolein), neutral or positively or negatively charged phospholipids (e.g., phosphatidylcholine dialkyl, phosphatidylserine dialkyl, etc.); and the like. More preferably, the surfactant is a nonionic surfactant. Most preferably, the surfactant is nonoxynol 100.

[0150] Suitably, the amount of surfactant in the film coating composition is in the range of 0.05% to 8% by weight. Preferably, the amount of surfactant in the film coating composition is in the range of 0.1% to 6% by weight. More preferably, the amount of surfactant in the film coating composition is in the range of 0.5% to 4% by weight.

[0151] In a most preferred embodiment, the acrylic polymer and surfactant are provided by Eudragit® NE30D in a composition, film coat or formulation as previously defined.

[0152] Suitably, the amount of sodium stearyl fumarate in the film coating composition is in the range of 0.05% to 8% by weight. Preferably, the amount of sodium stearyl fumarate in the film coating composition is in the range of 0.1% to 6% by weight. More preferably, the amount of sodium stearyl fumarate in the film coating composition is in the range of 0.5% to 4% by weight.

[0153] Preferably, the water-containing liquid comprises water and a water-miscible organic liquid, such as a lower alkanol, e.g., ethanol, propanol, or isopropanol. From a safety standpoint, it is preferable to keep the proportion of organic matter to a minimum, although small amounts, e.g., in the range of 0% to 20% by volume, are acceptable. Preferably, the liquid is water.

[0154] The film coating composition is particularly suitable for use as an aqueous film coating composition, where the film coat is applied using water as the liquid. When the liquid is water, the latex is preferably a poly(ethyl acrylate-co-methyl methacrylate) copolymer, such as Eudragit NE30D® (Rohm Pharma). This process is particularly advantageous because it does not require the use of environmentally unacceptable organic solvents, some of which also present processing problems due to their flammability, while also eliminating many of the problems experienced with the water-based coatings mentioned above.

[0155] Second sustained-release coating Alternatively, the film may comprise at least one film-coating polymer, which may be plasticized with one or more plasticizers. These plasticizers may differ in their solubility (hydrophobic / hydrophilic). The rate of drug release from the pellets can be controlled by varying the ratio of plasticizer to film-coating polymer, or the ratio between different plasticizers (if more than one is used). A controlled-release layer for a beta-blocker ER may comprise a hydrophobic film-coating polymer, such as ethyl cellulose, and at least two plasticizers, at least one hydrophilic and one hydrophobic, such as polyethylene glycol and dibutyl sebacate. Preferably, the ratio of hydrophobic plasticizer to hydrophilic plasticizer in the controlled-release layer of the pharmaceutical composition is 3:1 to 1:3, more preferably 1:1.

[0156] Furthermore, the controlled-release layer may contain at least about 70% water-insoluble compound (per weight of the controlled-release layer). Preferably, the controlled-release layer contains at least about 80%, more preferably at least about 90% water-insoluble compound (per weight of the controlled-release layer). Suitable water-insoluble compounds are, for example, cellulose-derived polymers. These controlled-release layer compounds are mixed with a solvent before application to the drug-coated pellets. Suitable solvents for use in mixing the controlled-release layer compounds are selected from ethanol, isopropyl alcohol, acetone, and purified water. A mixture of ethanol, acetone, and water is preferred for use in mixing the controlled-release layer compounds, especially when the controlled-release layer compound is a mixture of ethyl cellulose, dibutyl sebacate, and polyethylene glycol.

[0157] A method for preparing a beta-blocker ER component may include subcoating the initial cores / spheres to form an inert core. Subcoating the initial cores / spheres involves mixing a film-coating polymer with one or more plasticizers in a solvent to form a coating mixture. Such a mixture may be a solution, suspension, or slurry for applying a surface coating layer. The coating mixture is applied to the initial cores / spheres to form the subcoated initial cores / spheres to be used as inert cores. The film-coating polymer may be a hydrophobic polymer or a hydrophilic polymer, or a combination of the two. Suitable film-coating polymers may be cellulose-derived polymers or polymethacrylate polymers, preferably ethyl cellulose. The amount of ethyl cellulose is preferably about 75% to about 85%, more preferably about 80%, of the total weight of the subcoat. Additionally, a hydrophobic polymer or a hydrophilic plasticizer, or a combination of several plasticizers, may be used to plasticize the film-coating polymer. These compounds are mixed with a solvent before application to the initial cores / spheres. Suitable solvents for use in mixing the polymeric subcoating compound are selected from ethanol, isopropyl alcohol, acetone, and purified water. A mixture of ethanol, acetone, and water is preferred for use in mixing the polymeric subcoating compound.

[0158] Suitable plasticizers for use in subcoating the initial cores / spheres are selected from polyethylene glycol, dibutyl sebacate, and dibutyl phthalate. Preferred plasticizers are polyethylene glycol and dibutyl sebacate as the hydrophilic and hydrophobic plasticizers, respectively. Preferred amounts of plasticizer used in the method are about 10% to about 20% polyethylene glycol and 3% to about 7% dibutyl sebacate by weight of the subcoat. More preferred are about 15% polyethylene glycol and 5% dibutyl sebacate as the plasticizers.

[0159] For sustained-release coats, the amount of ethylcellulose is preferably about 75% to about 85%, more preferably about 80%, of the total weight of the coat. Suitable plasticizers for use in the ER coating are selected from polyethylene glycol, dibutyl sebacate, and dibutyl phthalate. Preferred plasticizers are polyethylene glycol and dibutyl sebacate as the hydrophilic and hydrophobic plasticizers, respectively. The preferred amount of plasticizer used in the method is about 5% to about 20% polyethylene glycol and dibutyl sebacate by weight of the ER coat. More preferably, the plasticizers are about 10% polyethylene glycol and 10% dibutyl sebacate.

