Compositions for affecting weight loss

[0001] The present invention belongs to the field of pharmaceutical compositions and their uses for the preparation of a medicament for the treatment of obesity and for influencing weight loss in individuals.

[0002] Obesity is a disorder characterized by an accumulation of excess fat in the body. Obesity has been recognized as one of the leading causes of disease and is emerging as a global problem. Rising complications such as hypertension, insulin-independent diabetes, arteriosclerosis, dyslipidemia, some forms of cancer, sleep apnea, and arthritis and bone have been associated with increasing cases of obesity in the general population.

[0003] Obesity was defined in terms of body mass index (BMI). BMI is calculated as weight (kg) / [height (m)) 2 According to the guidelines of the US Center for Disease Control and Prevention (CDC; US Centers for Disease Control and Prevention), and the World Health Organization (World Health Organization. Physical status : The use and interpretation of anthropometry. Geneva, Switzerland: World Health Organization 1995. WHO Technical Report Series), for adults over 20 years of age, BMI belongs to one of the categories: below 18.5 is considered underweight, 18.5 - 24.9 is considered normal, 25.0-29.9 is considered overweight, and 30.0 and more - is considered obesity.

[0004] Before 1994, obesity was usually considered a psychological problem. The discovery of the adipostatic leptin hormone in 1994 (Zhang et al., "Positional cloning of the mouse obese gene and its human homologue," Nature 1994; 372: 425-432) made it clear that in some cases, obesity may have a biochemical basis. The result of this realization was the idea that obesity treatment can be achieved through chemical approaches. Since then, a number of such chemical treatments have entered the market. The most famous of these attempts was the introduction of Fen-Phen, a combination of fenfluramine and phentermine. Unfortunately, fenfluramine has been found to cause cardiac valve complications that in some cases have resulted in death of the user. Fenfluramine was withdrawn from the market from that moment. Limited success has been seen with other combination therapy approaches, particularly in the field of psychological eating disorders. An example is the work of Devlin et al., Int. J. Eating Disord. 28: 325-332, 2000, in which the combination of phentermine and fluoxetine has shown some efficacy in the treatment of binge eating disorder. Of course, this disorder is a problem only for a small part of the population.

[0005] In addition to those individuals who meet the strict definition of medical obesity, a significant portion of the adult population is overweight. These overweight people would also benefit from the availability of an effective composition for weight loss. Thus, there is an unmet need in the art to provide pharmaceutical compositions that can affect weight loss without other adverse side effects.

Summary of the invention [0006] Disclosed are weight loss compositions comprising a first compound and a second compound, wherein the first compound is an opioid antagonist and the second compound causes increased melanocortin 3 receptor (MC3-R) or melanocortin 4 (MC4-R) receptor agonism compared to normal physiological conditions.

[0007] Also disclosed are uses for influencing weight loss, increasing energy consumption, increasing satiety in an individual, or suppressing an individual's appetite, including identifying an individual in need and acting on that individual to antagonize opioid receptor activity and to enhance α-MSH activity.

EP 1 617 832 [0008] Certain compounds are known to affect weight loss. For example, Olszewski PK et al. .

(Neuroreport 12 (8), 2001: 1727-1730) describes that naltrexone reduces food intake induced by aguti icv related protein in rats. Islam. A K. et al. . (Pharm. Biochem. And Behavior 48 (1) 1994:

193-201) also reports such naltrexone activity in reducing food intake.

[0009] Wemeke U. et al. (Int. Clin. Psycopharm. 17 (1), 1989: 1-15) also reports the use of naltrexone and sibutramine or fluoxetine as a treatment for weight loss but not in combination.

[0010] Fuller R. et al. (Drug. Development Res. 17 (1), 1989: 1-15) emphasizes that enhancing serotonin activity leads to reduced food intake and enumerates a number of serotonin compounds with such activity including SSRIs and serotonin agonists.

[0011] Drug therapy is also known for the treatment of other eating disorders such as bulimia nervosa (Spigset O. et al. Exp. Opin. Ther. Patents 11 (3), 2001: 463-477 and Zhu AJ et al., Can. J. Psychiatry 47 (3), 2002: 227-234) or uncontrolled hyperphagia syndrome (Zhu AJ et al., Can. J. Psychiatry 47 (3), 2002: 227-234).

[0012] On the other hand, certain combinations similar to those of the present invention are disclosed in WO 03013524, WO 9609047 and US 6071918. First of all, WO 9609047 and US 6071918 disclose a combination of opioid receptor antagonist and SSRIs although these documents do not mention its use to treat obesity.

Detailed Description of Preferred Embodiments [0013] Arcuate nucleus neurons are known to respond to a wide range of hormones and nutrients, including leptin, insulin, gonadal steroids and glucose. In addition to potential transport mechanisms, peripheral substances can reach these neurons through arcuate cell bodies and projections on medial elevation, an area that is considered a periventricular organ that has no blood-brain barrier. Cone et al., "The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis," Int'l Journal obesity (2001) 25, Suppl 5, S63-S67.

[0014] Administration of exogenous leptin activates a number of different neurons in groups of hypothalamic and brainstem cells that maintain the leptin receptor. Leptin-responsive neurons in the arcuate nucleus contain both those containing neuropeptide Y (NPY) and agouti related peptide (AgRP) in the middle of the nucleus as well as those containing propiomelanocortin (POMC) and its derivatives, including α-melanocyte stimulating hormone (α-MSH) as well as cocaine and amphetamine-related transcript (CART). Saper et al., "The need to feed: Homeostatic and hedonic control of eating," Neuron, 36: 199-211 (2002).

