WO2014195695A1 - Combinaisons thérapeutiques - Google Patents

Combinaisons thérapeutiques Download PDF

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Publication number
WO2014195695A1
WO2014195695A1 PCT/GB2014/051718 GB2014051718W WO2014195695A1 WO 2014195695 A1 WO2014195695 A1 WO 2014195695A1 GB 2014051718 W GB2014051718 W GB 2014051718W WO 2014195695 A1 WO2014195695 A1 WO 2014195695A1
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pharmaceutically acceptable
acceptable salt
triptan
receptor agonist
combination
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PCT/GB2014/051718
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English (en)
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Lora HEISLER
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Cambridge Enterprise Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • This invention relates to combinations, pharmaceutical compositions, and to methods for the treatment of disorders that can be treated by agonism of 5-hydroxytryptamine 2C (5- HT 2 c) receptors, such as obesity and type 2 diabetes.
  • 5-hydroxytryptamine 2C 5- HT 2 c
  • Obesity is a life-threatening disorder in which there is an increased risk of morbidity and mortality arising from concomitant diseases such as type 2 diabetes, hypertension, stroke, and cancer.
  • Obesity is now a major global healthcare issue, particularly relevant in the Western World and increasingly in some third world countries.
  • the increase in numbers of obese people globally is due largely to the increasing intake of high fat content foods and physical inactivity.
  • Worldwide obesity has nearly doubled since 1980.
  • WHO World Health Organization
  • At least 2.8 million adults die each year as a result of being overweight or obese.
  • 44% of the diabetes burden 23% of the ischaemic heart disease burden and between 7% and 41 % of certain cancer burdens are attributable to overweight and obesity.
  • BMI body mass index
  • m 2 body weight index
  • a person is considered to be overweight when they have a BMI in the range of 25-30 kg/m 2 , whereas a person with a BMI over 30 kg/m 2 is classified as obese.
  • Obesity is further divided into three classes, Class I (BMI of 30.0-34.9 kg/m 2 ), Class II (BMI of 35.0- 39.9 kg/m 2 ), and Class III (40 kg/m 2 or greater).
  • Class I BMI of 30.0-34.9 kg/m 2
  • Class II BMI of 35.0- 39.9 kg/m 2
  • Class III 40 kg/m 2 or greater
  • Raised BMI is a major risk factor for non-communicable diseases such as: cardiovascular diseases (mainly heart disease and stroke), which were the leading cause of death in 2008; diabetes; musculoskeletal disorders (especially osteoarthritis); and some cancers (endometrial, breast, and colon).
  • Type 2 diabetes (formerly called non-insulin-dependent or adult-onset diabetes) results from the body's ineffective use of insulin. 90% of people with diabetes around the world have Type 2 diabetes. The disease is largely the result of increased food intake beyond energy requirement (stored as fat), promoting hyperglycemia, which leads to hyperinsulinemia, which eventually promotes insulin resistance. Over time, diabetes can damage the heart, blood vessels, eyes, kidneys, and nerves. Diabetes increases the risk of heart disease and stroke.
  • Diabetic retinopathy is an important cause of blindness, and occurs as a result of long-term accumulated damage to the small blood vessels in the retina. Diabetes is among the leading causes of kidney failure. The overall risk of dying among people with diabetes is at least double the risk of their peers without diabetes.
  • the first line of treatment for both obesity and type 2 diabetes is to offer diet and life style advice such as reducing the fat content of the diet and increasing physical activity to promote weight loss.
  • diet and life style advice such as reducing the fat content of the diet and increasing physical activity to promote weight loss.
  • 5-hydroxytryptamine 5-hydroxytryptamine
  • 5-HT 5-hydroxytryptamine
  • serotonin 5-hydroxytryptamine
  • 5-HT 2 c receptor 5-hydroxytryptamine 2 c receptor
  • the 5-HT 2 c receptors are one of three subtypes that belong to the 5-HT2 receptor subfamily along with 5-HT 2A and 5-HT 2B receptors.
  • 5-HT 2C receptor agonists are attractive drug targets that have potential use in the treatment of a number of conditions including obesity, psychiatric disorders, sexual dysfunction and urinary incontinence.
  • the development of 5-HT 2C agonists has been a major obstacle, because of severe side effects due to a lack of selectivity over 5-HT 2A and 5-HT 2B receptors.
  • Activation of 5-HT 2A receptors can induce hallucinations, and activation of 5-HT 2A and 5-HT 2B receptors has been implicated in cardiac valvular insufficiency and possibly in pulmonary hypertension.
  • lorcaserin ((1 f?)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1 /-/-3- benzazepine) was approved by the United States Food and Drug Administration (FDA) for use in the treatment of obesity.
  • Lorcaserin is a potent and selective 5-HT 2 c receptor agonist with rapid oral absorption that shows dose-dependent decrease in food intake and body weight.