[0160] In one embodiment, the metoprolol ER tablet contains ingredients according to Table 4.

[0161] [Table 7]

[0162] In a preferred method of preparing the beta-blocker ER portion of the composition, the method comprises the following steps: a) providing a sugar sphere as the initial core; b) coating the sugar sphere with a subcoat, which comprises mixing a film of a hydrophobic polymer, a soluble (hydrophilic) plasticizer, and an insoluble (hydrophobic) plasticizer with a solvent mixture, for example, acetone, ethanol 95% and water, and spraying the mixture onto the sugar sphere to create a subcoat on the sugar sphere, resulting in an inert core; c) adding a drug, such as metoprolol succinate, and a binder, preferably povidone (PVP). K-30), preferably with water to form an aqueous dispersion, and applying the dispersion onto the subcoated pellets (inert cores) to form drug-coated pellets; d) applying a third layer onto the drug-coated pellets, comprising dissolving a hydrophobic film-coating polymer, a hydrophilic plasticizer, and a hydrophobic plasticizer in a solvent mixture, for example, acetone, ethanol 95%, and water, to form a mixture, and spraying the mixture onto the drug-coated pellets to create controlled-release drug-coated pellets; e) mixing the controlled-release drug-coated pellets with a powder mixture of one or more excipients to form a final blend; f) compressing the final blend into tablets or filling the final blend into capsules; and g) optionally, film-coating the tablets for cosmetic purposes.

[0163] In this method, the hydrophobic polymer is preferably ethyl cellulose (EC), the soluble / hydrophilic plasticizer is preferably polyethylene glycol (PEG), and the insoluble / hydrophobic plasticizer is preferably dibutyl sebacate (DBS). Furthermore, in preparing the mixture for coating sugar spheres with a subcoat and the drug-coated pellets with a controlled-release layer, ethyl cellulose is preferably first dissolved in acetone and 95% ethanol, followed by the addition of PEG and DBS, followed by water, and mixing the solution until homogenized. Preferably, spraying the solution or dispersion onto the sugar spheres or drug-coated pellets in this method uses a fluidized bed coater with a Worcester insert. Furthermore, the binder used in coating the subcoated sugar spheres with the drug layer promotes binding of the drug to the inert core of the subcoated sugar spheres. Furthermore, in this method, the ratio of powder mixture to controlled-release drug-coated pellets in the final tableting blend is preferably about 20% to about 60% (by weight), more preferably about 30% to about 50% (by weight), and most preferably about 35% to about 45% (by weight), resulting in the production of a uniform final tableting blend and tablets.

[0164] Third sustained-release coating The sustained-release phase may include at least one high-viscosity hypromellose (HPMC) component. HPMC is a water-soluble matrix-forming polymer used to provide sustained release of metoprolol. The viscosity of the HPMC used in the ER phase may be up to 100,000 centipoise, for example, in the range of about 3500 to 6000 cps.

[0165] A sustained release phase having a therapeutically effective amount of a beta-blocker, such as metoprolol or carvedilol, can be made with high viscosity hypromellose alone.

[0166] In another embodiment, the sustained-release phase comprises a therapeutically effective amount of a beta-blocker, such as metoprolol or carvedilol, at least one high-viscosity hypromellose, at least one binder, a low-viscosity hypromellose, at least one modified starch, and optionally one or more other pharmaceutically acceptable intragranular components, other pharmaceutically acceptable excipients, and / or adjuvants, including, but not limited to, a second pharmaceutically acceptable active ingredient. In one embodiment, the ratio of high-viscosity hypromellose to low-viscosity hypromellose is about 3.3 to about 0.85. In another embodiment, the high-to-low ratio is about 3:1.

[0167] Preferably, the viscosity of the low-viscosity hypromellose ranges from about 10 centipoise to 30 centipoise, hi another embodiment, the low viscosity is about 15 centipoise.

[0168] The amount of at least one binder in the extended release phase of the bilayer tablet can be about 0.5% to about 3% w / w. In one embodiment, there are at least two binders present in the ER phase. Preferably, the amount of at least one modified starch in the extended release phase of the bilayer tablet is about 0.5% to about 3% w / w. In one embodiment, the amount of modified starch is about 1% w / w of the ER phase. In one embodiment, there are at least two modified starches present in the ER phase. Preferably, the modified starches are pregelatinized.

[0169] Preferably, the amount of high viscosity hypromellose present in the sustained release phase is about 3% to about 7% by weight of the sustained release phase formulation. In another embodiment, the amount of high viscosity hypromellose is about 4% to about 6%. In yet another embodiment, an amount of >20% hypromellose is used in the sustained release phase.

[0170] In yet another embodiment, the amount of high viscosity HPMC is present in an amount of about 5% w / w by weight of the sustained release phase formulation.

[0171] Preferably, the amount of low viscosity hypromellose present in the sustained release phase is about 0.5% to about 3% by weight of the sustained release phase formulation. In another embodiment, the amount of low viscosity hypromellose is about 1% to about 2% by weight of the sustained release phase formulation.

[0172] Instead, the total amount of cellulose derivatives of HPMC present in the ER granules ranges from about 3% to about 10% by weight of the total amount of sustained release ingredients, which includes both high viscosity HPMC and low viscosity HPMC.

[0173] In one embodiment, the ER phase comprises metoprolol, povidone, pregelatinized cornstarch, and high and low viscosity HPMC.