[0015] Leptin-responsive POMC neurons in the arcuate nucleus are thought to cause anorexia and weight reduction by the action of α-MSH on melanocortin 3 and / or 4 receptors (MC3-R, MC4-R). The highest level of MC3-R expression is in the hypothalamus and limbic system, while MC4-R mRNA is expressed in potentially all major brain regions. Some of the metabolic effects resulting from MC4-R stimulation are reduced food intake and increased energy consumption by stimulation of thyrotropin-releasing hormone and activation of the sympathetic nervous system. The targeted deletion of the MC4-R gene produces obesity, gluttony, hyperinsulinemia, and reduced energy consumption. The targeted deletion of MC3-R leads to increased obesity due to reduced energy consumption. Komer et al., "The emerging science of body weight regulation and its impact on obesity treatment," J. Clin. Invest., 111 (5): 565570 (2003). Thus, increased concentrations of α-MSH in the central nervous system (CNS) increase its effect on MC3-R and / or MC4-R and lead to suppression of appetite.

EP 1 617 832 [0016] POMC neurons also release β-endorphin when they release α-MSH. β-endorphin is an endogenous μ-opioid receptor (MOP-R) agonist found on POMC neurons. MOP-R stimulation reduces the release of α-MSH. It is a biological feedback mechanism that controls the concentration of α-MSH in the CNS under normal physiological conditions. Thus, blocking MOP-R by opioid antagonists will break the feedback mechanism that leads to continuous secretion of α-MSH and an increase in its concentration in the CNS.

[0017] A second population of neurons in the arcuate nucleus tonically inhibits POMC neurons. These POMC inhibiting neurons secrete NPY, γ-aminobutyric acid (GABA) neurotransmitter, and AgRP. NPY and GABA inhibit POMC neurons by the NPY Y1 and GABA receptors, respectively. Thus, in the arcuate nucleus, NPY and GABA inhibit the release of α-MSH, and are therefore feeding stimulants. It is known that leptin inhibits the release of GABA from NPY terminals that sync to POMC neurons, while ghrelin [= acylated growth hormone releasing peptide] - orexygenic peptide, stimulates ghrelin receptors on NPY neurons and increases NPY and GABA secretion into POMC cells, which in turn inhibit the release of α-MSH.

[0018] AgRP stimulates food intake in the rat by antagonism of the α-MSH interaction at MC4-R. AgRP gene expression is inhibited by leptin.

[0019] Serotonin, also known as 5-hydroxytryptamine or 5-HT, activates POMC neurons to secrete α-MSH. However, serotonin is absorbed and removed from action by specific transporters, so that a single serotonin molecule has a short-term effect. It is known that selective serotonin reuptake inhibitors (SSRIs) prevent serotonin uptake and increase its concentration in the CNS. Therefore, SSRIs also increase the secretion of α-MSH and its concentration in the CNS.

[0020] Dopamine also increases POMC neuron activity to secrete α-MSH. Like serotonin, dopamine is also absorbed and removed from action, so that a single dopamine molecule has an effect for a short time. Dopamine reuptake inhibitors that prevent or reduce dopamine uptake may also increase α-MSH secretion and CNS levels.

[0021] Thus, increased secretion of α-MSH by various mechanisms, such as inhibiting serotonin reuptake, are among the strategies that the pharmaceutical uses and compositions of the present invention implement to produce a biochemical anorexygenic effect.

[0022] The present invention provides a multi-faceted combination therapy approach to the problem of weight loss. It does not simply refer to individual molecules, "informants", or receptors, but instead acts on many points on the feeding and satiety path. Aspects of the present invention are directed to increasing the concentration of α-MSH in the CNS, by stimulating the release of α-MSH, inhibiting its metabolism, reducing the antagonism of its interaction with MC3 / 4-R, and inhibiting any feedback mechanisms that slow down or stop its release. Aspects of the present invention include pharmaceutical compositions whose ingredients achieve one or more of these functions. The present inventors have found that the combination of two or more compounds disclosed herein leads to a synergistic effect that affects weight loss faster and on a more stable basis.

[0023] The present invention is directed to a composition for treating obesity or as affecting weight loss comprising a first compound and a second compound, where the first compound is an opioid antagonist and the second compound causes increased agonism of the melanocortin 3 (MC3-R) receptor or melanocortin 4 receptor (MC4-R) compared to normal physiological conditions.

[0024] In some embodiments, the second compound causes increased POMC neuron activity, leading to greater agonism at MC3-R and / or MC4-R.

[0025] In some embodiments, the opioid antagonist antagonizes the μ-opioid receptor (MOP-R) in a mammal. The mammal may be selected from the group consisting of mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, primates such as monkeys, chimpanzees and tailless monkeys, and humans.

[0026] In some embodiments, the opioid antagonist is selected from the group consisting of alvimopane, norbinaltorfimine, nalmefene, naloxone, naltrexone, methylnaltrexone, and nalorphine, and pharmaceutically acceptable salts or prodrugs thereof.

[0027] In other embodiments, the opioid antagonist is a partial opioid agonist. Compounds of this class have some agonist activity at opioid receptors. However, because they are weak agonists, they function as de facto antagonists. Examples of partial opioid agonists include pentacosin, buprenorphine, nalorphine, propiram and lofexidine.

[0028] The term "pharmaceutically acceptable salt" refers to a preparation of a compound that does not cause significant irritation to the organism to which it is administered and does not counteract the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reacting a compound of the invention with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Pharmaceutical salts can also be obtained by reacting a compound of the invention with a base to form a salt such as an ammonium salt, an alkali metal salt such as sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, an organic base salt such as dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylamine, and their salts with amino acids such as arginine, lysine and the like.