  • Lorcaserin has a high affinity for 5-HT 2 c receptors.
  • the binding affinity (Ki) of lorcaserin for 5-HT 2 c receptors is 13nM, compared with 147nM for 5-HT 2 B receptors, and 92nM for 5-HT 2A receptors.
  • the potency (EC 50 ) of lorcaserin at 5-HT 2C receptors is 39nM, compared with 2380nM for 5-HT 2B receptors, and 553nM for 5-HT 2A receptors.
  • BELVIQ (lorcaserin hydrochloride) will be available to patients in the United States by prescription.
  • Some side effects have also been reported following administration of BELVIQ.
  • the most common side effects include: headache, dizziness, fatigue, nausea, dry mouth, constipation, cough, low blood sugar (hypoglycemia) in patients with diabetes, and back pain.
  • RxList placebo-treated patients
  • Triptans are a family of tryptamine-based drugs used in the treatment of migraines.
  • Triptans include sumatriptan, rizatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, and avitriptan. They act by causing vasoconstriction of dilated meningeal arteries. Triptans are generally well tolerated. However, because of their vasoconstrictive properties, triptans act on coronary blood vessels as well as meningeal arteries. Therefore, all of the triptans are contra-indicated in patients with coronary disease, cerebrovascular disease, or untreated hypertension. They should also be used with extreme caution in patients with risk factors for cardiovascular disease, such as obesity and type 2 diabetes.
  • the combination of a 5-HT 2 c receptor agonist and a triptan significantly suppressed appetite in two different mouse models representative of human obesity, common high fat diet-induced obesity (DIO) and genetically driven hyperphagia and obesity due to a deficiency in the melanocortin4 receptor.
  • the combination also significantly reduced body weight gain in rats and body weight in DIO mice.
  • a combination particularly a therapeutic combination, which comprises: (a) a 5-HT 2c receptor agonist, or a pharmaceutically acceptable salt thereof; and (b) a triptan, or a pharmaceutically acceptable salt thereof.
  • the combination is a combined preparation for simultaneous, separate, or sequential use.
  • combined preparation refers to a "kit of parts" in the sense that the combination components (a) and (b) as defined above can be dosed independently or by use of different fixed combinations with distinguished amounts of the combination components (a) and (b).
  • the components can be administered simultaneously or one after the other. If the components are administered one after the other, preferably the time interval between administration is chosen such that the effect on the treated disorder or disease in the combined use of the components is greater than the effect which would be obtained by use of only any one of the combination components (a) and (b).
  • the components of the combined preparation may be present in one combined unit dosage form, or as a first unit dosage form of component (a) and a separate, second unit dosage form of component (b).
  • the ratio of the total amounts of the combination component (a) to the combination component (b) to be administered in the combined preparation can be varied, for example in order to cope with the needs of a patient sub-population to be treated, or the needs of the single patient, which can be due, for example, to the particular disease, age, sex, or body weight of the patients.
  • there is at least one beneficial effect for example an enhancing of the effect of the 5-HT 2 c receptor agonist, or a mutual enhancing of the effect of the combination components (a) and (b), for example a more than additive effect, additional advantageous effects, fewer side effects, less toxicity, or a combined therapeutic effect compared with a non-effective dosage of one or both of the combination components (a) and (b), and very preferably a synergism of the combination components (a) and (b).
  • beneficial effect for example an enhancing of the effect of the 5-HT 2 c receptor agonist, or a mutual enhancing of the effect of the combination components (a) and (b), for example a more than additive effect, additional advantageous effects, fewer side effects, less toxicity, or a combined therapeutic effect compared with a non-effective dosage of one or both of the combination components (a) and (b), and very preferably a synergism of the combination components (a) and (b).
  • a combination of the invention may be provided as a pharmaceutical combination for administration to a mammal, preferably a human.
  • the 5-HT 2c receptor agonist, or pharmaceutically acceptable salt thereof may optionally be provided together with a pharmaceutically acceptable carrier, excipient, or diluent, and/or the triptan, or pharmaceutically acceptable salt thereof, may optionally be provided together with a pharmaceutically acceptable carrier, excipient, or diluent.
  • a pharmaceutical composition which comprises: (a) a 5-HT 2c receptor agonist, or a pharmaceutically acceptable salt thereof; and (b) a triptan, or a pharmaceutically acceptable salt thereof; and optionally (c) a pharmaceutically acceptable carrier, excipient, or diluent.
  • the invention also provides a package, which comprises:
  • a 5-HT 2c receptor agonist or a pharmaceutically acceptable salt thereof, in unit dosage form
  • a method of preventing, treating, or ameliorating a disorder or condition that can be prevented, treated, or ameliorated by agonism of a 5-HT 2c receptor which comprises administering a 5-HT 2c receptor agonist, or a pharmaceutically acceptable salt thereof, and a triptan, or a pharmaceutically acceptable salt thereof, to a subject in need of such prevention, treatment, or amelioration.