[0174] In one embodiment, the ER phase includes carvedilol, povidone, pregelatinized cornstarch, and high and low viscosity HPMC.

[0175] Tablets and capsules The film-coated beads or spheres can be provided in sachets, formulated as capsules, e.g., hard gelatin capsules, or compressed to form tablets using known methods, with the optional addition of other pharmaceutically acceptable excipients, and with the addition of the beta-blocker IR and tesofensine components described herein. The coated beads to be compressed into tablets can be obtained by conventional techniques known to those skilled in the art.

[0176] Other suitable agents may also be added during this process. For example, during the tableting step, suitable fillers such as microcrystalline cellulose, lactose monohydrate, talc, sodium stearyl fumarate, etc. may be utilized to impart acceptable compression characteristics to the formulation, such as tablet hardness.

[0177] These additives can be granulated by one of the conventional granulation methods. However, preferably, a series of additives, e.g., a powder mixture that can be directly compressed into tablets, is provided. Such a powder mixture functions as a filler, buffer, disintegrant, glidant, and lubricant mixture. Furthermore, the ratio of controlled-release drug-coated pellets to additives in the final (e.g., tableting) blend of the pharmaceutical composition is particularly important for preparing a uniform product, e.g., a tablet.

[0178] To prepare a uniform product, preferably, at least 50% (by weight) of the powder mixture will have a particle size of about 30 μm to about 800 μm, preferably about 80 μm to about 600 μm, and more preferably about 100 μm to about 300 μm. More preferably, at least 65% (by weight) of the powder mixture will have a particle size of about 30 μm to about 800 μm, preferably about 80 μm to about 600 μm, and more preferably about 100 μm to about 300 μm. Most preferably, at least 80% (by weight) of the powder mixture will have a particle size of about 30 μm to about 800 μm, preferably about 80 μm to about 600 μm, and most preferably about 100 μm to about 300 μm.

[0179] Furthermore, to prepare such a uniform product, the amount of controlled-release drug-coated pellets in the final tableting blend is preferably about 20% to about 60% (by weight), more preferably about 30% to about 50% (by weight), and most preferably about 35% to about 45% (by weight).

[0180] Suitable powder blends include, but are not limited to, blends of two or more of the following compounds: Starlac® (a spray-dried compound available from Meggle consisting of 85% alpha-lactose monohydrate and 15% corn starch dry matter), Cellactose® (a spray-dried compound available from Meggle consisting of 75% alpha-lactose monohydrate and 25% cellulose powder dry matter), Parteck® (a directly compressible sorbitol available from Merck KGaA), crospovidone, silicon dioxide, magnesium stearate, talc, zinc stearate, polyoxyethylene stearate, stearic acid, sodium stearyl fumarate cellulose derivatives, microcrystalline cellulose, and lactose monohydrate.

[0181] If the dosage form is a bilayer or trilayer tablet, the immediate-release layer(s) may be compressed directly onto the pre-partially compressed sustained-release layer, or alternatively, the sustained-release layer may be compressed onto the pre-partially compressed immediate-release layer(s).

[0182] Compositions can be formulated by conventional methods of mixing, such as granulating, blending, filling, and compressing. For example, tablets can be produced by a wet granulation process, in which an immediate-release phase and a sustained-release phase are prepared separately. Preferably, for either the immediate-release or sustained-release phase, the active drug substance and excipients are sieved and mixed in a high-shear mixer granulator or fluid-bed dryer. The blend is granulated by adding the drug dissolved / dispersed in a granulation solution (typically purified water, a disintegrant dissolved / dispersed in purified water, or purified water or a suitable solvent) sprayed into the high-shear mixer granulator or fluid-bed dryer. If desired, a wetting agent, such as a surfactant, can be added. The resulting granules (optionally pelletized) are typically dried to a residual moisture of 1% to 5% by tray, fluid-bed, or microwave drying techniques. The dried granules are milled to produce a uniform particle size, and the granules are blended with extragranular excipients, typically lubricants and glidants (e.g., magnesium stearate, silicon dioxide), as needed. The separately prepared immediate-release granules and sustained-release granules can then be compressed together, if desired, using a rotary tablet press (such as a bilayer tablet press). If the dosage form is a single-layer tablet, the sustained-release granules are mixed with the immediate-release extragranular components and compressed together using a rotary tablet press or the like. All of these resulting tablets are typically coated with a 1% to 5% aqueous film coat in a pan coater, followed by wax polishing.

[0183] Alternatively, tablets can be produced by a direct compression process. Preferably, the active pharmaceutical ingredient and excipients for the immediate-release and sustained-release phases are sieved separately and mixed in a suitable blender, such as a cone, cube, or V-blender. Other excipients are added as needed and further blended. The separately prepared immediate-release and sustained-release phases can be combined and compressed together using a rotary tablet press as described hereinabove. The resulting tablets can be coated in a pan coater.

[0184] Tablets can also be prepared by using both wet granulation and direct compression methods. For example, the sustained-release phase can be prepared by wet granulation as described herein, while the immediate-release phase can be prepared by blending excipients for direct compression. The two phases can then be combined and compressed together as described herein above.

[0185] Immediate release phase(s) The immediate-release layer(s) can be prepared by combining a directly compressible, commercially available grade of a beta-blocker, such as metoprolol, and tesofensine with a lubricant and, if necessary or desired, one or more disintegrants. Binders and other excipients and / or adjuvants may also be included in the immediate-release layer(s) as necessary or desired. The beta-blocker and tesofensine in the immediate-release layer may be combined with a binder, plasticizer, pigment, and lubricant, such as pregelatinized starch, modified starch, e.g., cornstarch, polyethylene glycol, and a disintegrant, or a superdisintegrant, such as croscarmellose sodium or Explotab®, methylcellulose, or hypromellose polymer.