[0029] In some embodiments, the second compound in the pharmaceutical compositions of the present invention triggers the release of α-melanocyte stimulating hormone (α-MSH). The second compound may increase extracellular serotonin levels in the hypothalamus. In some embodiments, the second compound is a selective serotonin reuptake inhibitor (SSRI).

[0030] In further embodiments, the second compound is selected from fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, escitalopram, sibutramine, duloxetine and venlafaxine, and pharmaceutically acceptable salts thereof.

[0031] In certain other embodiments, the second compound is a bupropion norepinephrine reuptake inhibitor. [0032] In another aspect, the present invention relates to influencing weight loss, including identifying an individual in need and treatment of that individual to antagonize opioid receptor activity and to enhance α-MSH activity.

[0033] In some embodiments, the subject has a body mass index (BMI) greater than 25. In other embodiments, the subject has a BMI greater than 30. In yet other embodiments, the subject has a BMI greater than 40. However, in some embodiments, the subject may have BMI less than 25. In these embodiments, it may be beneficial for health or cosmetic purposes to affect weight loss, thereby reducing BMI even more.

[0034] In some embodiments, the opioid receptor activity is antagonized by administration of the opioid receptor antagonist. The opioid receptor antagonist may be an MOP receptor antagonist. In some embodiments, the opioid receptor antagonist is selected from alvimopan,

EP 1 617 832 norbinaltorfimine, nalmefene, naloxone, naltrexone, methylnaltrexone and nalorphine, and pharmaceutically acceptable salts thereof.

[0035] In some of the embodiments cited above, α-MSH activity is enhanced by administering the compound, where the compound triggers the release of α-MSH or increases the activity of neurons that express αMSH. In some embodiments, the compound is a selective serotonin reuptake inhibitor (SSRI). Examples of SSRIs that can be used in the present invention include fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, escitalopram, sibutramine, duloxetine, and venlafaxine, and pharmaceutically acceptable salts thereof.

[0036] In some embodiments, the method of the invention cited above is carried out with the condition that the subject does not suffer from Prader-Willi syndrome or uncontrolled hyperphagia syndrome. Thus, certain embodiments of the invention should be distinguished from combination therapy associated with the use of SSRI antidepressants (e.g., fluoxetine) used to treat physiological eating disorders, such as uncontrolled hyperphagia syndrome or Prader-Willi syndrome. In these embodiments, the target population is the population of individuals in need or demanding weight loss, in addition to the need to treat Prader-Willi syndrome or uncontrolled hyperphagia syndrome.

[0037] Subjects suffering from depression may gain weight as a result of their depression. In addition, some depressed individuals gain weight as a side effect of depression therapy. In some embodiments, the method of the invention cited above is performed provided that the subject is not suffering from depression. In some embodiments, the individual's overweight condition was not caused by the treatment of depression. [0038] The invention cited above is carried out under the condition that if the opioid receptor is antagonized using naltrexone, then the release of α-MSH is not stimulated by fluoxetine. However, the combination of naltrexone and fluoxetine can be used to affect weight loss in individuals who want to lose weight, regardless of whether they are cloned as obese. These individuals may include those with a BMI greater than 25, or those with a BMI less than 25 who still want to lose extra weight. This particular combination can also be used to treat general obesity. In some embodiments, the individual who wants to lose extra weight does not suffer from uncontrolled hyperphagia syndrome.

[0039] In some embodiments, the treatment step comprises administering to the subject a first compound and a second compound, wherein the first compound is an opioid antagonist and the second compound enhances αMSH activity.

[0040] In some embodiments, the first compound and the second compound are administered more or less simultaneously. In other embodiments, the first compound is administered before the second compound. In yet other embodiments, the first compound is administered after the second compound.

[0041] In some embodiments, the first compound and the second compound are administered individually. In other embodiments, the first compound and the second compound are covalently attached to each other to form one chemical moiety. One chemical moiety is then digested and metabolized into two separate physiologically active chemical moieties, one of which is the first compound and the other is the second compound.

[0042] In another aspect, the present invention relates to increasing satiety in an individual by identifying the individual in need thereof and treating that individual to antagonize opioid receptor activity and to enhance α-MSH activity.

[0043] In some embodiments, the treatment step comprises administering to the subject a first compound and a second compound, wherein the first compound is an opioid antagonist and the second compound enhances αMSH activity.

[0044] In some embodiments, the first compound and the second compound are administered almost simultaneously. In other embodiments, the first compound is administered before the second compound. In yet other embodiments, the first compound is administered after the second compound.

[0045] In yet another aspect, the present invention relates to suppressing the appetite of an individual comprising identifying the individual in need thereof and treating the individual to antagonize opioid receptor activity and to enhance α-MSH activity.

[0046] In some embodiments, the treatment step comprises administering to the subject a first compound and a second compound, wherein the first compound is an opioid antagonist and the second compound enhances αMSH activity.

[0047] In some embodiments, the first compound and the second compound are administered almost simultaneously. In other embodiments, the first compound is administered before the second compound. In yet other embodiments, the first compound is administered after the second compound.

[0048] In another aspect, the present invention relates to increasing energy consumption in an individual by identifying the individual in need thereof and treating the individual to antagonize opioid receptor activity and to enhance α-MSH activity.

[0049] In some embodiments, the treatment step comprises administering to the subject a first compound and a second compound, wherein the first compound is an opioid antagonist and the second compound enhances αMSH activity.