  • a combination of the invention, or a composition of the invention for use in preventing, treating, or ameliorating a disorder or condition that can be prevented, treated, or ameliorated by agonism of a 5-HT 2c receptor.
  • a combination of the invention, or a composition of the invention in the manufacture of a medicament for the prevention, treatment, or amelioration of a disorder or condition that can be prevented, treated, or ameliorated by agonism of a 5-HT 2c receptor.
  • agonist as used herein is intended to mean moieties that activate the intracellular response when they bind to the receptor, or enhance GTP binding to membranes.
  • a 5HT 2 c receptor agonist can be utilized for modulating the activity of the 5HT 2 c receptor, decreasing food intake, inducing satiety (i.e., a feeling of fullness), preventing or controlling weight gain, preventing or treating obesity, decreasing body weight and/or affecting metabolism such that the recipient loses weight and/or maintains weight.
  • Such agonists can be used in the context of disorders and/or diseases where weight gain is a component of the disease and/or disorder such as, for example, obesity.
  • Suitable 5-HT 2c receptor agonists include:
  • Suitable 5-HT 2c receptor agonists are disclosed in WO 2010/060952.
  • Preferred examples disclosed in this document include:
  • the 5-HT 2 c receptor agonist has selectivity (in terms of its binding affinity and/or potency) for 5-HT 2 c receptors over 5-HT 2 A and 5-HT 2 B receptors.
  • the 5-HT 2C receptor agonist may have at least 5-fold selectivity, in terms of its binding affinity (Ki), for 5-HT 2C receptors over 5-HT 2A and 5-HT 2B receptors, and/or at least 10-fold selectivity, in terms of its potency (EC 50 ) for 5-HT 2C receptors over 5-HT 2A and 5-HT 2B receptors.
  • the 5-HT 2c receptor agonist may have at least 10-fold selectivity, in terms of its binding affinity (Ki), for 5-HT 2C receptors over 5-HT 2A and/or 5-HT 2B receptors, and/or at least 50-fold selectivity, in terms of its potency (EC 50 ) for 5-HT 2C receptors over 5-HT 2A and/or 5-HT 2B receptors.
  • a preferred 5-HT 2c receptor agonist is lorcaserin, or a pharmaceutically acceptable salt thereof, such as lorcaserin hydrochloride.
  • a further preferred 5-HT 2C receptor agonist is WAY161503, or a pharmaceutically acceptable salt thereof.
  • triptans examples include: 1-[3-(2-dimethylaminoethyl)-1 H-indol-5-yl]- N-methyl-methanesulfonamide (sumatriptan);
  • (+)-(R)-3-methylamino-6-carboxamido-1 ,2,3,4-tetrahydrocarbazole frovatriptan
  • frovatriptan a pharmaceutically acceptable salt thereof.
  • a preferred triptan is sumatriptan, or a pharmaceutically acceptable salt thereof.
  • a further preferred triptan is naratriptan, or a pharmaceutically acceptable salt thereof.
  • the choice of appropriate dosages of the components used in combination therapy according to the present invention can be determined and optimized by the skilled person, for example, by observation of the patient, including the patient's overall health, and the response to the combination therapy. Optimization, for example, may be necessary if it is determined that a patient is not exhibiting the desired therapeutic effect or conversely, if the patient is experiencing undesirable or adverse side effects that are too many in number or are of a troublesome severity.
  • the doses of the components used in combination therapy according to the invention should be chosen to provide a therapeutically effective amount of the components in combination.
  • an "effective amount" of the combination therapy is an amount that results in a reduction of at least one pathological parameter associated with the disorder or condition that can be prevented, treated, or ameliorated by agonism of a 5-HT 2 c receptor agonist.
  • an effective amount of the combination therapy is an amount that is effective to achieve a reduction of at least about 10%, at least about 15%, at least about 20%, or at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95%, compared to the expected reduction in the parameter associated with the disorder or condition.
  • combination treatment may be employed to increase the therapeutic effect of the 5-HT 2 c receptor agonist, compared with the effect of the agonist as a monotherapy, or to decrease the doses of the individual components in the resulting combinations while preventing or further reducing the risk of unwanted or harmful side effects of the individual components.
  • the 5-HT 2 c receptor agonist and the triptan are each prescribed at a dose that is within a typically prescribed dose range for each compound as a monotherapy.
  • the compounds may be prescribed as separate dosages or as a combination dosage. Such combinations provide increased efficacy compared with the effect of the 5-HT 2 c receptor agonist as a monotherapy.