[0186] The immediate-release phase may comprise two separate layers of a beta-blocker and tesofensine, respectively. Alternatively, the immediate-release phases may be combined into one and the same layer. The immediate-release phase may also be formulated into the extragranular phase of the tablet or granulated into one or two separate immediate-release granules. For tesofensine, the preferred formulation is granulation of tesofensine compared to direct compression of tesofensine due to the relatively low dose.

[0187] Monolithic Dosage Form In one embodiment, there is only a single-phase tablet with a sustained-release intragranular phase and two immediate-release extragranular phases. The sustained-release phase is composed of the intragranular component of the beta-blocker and the excipients as described above. These components form ER granules. The ER blend can be made into pellets and thus compressed with the extragranular immediate-release blend.

[0188] A suitable extragranular component or phase, i.e., immediate-release phase, can be prepared by combining a directly compressible commercially available grade of beta-blocker, such as metoprolol, and tesofensine citrate with a lubricant and, if necessary or desired, one or more disintegrants. As described above for tesofensine, a preferred process is to prepare granules of tesofensine before compression. Binders and other excipients and / or adjuvants may be included in the extragranular phase, if necessary or desired. Alternatively, the extragranular component can be prepared by combining a beta-blocker, such as metoprolol, and tesofensine with a modified starch, such as pregelatinized starch (e.g., cornstarch), a disintegrant or superdisintegrant, such as croscarmellose sodium, a binder, and a lubricant.

[0189] excipients The composition may include a component that functions as a binder or binding agent. Preferably, the binding agent may include a first binding agent and a second binding agent. Suitable binding agents for use herein include conventional binding agents used in the art, such as gelatin, starch, povidone, polymers and cellulose derivatives, or combinations thereof.

[0190] Preferably, the starch is of plant origin, such as corn (or maize) starch, modified corn starch, wheat starch, modified wheat starch, potato starch, or pregelatinized starch, such as those commercially available as Starch 1500G or Prejel; or a combination of two or more thereof.

[0191] Binders include cellulose derivatives such as (low to medium viscosity) hydroxypropyl cellulose (HPC), such as those commercially available under the trade name Klucel®, e.g., Klucel GF, Klucel JF, Klucel LF, and Klucel EF, from Hercules Incorporated, Aqualon division of The Dow Chemical Company; microcrystalline cellulose (MCC); carboxymethyl cellulose (MC); sodium carboxymethyl ethyl cellulose; or combinations of two or more thereof. Combinations of cellulose derivatives with other binders listed above are also contemplated. Generally, the total amount of cellulose derivatives present in the granules ranges from about 3% to about 10% by weight of the sustained-release component. It is recognized in the art that certain cellulose derivatives, such as hypromellose, fulfill different roles in formulations depending on the amount used. For example, hypromellose (low or medium viscosity) can function as a binder, coating agent, or matrix-forming agent.

[0192] It is also recognized that while the binder is present as an intragranular component, a moderate amount of binder may also be present extragranularly, e.g., up to an additional about 3.0% > to 10.0% by weight of the intragranular binder content of the composition.

[0193] In one embodiment, the starch is suitably pregelatinized starch. Pregelatinized starch is starch that has been chemically and / or mechanically treated. Typically, pregelatinized starch contains 5% free amylase, 15% free amylopectin, and 80% raw starch. Pregelatinized starch can be obtained from corn (or maize), potato, or rice starch.

[0194] The granules provide an intimate mixture of the component combination, which can then be mixed with one or more pharmaceutically acceptable extragranular components of the composition, i.e., any pharmaceutically acceptable component such as a diluent, flavoring, sweetener, binder, disintegrant, glidant, lubricant, anti-adherent, antistatic agent, antioxidant, desiccant, or second pharmaceutically acceptable active agent, It is recognized that these same components may be present as both intragranular and extragranular components.

[0195] As noted above, there are optionally other inactive ingredients that may be used in relatively small amounts, including lubricants, flow agents, and binders to facilitate compaction.

[0196] Suitable disintegrants include non-super disintegrants, super disintegrants, or a combination of both. Suitable non-super disintegrants include conventional disintegrants such as starch (corn or maize), pregelatinized starch, e.g., Starch 1500G, clay (e.g., VEEGUM (Vanderbilt Minerals, LLC) or bentonite (an absorbent aluminum phyllosilicate clay primarily composed of montmorillonite)), microcrystalline cellulose, cellulose, or powdered cellulose. It is recognized in the art that some excipients may play more than one role in a given pharmaceutical formulation. For example, certain excipients, such as starch, including pregelatinized starch, and microcrystalline cellulose (identified herein above as binders), function as both binders and disintegrants.