[0050] In some embodiments, the first compound and the second compound are administered almost simultaneously. In other embodiments, the first compound is administered before the second compound. In yet other embodiments, the first compound is administered after the second compound.

[0051] The structure-activity relationship of opioid agonists and antagonists was reviewed. See e.g., Zimmerman, DM; Leander, JDJ Med. Chem. 1990, 33, 895; Portoghese, PSJ Med. Chem. 1992, 35.1927; Carroll, FIJ Med. Chem. 2003, 46.1. Opioid antagonists, nalmefene (1), naltrexone (2), naloxone (3) and naphrerexamine (4) are theebaine derivative structures that share a common opiate type template. Selective opioid antagonists of the μ subtype are currently of considerable interest as agents for the treatment of obesity (Glass, MJ; Billington, CJ; Levine, AS Neuropeptides 1999, 33, 350) and CNS disorders (Reneric, JP; Bouvard, MP CNS Drugs 1998,10,365) .

<img file="PL1617832T3_D0001.tif" />

[0052] N-methyl and N-2-phenylethyl substituted opioids tend to exhibit opioid agonist activity while N-allyl and N-cyclopropylmethyl substituted analogs tend to exhibit opioid antagonist activity.

EP 1 617 832 [0053] Both nalmefene and naltrexone are potent μ-opioid antagonists. The only structural difference is that nalmefene has a methylene group in place of the ketone oxygen atom in naltrexone. Therefore, it is postulated that significant changes in the structure of the ketone oxygen atom in naltrexone do not significantly affect the potency of the antagonist.

<img file="PL1617832T3_D0002.tif" />

fluoxetine

N-metylofluoksetyna

Paroxetine [0054] Limited SAR for fluoxetine (5) was published in USP 4,214,081. N-Methylfluoxetine (6) shows comparable potency and selectivity as fluoxetine to inhibit serotonin reuptake. Thus, attachment of the linker to the fluoxetine nitrogen can lead to maintaining the strength and selectivity of fluoxetine itself. However, the present disclosure is not limited to the fluoxetine SSRI series. One can imagine that many SSRIs such as paroxetine (Dechant, KL; Clissold,

SP Drugs, 1991,41,225-253) or this or other of the bivalent SSRIs described by Kozikowski et al. (Tamiz, AP; Zhang, J .; Zhang, M .; Wang, CZ; Johnson, KM; Kozikowski, APJ Am. Chem. Soc. 2000,122,5393-5394; Tamiz, AP; Bandyopadhyay, BC; Zhang, J .; Flippen-Anderson, JL; Zhang, M .; Wang, CZ; Johnson, KM; Tella, S .; Kozikowski, APJ Med. Chem. 2001,44,1615-1622) can also be used to build hetero-bivalent therapeutic molecules of the present invention.

In another aspect, the invention relates to a pharmaceutical composition comprising a combination of an opioid antagonist and a compound that causes increased melanocortin 3 receptor (MC3R) or melanocortin 4 (MC4-R) agonism as compared to normal physiological conditions as described above, and a physiologically acceptable carrier, diluent, or excipient, or a combination thereof.

[0056] The term "pharmaceutical composition" refers to a mixture of a compound of the invention with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates the administration of the compound into the body. There are a number of techniques in the art for administering the compound including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

[0057] The term "carrier" defines a chemical compound that facilitates the incorporation of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a widely used carrier because it facilitates the uptake of many organic compounds into the body's cells or tissues.

[0058] The term "diluent" defines chemical compounds dissolved in water that will dissolve the compound in question and stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are used as diluents in the prior art. Widely used

The buffered solution is a phosphate buffered saline because it mimics salt conditions in human blood. Because buffer salts can control the pH of the solution at low concentrations, the buffered diluent rarely modifies the biological activity of the compound.

[0059] The term "physiologically acceptable" defines a carrier or diluent that does not counteract the biological activity and properties of the compound.

[0060] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, such as in combination therapy, or with appropriate carriers or excipient (s). Techniques for assembling and administering the compounds of the present application can be found in: "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990.

[0061] Suitable routes of administration may, e.g., include oral, rectal, transmucosal, or intestinal administration; parenteral administration, including intramuscular, subcutaneous, intravenous, intrathecal injection, and intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injection.

[0062] Alternatively, the compound may be administered topically instead of systemically, eg, by injecting the compound directly into the renal or cardiac region, often in a "depot" or sustained release formulation. In addition, the drug can be administered in a targeted drug delivery system, e.g., in a liposome coated with a tissue-specific antibody. Liposomes will be targeted and absorbed selectively by the organ.

[0063] The pharmaceutical compositions of the present invention can be prepared in a manner that is known per se, e.g., by means of conventional mixing, dissolving, granulating, coating, comminuting, emulsifying, encapsulating, placing (matrix) or tableting processes.

[0064] Pharmaceutical compositions for use in accordance with the present invention may thus be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries that facilitate processing of the active compounds into preparations which can be used pharmaceutically. The correct formulation depends on the chosen route of administration. Any of the well-known techniques, carriers and excipients may be used as appropriate and as understood in the art; e.g. in Remington's Pharmaceutical Sciences, supra.

[0065] For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers, such as Hanks solution, Ringer's solution, or physiological saline buffer. For mucosal administration, penetrants suitable for penetrating the barrier are used in the formulation. Such penetrants are usually known in the art. [0066] For oral administration, the compounds can easily be combined by the combination of active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers allow the compounds of the invention to be combined as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral swallowing by a patient undergoing treatment. Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with the pharmaceutical combination of the invention, optionally comminuting the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, starch

Potato, gelatin, gum tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrants such as crosslinked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate, may be added.