[0197] "Superdisintegrants" generally refer to a class of disintegrants that can be used in smaller amounts in pharmaceutical formulations compared to conventional disintegrants. Examples of superdisintegrants include sodium starch glycolate, sodium salt of carboxymethyl starch, modified cellulose, and cross-linked polyvinylpyrrolidone. Sodium starch glycolate is commercially available under the trade names Explotab® (Edward Mendell Co. JRS Pharma), Primojel® (Generichem Corp; DFE Pharma), and Tablo® (Blanver, Brazil). Examples of modified cellulose include croscarmellose sodium, the sodium salt of sodium carboxymethylcellulose. Croscarmellose sodium is commercially available under the trade names AcDiSol® (FMC Corp.), Nymcel ZSX® (Nyma, Netherlands), Primellose® (Avebe, Netherlands), and Solutab® (Blanver, Brazil). Examples of cross-linked polyvinylpyrrolidones include crospovidone, which is commercially available under the trade names Kollidon CL® or Kollidon CL-M (Basf Corp.), and Polyplasdone XL® (ISP Corp; Ashland). Suitable superdisintegrants include croscarmellose sodium or sodium starch glycolate (e.g., Explotab® (JRS Pharma)), or combinations thereof. Superdisintegrants may be used extragranularly in amounts ranging from about 0.5% to about 5.0% by weight of the composition. Suitable preservatives or antimicrobial agents for use include potassium sorbate or parabens, i.e., one or more hydroxybenzoic acid esters, e.g., methyl, ethyl, propyl, or butyl, suitably alone or in admixture. Parabens are commercially available under the Nipa® trade name, e.g., Nipasept® sodium (Aako BV).

[0198] Suitable lubricants include magnesium, calcium or sodium stearic acid, stearic acid or talc, which may be added in suitable amounts, hi one embodiment, the lubricant is magnesium stearate.

[0199] Suitable flow agents include silicon dioxide (e.g., Cab-O-Sil® (Cabot Corporation), Syloid™ (W.R. Grace & Company)) and colloidal silicon dioxide (Aerosil® (Evonik Resource Efficiency GmbH)), which may be added in an amount of about 0.5% to about 1% by weight.

[0200] The compressed tablets may further comprise a film coat, such as hypromellose or partially hydrolyzed polyvinyl alcohol (PVA). Suitable film coats are transparent film coats, such as dyes, although opaque film coats, such as those obtained when film coats are used in combination with opacifiers or pigments, such as titanium dioxide or lakes, can also be used. For example, one commercially available film coat is the Opadry® coating system from Colorcon.

[0201] Terms 1. A method for the treatment of hypothalamic obesity comprising the daily administration to a patient suffering from hypothalamic obesity of a pharmaceutical composition comprising 0.01 mg to 1.5 mg of tesofensine or a pharmaceutically acceptable salt thereof.

[0202] 2. The method of clause 1, wherein tesofensine is selected from the free base, citrate, and tartrate salts.

[0203] 3. The method of any one of the preceding clauses, wherein the pharmaceutical composition further comprises a beta-blocker or a pharmaceutically acceptable salt thereof.

[0204] 4. The method of any one of the preceding clauses, wherein tesofensine is administered in combination with a beta-blocker or a pharmaceutically acceptable salt thereof.

[0205] 5. The method according to any one of the preceding clauses, wherein the daily dose of the beta-blocker is less than 125 mg, for example between 10 mg and 100 mg, for example less than 100 mg, for example 75 mg, 50 mg, 25 mg, or 12.5 mg.

[0206] 6. The method according to any one of the preceding clauses, wherein the daily dose of tesofensine is less than 1.5 mg API, such as less than 1 mg, for example less than 0.75 mg, such as 0.5 mg, 0.25 mg, or 0.125 mg.

[0207] 7. The method of any one of the preceding clauses, wherein the beta blocker is selected from the group consisting of beta1-selective beta blockers, mixed alpha and beta blockers, non-selective beta blockers and beta2-selective beta blockers.

[0208] 8. The method according to any one of the preceding clauses, wherein the beta-blocker is a beta-1 selective beta-blocker, such as a beta-1 selective beta-blocker selected from the group consisting of metoprolol, acebutolol, atenolol, betaxolol, bisoprolol, esmolol, landiolol, nebivolol, and pharmaceutically acceptable salts thereof.

[0209] 9. The method of any one of the preceding clauses, wherein the beta blocker is a combined alpha and beta blocker, such as a combined alpha and beta blocker selected from the group consisting of carvedilol, celiprolol, labetalol, and pharmaceutically acceptable salts thereof.

[0210] 10. The method of any one of the preceding clauses, wherein the beta-blocker is a non-selective beta-blocker, such as a non-selective beta-blocker selected from the group consisting of alprenolol, amosulalol, bucindolol, carteolol, levobunolol, mepindolol, metipranolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, timolol, and pharmaceutically acceptable salts thereof.

[0211] 11. The method according to any one of the preceding clauses, wherein the beta-blocker is a beta-2 selective beta-blocker, such as butaxamine or a pharmaceutically acceptable salt thereof.

[0212] 12. The method according to any one of the preceding clauses, wherein the beta-blocker is metoprolol or a pharmaceutically acceptable salt thereof.

[0213] 13. The method of any one of the preceding clauses, wherein the beta-blocker is selected from metoprolol succinate and metoprolol tartrate.

[0214] 14. The method according to any one of the preceding clauses, wherein the beta-blocker is carvedilol or a pharmaceutically acceptable salt thereof.

[0215] 15. The method of any one of the preceding clauses, wherein the beta-blocker is released as a sustained release formulation having a substantially linear release over a period of 16 to 24 hours after administration.

[0216] 16. The method of any one of the preceding clauses, wherein the beta-blocker prevents or alleviates the cardiovascular side effects of tesofensine.

[0217] 17. A pharmaceutical composition comprising: a. a first composition comprising an extended release (ER) composition of an active ingredient (API) selected from a beta-blocker or a pharmaceutically acceptable salt thereof; b. a second composition comprising an active ingredient (API) selected from tesofensine or a pharmaceutically acceptable salt thereof, and optionally c. A third composition comprising an immediate release (IR) composition of an active ingredient (API) selected from a beta-blocker or a pharmaceutically acceptable salt thereof. 2. The method according to any one of the preceding clauses, comprising:

[0218] 18. The method of any one of the preceding clauses, comprising administering 10 mg to 10 mg of ER metoprolol, 2.5 mg to 25 mg of IR metoprolol, and 0.125 mg to 1 mg of tesofensine, for example 10 mg to 80 mg of ER metoprolol, 2.5 mg to 20 mg of IR metoprolol, and 0.125 mg to 1 mg of tesofensine, for example 10 mg to 60 mg of ER metoprolol, 0.25 mg to 15 mg of IR metoprolol, and 0.125 mg to 0.75 mg of tesofensine.

[0219] 19. The method of any one of the preceding clauses comprising administering 10 mg to 125 mg of ER metoprolol and 0.125 mg to 1.5 mg of tesofensine; for example, 10 mg to 100 mg of ER metoprolol and 0.125 mg to 1 mg of tesofensine, for example, 12.5 mg to 75 mg of ER metoprolol and 0.125 mg to 0.75 mg of tesofensine.

[0220] 20. The method of any one of the preceding clauses, wherein the tesofensine and the beta-blocker are administered separately.

[0221] 21. The method of any one of the preceding clauses, wherein tesofensine and a beta-blocker are administered in combination.

[0222] 22. The method according to any one of the preceding clauses, wherein the pharmaceutical composition is administered once, twice or three times daily.

[0223] 23. Subject must be able to maintain a minimum of 25 kg / m 2 , such as having a BMI of at least 30, such as at least 35.

[0224] 24. The method of any one of the above clauses, wherein the subject has diabetes.

[0225] 25. The method according to clause 24, wherein the serum HbA1c level is reduced by at least 10 mmol / mol, such as at least 20, such as at least 25, such as at least 30, such as at least 35 mmol / mol after 24 weeks of treatment.

[0226] 26. The method according to any one of the preceding clauses, wherein the patient's body weight is reduced by at least 3%, for example 5% to 10%, or 6% to 8% after 6 months of treatment.

[0227] 27. The method according to any one of the preceding clauses, wherein the patient's abdominal circumference is reduced by at least 4 cm, for example, 4 cm to 6 cm, or 6 cm to 10 cm, 6 months after treatment.

[0228] 28. The method according to any one of the preceding clauses, wherein the patient's fat mass is reduced by at least 2 kg, for example 2 kg to 8 kg, or 3 kg to 6 kg, 6 months after treatment.

[0229] 29. The method of any one of the above clauses, wherein the treatment reduces the amount of visceral fat.

[0230] 30. The method of any one of the preceding clauses, wherein the treatment reduces one or more symptoms of prediabetes, metabolic syndrome, dyslipidemia, atherosclerosis, binge eating, bulimia nervosa, binge eating disorder, compulsive overeating, impaired appetite regulation, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH).

[0231] 31. A method for reducing weight in a patient suffering from hypothalamic obesity, comprising daily administration to said patient of a pharmaceutical composition comprising 0.01 mg to 1.5 mg of tesofensine or a pharmaceutically acceptable salt thereof.

[0232] 32. A method for reducing waist circumference in a patient suffering from hypothalamic obesity, comprising daily administration to said patient of a pharmaceutical composition comprising 0.01 mg to 1.5 mg of tesofensine or a pharmaceutically acceptable salt thereof.

[0233] 33. A method for reducing body fat in a patient suffering from hypothalamic obesity, comprising daily administration to said patient of a pharmaceutical composition comprising 0.01 mg to 1.5 mg of tesofensine or a pharmaceutically acceptable salt thereof.

[0234] 34. The method of clause 33, wherein said body fat is visceral fat.

[0235] 35. A method for reducing liver fat in a patient suffering from hypothalamic obesity, comprising daily administration to said patient of a pharmaceutical composition comprising 0.01 mg to 1.5 mg of tesofensine or a pharmaceutically acceptable salt thereof.

[0236] 36. A method for reducing serum HbA1c levels in a patient suffering from hypothalamic obesity, comprising daily administration to the patient of a pharmaceutical composition comprising 0.01 mg to 1.5 mg of tesofensine or a pharmaceutically acceptable salt thereof.

[0237] 37. The method according to clause 36, wherein the subject suffers from type 2 diabetes, prediabetes, metabolic syndrome, insulin resistance, or glucose intolerance, preferably type 2 diabetes.

[0238] 38. Use of a pharmaceutical composition comprising 0.01 mg to 1.5 mg of tesofensine, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of hypothalamic obesity.

[0239] Example Example 1. Phase 2 Clinical Trial The overall safety and tolerability of coadministration of tesofensine and metoprolol (Tesomet) in subjects with hypothalamic injury-induced obesity (HIO) was studied in a phase 2, double-blind, randomized, placebo-controlled, single-center safety and efficacy study, followed by an open-label extension, for a total of 48 weeks.

[0240] Part 1: 24 weeks of double-blind treatment Next Part 2: 24-week open-label extension

[0241] subject The population studied was subjects suffering from obesity that developed in association with damage to the hypothalamus (HO), whether due to trauma, hemorrhage, infection, tumor, surgery or radiation.

[0242] Modified Intention-to-Treat Population (mITT): All randomized subjects with a complete baseline assessment and at least one post-baseline assessment were included. Subjects were included in separate mITT populations for the double-blind and open-label phases. Subjects in the mITT population contributed to the "randomized" assessment.

[0243] Protocol-Following Population (PPP): All randomized subjects without major protocol violations will be included. Subjects in the PPP will contribute to the "randomized" evaluation.