[0067] Dragee cores are provided with suitable coatings. To this end, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the dragee or tablet coatings for identification or to characterize different combinations of active compound doses.

[0068] Pharmaceutical preparations that can be used orally contain push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerin or sorbitol. The push-fit capsules may contain the active ingredients in admixture with a filler such as lactose, binders such as starches, and / or glidants such as talc or magnesium stearate and, optionally, stabilizing agents. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as liquid fats, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizing agents may be added. All formulations for oral administration should be in dosages suitable for such administration.

[0069] For buccal administration, the compositions may take the form of tablets or lozenges arranged in conventional manner.

[0070] When administered by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray from pressurized packages or a nebulizer, using a suitable propellant gas, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas . In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or nebulizer may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. [0071] The compounds may be formulated for parenteral administration by injection, e.g., one high dose by injection or permanent infusion. Injectable preparations may be in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. [0072] Pharmaceutical preparations for parenteral administration contain aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or excipients' contain liquid fats such as sesame oil, or synthetic fatty acid esters such as triglycerides or ethyl oleate, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizing agents or agents that increase the solubility of the compounds to allow for the preparation of high concentration solutions.

[0073] Alternatively, the active ingredient may be in the form of a powder to be combined with a suitable excipient, e.g., sterile pyrogen-free water, before use.

[0074] The compounds may also be formulated in rectal compositions, such as suppositories or enemy retainers, eg, containing conventional suppository bases, such as cocoa butter or other glycerides.

[0075] In addition to the preparations previously described, the compounds may also be formulated as "depot" preparations. Such long acting preparations can be administered by implantation (e.g. subcutaneous or intramuscular) or by intramuscular injection. Thus, e.g., the compounds may be combined with suitable polymeric or hydrophobic materials (e.g. as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.

[0076] The pharmaceutical carrier for the hydrophobic compounds of the invention is a co-solvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase. A common cosolvent system used is the VPD cosolvent system, which is a solution of 3% w / v benzyl alcohol, 8% w / v non-polar surfactant Polisorbate 80TM, and 65% w / v polyethylene glycol 300, made up to volume with absolute ethanol. Of course, the proportions of the co-solvent system can be significantly changed without destroying its solubility and toxicity characteristics. In addition, the identity of the co-solvent ingredients can be changed: e.g., other low-toxicity non-polar surfactants can be used instead of POLISORBATE 80lM; the proportion of polyethylene glycol may be changed; polyethylene glycol can replace other biocompatible polymers, e.g. polyvinylpyrrolidone; and dextrose can be replaced by other sugars or polysaccharides.

[0077] Alternatively, other hydrophobic pharmaceutical compound delivery systems can be used. Liposomes and emulsions are well known examples of excipients or carriers for the administration of hydrophobic drugs. Certain organic solvents such as dimethyl sulfoxide may also be used, although usually at the cost of greater toxicity. In addition, the compounds may be delivered using a sustained release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained release materials have been established and are well known to those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release compounds for several weeks to more than 100 days. Depending on the chemical nature and biological stability of the therapeutic reagent, additional protein stabilization strategies may be used. [0078] Many of the compounds used in the pharmaceutical combinations of the invention can be provided as salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts can be formed with many acids, including, but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic acid. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free acid forms or rules.

[0079] Pharmaceutical compositions suitable for use in the present invention contain compositions wherein the active ingredients are contained in an amount effective to achieve its intended purpose. In particular, a therapeutically effective amount means an amount of the compound effective to prevent, relieve or ameliorate symptoms of the disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the skill of the skilled person, especially in light of the detailed disclosure provided herein.

[0080] The exact formulation, route of administration and dosage for the pharmaceutical compositions of the present invention may be selected by the individual physician in view of the patient's condition. (See, e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", chapter 1 p. 1). In a typical case, the dose range of the composition administered to a patient may be from about 0.5 to 1000 mg / kg by weight

EP 1 617 832 of the patient's body. The dose may be a single dose or a series of two or more administered on one or more days as needed by the patient. It should be noted that for almost all specific compounds mentioned in the present disclosure, dosages have been established for humans to treat at least a certain condition. Thus, in most cases, the present invention will use the same doses or doses that are between about 0.1% and 500%, more preferably between about 25% and 250% of the established human dose. In the case where no human dose has been established, as will be the case for newly discovered pharmaceutical compounds, the appropriate human dose can be deduced from ED50 or ID50 values, or other appropriate values ​​derived from in vitro or in vivo tests such as those determined by toxicity and efficacy studies in animals.

[0081] Although exact dosages will be determined on a drug-to-drug basis, in most cases, some generalizations regarding dosage can be made. The daily dosage regimen for an adult human patient may, e.g., be an oral dose between 0.1 mg and 500 mg of each component, preferably between 1 mg and 250 mg, e.g. 5 to 200 mg, or an intravenous, subcutaneous or intramuscular dose of each component between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 up to 40 mg of each component of the pharmaceutical compositions of the present invention or a pharmaceutically acceptable salt thereof calculated as the free base, the composition being administered 1 to 4 times a day. Alternatively, the compositions of the invention may be administered by continuous intravenous infusion, preferably at a dose of each ingredient up to 400 mg per day. Thus, the total daily dose by oral administration of each component will typically be in the range of 1 to 2000 mg and the total daily dose by parenteral administration will typically be in the range of 0.1 to 400 mg. Accordingly, the compounds will be administered over a period of continuous therapy, e.g., for a week or more, or for months or years.