[0244] Twenty-one subjects were studied, 13 of whom received IMP and 8 received placebo. All participants were Caucasian and non-Hispanic or non-Latino. Five participants were male (3 received IMP and 2 received placebo), and 16 participants were female (10 received IMP and 6 received placebo).

[0245] [Table 8]

[0246] methodology This randomized, double-blind, placebo-controlled phase 2 study, performed at Rigshospitalet in Copenhagen, Denmark, evaluated Tesomet (tesofensine 0.5 mg + metoprolol 50 mg) administered daily to patients with HO.

[0247] The primary endpoint of the study was overall safety and tolerability, as measured by all safety data collected during the study, including recorded adverse events, laboratory data, blood pressure, and heart rate. Efficacy endpoints included weight; body composition; waist circumference, satiety, and appetite; lipid and glycemic control; quality of life; and cravings for sweet, salty, and oily foods.

[0248] Part 1 - Double-blind: Patients received either Tesomet or matching placebo (2:1 randomization) for 24 weeks. Active medication group: 24 weeks of daily co-administration of 0.5 mg tesofensine / 50 mg metoprolol ER. One tablet of each product. Placebo group: matching placebo tablets daily for 24 weeks.

[0249] Part 2 - Open Label: All subjects: 24 weeks of daily co-administration of 0.5 mg tesofensine / 50 mg metoprolol ER. One tablet of each product.

[0250] The term "IMP" stands for Investigational Medicinal Product and corresponds to co-administration of tesofensine (0.5 mg) / metoprolol (50 mg).

[0251] result Eighteen of the 21 study participants completed the placebo-controlled portion of the study (two dropouts in the placebo group; one dropout in the treatment group).

[0252] Continuous secondary efficacy endpoints were compared between treatment groups by means of analysis of covariance (ANCOVA) with treatment as a fixed factor and baseline value as a covariate. Estimates and 95% confidence intervals of treatment differences were calculated.

[0253] safety Tesomet was found to be safe and well tolerated. Side effects more frequently observed in treated patients included sleep disturbances, dry mouth, and headache, which are well-known side effects associated with tesofensine and / or metoprolol. There was one instance of Tesomet-associated anxiety / paranoia reported as a serious adverse event (SAE), which improved after treatment was discontinued. Notably, there were no clinically meaningful differences in heart rate or blood pressure between treatment groups, demonstrating that the doses of tesofensine and metoprolol were well balanced.

[0254] body weight Treatment with Tesomet resulted in a statistically significant 6.8% mean reduction in body weight compared to placebo (p<0.001). The data are presented in Table 6 and Figure 1.

[0255] [Table 9]

[0256] Waist circumference The mean waist circumference in Tesomet-treated patients was significantly reduced by 7.9% compared to placebo (p<0.001). The data are presented in Table 7 and Figure 2.

[0257] [Table 10]

[0258] Body composition - fat mass Treatment with Tesomet resulted in a reduction in body fat compared to placebo (NS, P=0.0988). The data are presented in Table 8.

[0259] [Table 11]

[0260] Blood sugar control (HbA1c) Tesomet treatment improved glycemic control as measured by a statistically significant 14.6% reduction in hemoglobin A1c (HbA1c) compared to placebo (p=0.015). The data are presented in Table 9.

[0261] [Table 12]

[0262] Example 2. Open-label extension of a Phase 2 study TM005 was a 24-week, Phase 2, double-blind, randomized, placebo-controlled, single-center safety and efficacy study followed by a 24-week, open-label extension treatment period designed to evaluate the overall safety and tolerability of Tesomet (coadministration of 0.5 mg tesofensine and 50 mg metoprolol) in patients with hypothalamic obesity (HO).

[0263] The study's primary endpoint was overall safety and tolerability, as measured by all safety data collected during the study, including recorded adverse events, laboratory data, blood pressure, and heart rate. Secondary efficacy endpoints included weight, waist circumference, glycemic control, and other measurements. During the double-blind (DB) portion of the study, patients received either Tesomet or a matching placebo (2:1 randomization) for 24 weeks.

[0264] All 21 patients (13 Tesomet, 8 placebo) were randomized into the double-blind (DB) period. All patients who completed the DB period of the study were offered the opportunity to receive Tesomet in an additional 24-week open-label extension (OLE) period of the study. All 18 patients who completed the DB period chose to participate in the OLE period, and all of these patients completed the OLE period. Patients who entered the OLE period were 83.3% female, averaged 44.9 years old, weighed 110.4 kg (243 lb), and had a BMI of 37.2 kg / m2.

[0265] For the open-label extension portion of the study, the Tesomet group will still be labeled as Tesomet in the results. The placebo group will also be labeled as placebo, but in the open-label extension, they will also receive Tesomet.

[0266] Tesomet was well tolerated in patients with hypothalamic obesity over the 48-week study period, with no clinically meaningful differences in heart rate or blood pressure observed.

[0267] Treatment with Tesomet compared with placebo resulted in a statistically significant difference in the number of responders with a ≥5% weight loss from baseline through 24 weeks during the double-blind treatment period, and this effect was maintained after an additional 24 weeks of open-label Tesomet treatment (Figure 3a). Patients treated with placebo during the initial 24-week double-blind period of the study and then receiving 24 weeks of Tesomet treatment during the open-label extension period also showed a significant improvement in the number of responders with a ≥5% weight loss from baseline.

[0268] Treatment with Tesomet compared with placebo resulted in a statistically significant difference in the number of responders with a ≥10% weight loss from baseline by week 24 during the double-blind treatment period, and this effect remained high after an additional 24 weeks of open-label Tesomet treatment (Figure 3b). Patients treated with placebo during the initial 24-week double-blind period of the study, followed by 24 weeks of Tesomet treatment during the open-label extension period, also showed a significant improvement in the number of responders with a ≥10% weight loss from baseline.