[0082] The amount and dosage range can be adjusted individually to provide plasma levels of the active moiety that are sufficient to maintain modulating effects, or a minimum effective concentration (MEC). MEC will vary for each compound but can be evaluated from in vitro data. The data necessary to obtain the MEC will depend on the individual characteristics and route of administration.

However, HPLC assays or bioassays can be used to determine plasma concentrations.

[0083] Dosage ranges can also be determined using the MEC value. The compositions should be administered using a mode that maintains plasma levels above MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.

[0084] In cases of local administration or selective uptake, effective local drug concentration may not be related to plasma concentration.

[0085] The amount of composition administered will, of course, depend on the subject being treated, the subject's weight, the severity of the disease, the method of administration and the judgment of the prescribing physician.

[0086] The compositions may, if desired, be in a package or in a metering device, which may contain one or more unit dosage forms containing the active substance. The packaging may e.g. comprise metal or plastic foil, such as a blister pack. The packaging or measuring device may be accompanied by instructions for administration. The packaging or measuring device may also be accompanied by information related to the container in the form prescribed by a government agency regulating the manufacture, use or sale of pharmaceuticals, which information is a reflection of the agency's approved form of the drug for administration in human or veterinary medicine. Such information, e.g., may be a US approved label Food and Drug Administration for prescription drugs, approved information leaflet

EP 1 617 832 product. Compositions comprising a compound of the invention in a compatible pharmaceutical carrier may also be prepared, placed in a suitable container, and labeled for the treatment of an indicated condition.

[0087] Those skilled in the art will understand that numerous and various modifications can be made without departing from the spirit of the present invention. Thus, it should be clearly understood that the forms of the present invention are merely illustrative and are not intended to limit the scope of the present invention.

Example 1: Combination of fluoxetine and naltrexone:

[0089] Individuals with a BMI greater than 25 have been identified. Each individual was instructed to take one 20 mg fluoxetine tablet daily (PROZAC®) in addition to one 50 mg naltrexone tablet daily. [0090] The subjects were monitored for a period of months. It is recommended to adjust the dose in such a way that each individual loses weight at a rate of 10% of the initial weight every 6 months. However, the rate of weight loss for each individual can be adjusted by the attending physician based on the particular needs of the individual.

[0091] If the initial dose is not effective, then the fluoxetine dose may be increased by 20 mg per day, but it never exceeds the total amount of 80 mg per day. If the initial dose results in faster weight loss than the above rate, the dose of both fluoxetine and naltrexone may be reduced.

[0092] Fluoxetine has a physiological half-life of about 9 hours while for naltrexone it is about 1.5 hours. Thus, in some cases, it is preferable to administer one dose of fluoxetine per day in combination with two or three or more doses of naltrexone per day. Naltrexone may also be in the form of a release formulation over time, where the dose is administered once a day, but naltrexone is gradually injected into the blood stream during the day, or over a period of 12 hours.

Example 2: Combination of fluoxetine and nalmefene:

[0093] Individuals with a BMI greater than 25 were identified. Each individual was instructed to take one 20 mg fluoxetine tablet (PROZAC®) per day. In addition, each individual is injected intravenously, intramuscularly or subcutaneously with 1 ml of a solution of 100 ug nalmefene in 1 ml of saline.

[0094] The subjects were monitored for a period of months. It is recommended to adjust the dose in such a way that each individual loses weight at a rate of 10% of the initial weight every 6 months. However, the rate of weight loss for each individual can be adjusted by the attending physician based on the particular needs of the individual.

[0095] If the initial dose is not effective, then the fluoxetine dose may be increased by 20 mg per day, but it never exceeds a total of 80 mg per day. In addition, the dose of nalmefene can be increased to 2 ml of a solution of 1 mg nalmefene in 1 ml of saline. If the initial dose results in faster weight loss than the above rate, the dose of both fluoxetine and nalmefene may be reduced.

Example 3: Combination of fluoxetine and naloxone:

[0096] Individuals with a BMI greater than 25 were identified. Each individual was instructed to take one 20 mg fluoxetine tablet (PROZAC®) per day. In addition, each individual is injected intravenously, intramuscularly or subcutaneously with 1 ml of a solution of 400 ug naloxone in 1 ml of saline.

EP 1 617 832 [0097] The subjects were monitored for a period of months. It is recommended to adjust the dose in such a way that each individual loses weight at a rate of 10% of the initial weight every 6 months. However, the rate of weight loss for each individual can be adjusted by the attending physician based on the particular needs of the individual.

[0098] If the initial dose is not effective, then the fluoxetine dose may be increased by 20 mg per day, but it never exceeds the total amount of 80 mg per day. If the initial dose results in faster weight loss than the above rate, the dose of both fluoxetine and nalmefene may be reduced.

Example 4: Combination of opioid antagonist and sibutramine:

[0099] Individuals with a BMI greater than 25 were identified. Each individual was instructed to take nalmefene, naltrexone or naloxone at the dose set in Examples 1-3. In addition, each individual was instructed to take 10 mg of sibutramine orally once daily.

[0100] The subjects were monitored over a period of months. It is recommended to adjust the dose in such a way that each individual loses weight at a rate of 10% of the initial weight every 6 months. However, the rate of weight loss for each individual can be adjusted by the attending physician based on the particular needs of the individual.

[0101] If the initial dose is not effective, the sibutramine dose can be increased to 15 mg per day. Doses of sibutramine above 15 mg per day are not recommended. If the initial dose leads to faster weight loss than the above rate, the dose of both sibutramine, nalmefene, naltrexone and naloxone may be reduced.