[0269] Tesomet treatment resulted in clinically meaningful reductions in HbA1c levels in patients with type 2 diabetes after 24 and 48 weeks of treatment, while no effect was seen in normoglycemic patients (Figure 4).

[0270] Patients who received Tesomet for all 48 weeks of the study demonstrated statistically significant and clinically meaningful reductions in weight and waist circumference from baseline to week 48, as well as improvements in glycemic control. The improvements observed in DB patients in the study were maintained throughout the OLE period (Figure 5).

[0271] Patients who received placebo during the DB period of the study and then switched to Tesomet during the OLE period also achieved clinically meaningful reductions in weight, waist circumference (data not shown), and BMI (data not shown) after being switched to Tesomet during the 24-week OLE period (see Figure 5).

[0272] Compared to placebo, treatment with Tesomet resulted in a clinically meaningful reduction in fat mass from baseline through 24 weeks of treatment, and this effect was maintained after an additional 24 weeks of open-label Tesomet treatment. Patients treated with placebo for the first 24 weeks of the study, followed by 24 weeks of open-label Tesomet treatment, also demonstrated clinically meaningful reductions in fat mass from baseline (Figure 6).

[0273] Patients treated with Tesomet during the 24-week double-blind phase, followed by an additional 24 weeks of open-label Tesomet treatment, showed evidence of increased lean tissue mass during the open-label extension (Figure 7). In contrast, patients who received placebo during the 24-week double-blind phase, followed by an additional 24 weeks of open-label Tesomet treatment, showed evidence of decreased lean tissue mass. The same trend in lean mass loss was seen in Tesomet patients during the 24-week double-blind phase.

[0274] In summary, the results of the OLE phase of the study reinforce the significant positive effects of Tesomet on body weight, body composition, and metabolic dysregulation observed in the DB period of the Phase 2 trial in patients with hypothalamic obesity.

Claims

1. 1. A pharmaceutical composition for use in treating hypothalamic obesity in a subject suffering from hypothalamic obesity, the pharmaceutical composition comprising 0.01 mg to 1.5 mg of tesofensine or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition of claim 1 , wherein the subject has a BMI of at least 25 kg / m 2 .

3. The pharmaceutical composition according to any one of claims 1 to 2, wherein the subject has diabetes.

4. 4. The pharmaceutical composition of claim 3, wherein serum HbA1c levels are reduced by at least 10 mmol / mol after 24 weeks of treatment.

5. The pharmaceutical composition of any one of claims 1 to 4, wherein the subject's body weight is reduced by at least 3% after 6 months of treatment.

6. the subject's waist circumference decreases by at least 4 cm after 6 months of treatment, and / or the subject loses at least 2 kg of fat mass after 6 months of treatment; The pharmaceutical composition according to any one of claims 1 to 5.

7. 7. The pharmaceutical composition of any one of claims 1 to 6, wherein said treatment reduces one or more symptoms of prediabetes, metabolic syndrome, dyslipidemia, atherosclerosis, overeating, bulimia nervosa, binge eating disorder, compulsive overeating, appetite regulation disorders, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).

8. The pharmaceutical composition of any one of claims 1 to 7, further comprising a beta-blocker or a pharmaceutically acceptable salt thereof.

9. 9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is administered daily and the daily dose of the beta-blocker is less than 125 mg.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the pharmaceutical composition is administered daily and the daily dose of tesofensine is less than 1.5 mg API.

11. The beta-blocker a) a beta 1 selective beta blocker selected from the group consisting of metoprolol, acebutolol, atenolol, betaxolol, bisoprolol, esmolol, landiolol, nebivolol and pharmaceutically acceptable salts thereof; b) a combined alpha and beta blocker selected from the group consisting of carvedilol, celiprolol, labetalol and pharmaceutically acceptable salts thereof; c) a non-selective beta-blocker selected from the group consisting of alprenolol, amosulalol, bucindolol, carteolol, levobunolol, mepindolol, metipranolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, timolol, and pharmaceutically acceptable salts thereof; and d) a beta-2 selective beta-blocker selected from butaxamine and its pharmaceutically acceptable salts; The pharmaceutical composition according to any one of claims 8 to 10, selected from the group consisting of:

12. The pharmaceutical composition according to any one of claims 8 to 11, wherein the beta-blocker is metoprolol or a pharmaceutically acceptable salt thereof.

13. The pharmaceutical composition comprises: a. a first composition comprising an extended release (ER) composition of an active ingredient (API) selected from the beta-blocker or a pharmaceutically acceptable salt thereof; and b. A second composition comprising an active ingredient (API) selected from tesofensine or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to any one of claims 1 to 12, comprising:

14. The pharmaceutical composition comprising: A third composition comprising an immediate release (IR) composition of an active ingredient (API) selected from a beta-blocker or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical composition of claim 13, comprising:

15. 15. The pharmaceutical composition of any one of claims 1 to 14, comprising 10 to 100 mg of ER metoprolol, 2.5 to 25 mg of IR metoprolol, and 0.125 to 1 mg of tesofensine.

16. A kit-of-parts for use in treating hypothalamic obesity in a subject, comprising at least two separate unit dosage forms (A) and (B); (A) comprises tesofensine or a pharmaceutically acceptable salt thereof; (B) comprises a beta-blocker or a pharmaceutically acceptable salt thereof; (A) and (B) are administered to the subject simultaneously, sequentially, or separately; Kit of parts.

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