Example 5: Combination of opioid antagonist and bupropion:

[0102] Individuals with a BMI greater than 25 were identified. Each individual was instructed to take nalmefene, naltrexone or naloxone at the dose set in Examples 1-3. In addition, each individual was instructed to take bupropion. A typical adult dose is 300 mg per day, given three times a day. Dosage should start from 200 mg per day, given twice a day for 100 mg. Based on clinical response, this dose may be increased to 300 mg per day, given three times a day for 100 mg. No single dose may exceed 150 mg.

[0103] The subjects were monitored over a period of months. It is recommended to adjust the dose in such a way that each individual loses weight at a rate of 10% of the initial weight every 6 months. However, the rate of weight loss for each individual can be adjusted by the attending physician based on the particular needs of the individual.

Example 6: Combinations with naltrexone:

[0104] In a multicentre, randomized, blinded, placebo-controlled clinical trial of 6 groups, the following drug combinations were tested:

* Group 1: Fluoxetine 60 mg once daily plus Naltrexone 50 mg once daily * Group 2: Fluoxetine 60 mg once daily plus N-placebo after QD * Group 3: Bupropion-SR 150 mg twice daily plus Naltrexone 50 mg once daily * Group 4: Bupropion-SR 150 mg twice daily plus N-placebo once daily * Group 5: P-placebo twice daily plus Naltrexone 50 mg once daily

EP 1 617 832 * Group 6: P-placebo twice daily plus N-placebo once daily [0105] In each of the above groups, the dose of fluoxetine may be in the range of 6 mg to 60 mg, for example, 6 mg, 10 mg, 12 mg, 18 mg, 20 mg, 24 mg, 30 mg, 36 mg, 40 mg, 42 mg, 45 mg, 48 mg, 54 mg, and 60 mg.

Bupropion can be administered in doses ranging from 30 mg to 300 mg, for example, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg,

190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, and 300 mg. Naltrexone can be administered in doses ranging from 5 mg to 50 mg, for example, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, and 50 mg.

[0106] During the study, participants are assessed as outgoing patients. All participants in this trial receive diet instructions, tips on changing behavior, and recommendations on how to increase their activity, the mode given for weight loss. Participants are randomized to achieve drug testing in various combinations.

[0107] Participants in groups 5 and 6 cross over treatment with fluoxetine plus naltrexone or bupropion SR plus naltrexone after week 16 to extend the treatment period, which provides additional data on the safety of combination therapies.

[0108] The baseline endpoint is the percentage and absolute change from baseline in body weight at week 16. Secondary endpoints include body weight at 24.36 and 48 weeks, number and proportion of participants who achieved at least 5% body weight loss and 10% body weight loss (respondent analysis), changes in obesity-related cardiovascular risk indicators cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, glucose and insulin) and waist circumference, and safety and tolerability. Adverse effects, laboratory parameters, vital signs and the Hospital Anxiety and Depression (HAD) scale are used to monitor safety and tolerability.

Example 7: Dose response experiments:

Seventy, 22-30 g four-week old male C57B16J mice (Jackson Laboratory) were mock-injected daily with 0.1 ml 0.9% saline (pH 7.4) for 1 week before the experiments. The day before the start of the experiments, the animals were weighed and randomized into 1 of 7 weight-adjusted dose groups (0, 1.5, 3, 5.5, 10, 18 and 30 mg / kg; n = 10 / group for fluoxetine; 0 , 1.5.3, 5.5, 10, 18 and 30 mg / kg; n = 3 / naltrexone group). Food was stopped between 4:30 and 5:30 in the afternoon on the day preceding the experiment. The animals received an intraperitoneal injection of 0.3 ml one high dose (fluoxetine) or 0.1 ml one high dose (naltrexone) between 9-10:30 am, and food was provided immediately after the injection. 3 animals / group received injections each day of the study (i.e. 3 sets of 3 / group; 1 zl series / group). Food was weighed 1,2, 4, 8 and 24 h after injection. Cumulative food intake ± SEM was calculated and analyzed using Prizm. The SEM for these numbers was between 0.0041 and 0.26. The doses were log-transformed and fitted to the sigmoidal curve, food intake was expressed as the ratio to food intake in saline treated animals. EC was determined from the curve₅0 for each time point for each drug.

[0110] Similar procedures as described above were used for fluvoxamine and nalmefene, bupropion and naltrexone.

EP 1 617 832 [0111] The results are shown in the following table.

<td rowspan="2"> □</td><td>Hour 1</td><td>Hour 2</td><td>Hour 4</td><td>Hour 8</td><td>Hour 24</td>

<td>AVERAGE</td><td>AVERAGE</td><td>AVERAGE</td><td>AVERAGE</td><td>AVERAGE</td>

<td>Saline solution</td><td> 1,00</td><td> 1,00</td><td> 1,00</td><td> 1,00</td><td> 1,00</td>

<td>fluvoxamine</td><td> 0,77</td><td> 0,85</td><td> 0,95</td><td> 0,91</td><td> 0,92</td>

<td>nalmefene</td><td> 0,0083</td><td> 0,11</td><td> 0,57</td><td> 0,81</td><td> 0,98</td>

<td>Fluvoxamine + Nalmefene</td><td> 0,0041</td><td> 0,019</td><td> 0,42</td><td> 0,79</td><td> 0,99</td>

<td>bupropion</td><td> 0,32</td><td> 0,64</td><td> 0,97</td><td> 0,96</td><td> 0,99</td>

<td>naltrexone</td><td> 0,41</td><td> 0,77</td><td> 0,99</td><td> 1,1</td><td> 0,98</td>

<td>Naltrexone + bupropion</td><td> 0,042</td><td> 0,34</td><td> 0,89</td><td> 0,97</td><td> 0,95</td>

<td>naltrexone</td><td> 0,30</td><td> 0,56</td><td> 0,83</td><td> 0,98</td><td> 1,01</td>

<td>fluoxetine</td><td> 0,36</td><td> 0,57</td><td> 0,68</td><td> 0,76</td><td> 1,05</td>

<td>Naltrexone + Fluoxetine</td><td> 0,070</td><td> 0,26</td><td> 0,72</td><td> 0,95</td><td> 1,04</td>

Example 9: Electrophysiological data:

[0112] To examine the hypothesis that drugs selectively activate POMC neurons, we used a strain of transgenic mice that express green fluorescent protein (EGFP, Clontech), to transcriptional control the genomic sequence of Pomc mice containing a region located between 13 kb and -2kb, required for accurate neuron expression.

Bright green fluorescence (509 nm) was found in two areas of the CNS where POMC is produced: ARC and the lone band nucleus. At UV excitation (450-480 nm), POMC neurons were clearly distinguished from adjacent non-fluorescent infrared visualized neurons.

[0113] Coronary slices 200 µm thick were cut from ARC of four-week-old male POMC-EGFP mice. The slices were kept in Krebs (NaCl (126 mM), KCl (2.5 mM), MgCL (91.2 mM), CaCl2.2H2O (2.4 mM), NaH2PO4.H2O (1.2 mM), NaHCO3 ( 21.4 mM), glucose (11.1 mM)) at 35 ° C and saturated with 95% O2 and 5% CO2 for 1 h before registration. Registrations were made in Krebs solution at 35 ° C. Slices were visualized using an Axioskop FS2 plus (Zeiss) through typical infrared optics and using epifluorescence through a set of FITC (longpass) filters. POMC-EGFP neurons in hypothalamic slices had a resting membrane potential of -40 to -45 mV and showed frequent spontaneous potentials. Cell-associated registrations were made from fluorescent neurons using an Axopatch 200B enhancer (Axon Instruments) and Clampex 8 (Axon Instruments). Potential frequencies were determined using an event detection program (Mini Analysis; Synaptosoft Inc., Decatur,

GA). Drugs were put into the bath for 3 min.

[0114] Data were analyzed by determining the average stimulation rate over 500 s prior to drug addition, and analyzing treatment at this frequency (i.e., stimulation rate normalized to the pre-treatment frequency). The proportions given for the combination are the ratio of the naltrexone effect in combination with the POMC activator relative to the naltrexone alone (this is the additional effectiveness that naltrexone gave this POMC activator).

EP 1 617 832

The average effects of the drugs themselves were also mentioned. fenfluramine

Fenfluramine + Naltrexone Fluoxetine

Fluoxetine + Naltrexone Dopamine

Dopamine + Naltrexone

2X height (n = 6) 5.2X (n = 8)

3X (n = l)

1.2X (n = l) lXX (n = 9)

1.5X (n = 3) [0115] Naltrexone itself has a strong (7X) but variable effect. Many cells do not respond to naltrexone alone, but give a significant response to combination therapy. Heisler et al. (Science 297 (5581): 609-11 (2002)) showed that fenfluramine alone produces a 200% effect.

<td>Bow</td><td>Dose</td><td>Effect (%)</td><td>Bow</td><td>Dose</td><td>Effect(%)</td><td>Ratio</td>

<td>naltrexone</td><td>1μΜ</td><td> 29650</td><td>naltrexone + fenfluramine</td><td>1 μΜ + 20μΜ</td><td> 15080</td><td> 0,51</td>

<td>naltrexone</td><td>1μΜ</td><td> 2200</td><td>naltrexone + fenfluramine</td><td>1 μΜ + 20μΜ</td><td> 11440</td><td> 520</td>

<td>naltrexone</td><td>1μΜ</td><td> 2500</td><td>naltrexone + fenfluramine</td><td>1 μΜ + 20μΜ</td><td>S56</td><td> 0,34</td>

<td>naltrexone</td><td>1μΜ</td><td> 417</td><td>naltrexone + fenfluramine</td><td>1 μΜ + 20μΜ</td><td> 5700</td><td> 13,67</td>

<td>naltrexone</td><td>1μΜ</td><td> 177</td><td>naltrexone + fenfluramine</td><td>1 μΜ + 20μΜ</td><td> 430</td><td> 2,43</td>

<td>naltrexone</td><td>1μΜ</td><td> 200</td><td>naltrexone + fenfluramine</td><td>1 μΜ + 20μΜ</td><td> 2933</td><td> 14,67</td>

<td>naltrexone</td><td>1μΜ</td><td> 700</td><td>naltrexone + fenfluramine</td><td>1 μΜ + 20μΜ</td><td></td><td></td>

<td>naltrexone</td><td>1μΜ</td><td> 900</td><td>naltrexone + fenfluramine</td><td>1 μΜ + 20μΜ</td><td> 1831</td><td> 2,03</td>

<td>naltrexone</td><td>1μΜ</td><td> 2273</td><td>naltrexone + fenfluramine</td><td>1 μΜ + 20μΜ</td><td></td><td></td>

<td>naltrexone</td><td>1μΜ</td><td> 300</td><td>naltrexone + fenfluramine</td><td>1 μΜ + 20μΜ</td><td> 920</td><td> 3,07</td>

EP 1 617 832