  • the 5-HT 2 c receptor agonist and the triptan are each prescribed at a dose that is below a typically prescribed dose for each component as a monotherapy, but at doses that have therapeutic efficacy in combination.
  • the components may be prescribed as separate dosages or as a combination dosage.
  • the dosages of the components in combination may be selected to provide a similar level of therapeutic efficacy as the 5-HT 2C receptor agonist as a monotherapy, but with the advantage that the lower doses of the agonist and triptan reduce the risk of adverse side effects compared to the prescribed dosages of each compound as a monotherapy.
  • the prescribed dosage of the 5-HT 2C receptor agonist is within a typically prescribed dose range for monotherapy, and the triptan is prescribed at a dosage that is below a typically prescribed dose for monotherapy.
  • the prescribed dosage of the 5-HT 2C receptor agonist is below a typically prescribed dose for monotherapy, and the triptan is prescribed at a dosage that is within a typically prescribed dose range for monotherapy.
  • the 5-HT 2 c receptor agonist may be administered at a dose ranging from 0.01-500 mg daily, such as from 10-400, and including from 20-400, and including from 50- 200, and including from 25-200 mg daily.
  • the 5-HT 2 c receptor agonist may be administered at a dose ranging from 1-250 mg daily, such as from 1-200, and including from 2-100, and including from 2-60, and including from 2-30 mg daily.
  • the 5-HT 2 c receptor agonist may be administered at a dose ranging from 0.01-100 mg daily, such as from 0.1-50 and including from 0.1-25 and including from 0.1-10 and including from 0.1-5 mg daily.
  • the 5-HT 2 c receptor agonist is lorcaserin, or a pharmaceutically acceptable salt thereof. This may be administered at a dose ranging from 0.01-50 mg daily, such as from 0.2-20 mg daily, including from 0.5-15 mg daily. In one aspect, lorcaserin is administered at a dose ranging from 0.2-10 mg daily, including from 3.5-7.5 mg daily.
  • BELVIQ lorcaserin hydrochloride
  • BELVIQ is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with an initial body mass index (BMI) of: 30 kg/m 2 or greater (obese), or 27 kg/m 2 or greater (overweight) in the presence of at least one weight related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes).
  • BMI body mass index
  • Each BELVIQ tablet contains 10.4 mg of crystalline lorcaserin hydrochloride hemihydrate, equivalent to 10.0 mg anhydrous lorcaserin hydrochloride. Peak plasma concentrations occur 1.5 to 2 hours after oral dosing. Lorcaserin has a plasma half life of about 1 1 hours; steady state is reached within 3 days after twice daily dosing.
  • the recommended dose of BELVIQ is 10 mg administered orally twice daily.
  • BELVIQ can be taken with or without food.
  • a typically prescribed dosage of lorcaserin, or a pharmaceutically acceptable salt thereof, as a monotherapy for the treatment of obesity or overweight is 10mg, administered orally once or twice daily.
  • Examples of dosages of lorcaserin, or a pharmaceutically acceptable salt thereof, that are within a typically prescribed dose range for monotherapy are dosages of at least 10mg, such as 10-50mg.
  • Examples of dosages of lorcaserin, or a pharmaceutically acceptable salt thereof, that are less than a typically prescribed dose for monotherapy are dosages of 0.01 mg to ⁇ 10mg.
  • Examples of dosages of lorcaserin, or a pharmaceutically acceptable salt thereof, that are up to 50% of a typically prescribed dose for monotherapy are dosages of 0.01 -5mg.
  • Examples of dosages of lorcaserin, or a pharmaceutically acceptable salt thereof, that are up to 25% of a typically prescribed dose for monotherapy are dosages of 0.01-2.5mg.
  • the triptan may be administered at a dose ranging from 0.01-500 mg daily, such as from 10-400, and including from 20-400, and including from 50-200, and including from 25-200 mg daily. In other aspects, the triptan may be administered at a dose ranging from 1-250 mg daily, such as from 1-200, and including from 2-100, and including from 2-60, and including from 2-30 mg daily. In another aspect, the triptan may be administered at a dose ranging from 0.01-100 mg daily, such as from 0.01-50 and including from 0.01-25 and including from 0.01-10 and including from 0.01-5 mg daily.
  • triptan compounds for treatment of migraines are described in Martindale The Complete Drug Reference 36th Edition - Pharmaceutical Press 2009, pages 616-628.
  • prescribed dosages of triptan compounds as a monotherapy for treatment of migraines in healthy subjects are given below.
  • Sumatriptan is rapidly but incompletely absorbed when given orally. Peak plasma concentrations after oral doses are achieved in about 2 hours. Bioavailability is much higher (96%) after subcutaneous doses with peak concentrations occurring within 25 minutes. Bioavailability after intranasal doses is 16% of that achieved subcutaneously, with peak concentrations occurring in about 1.5 hours. The elimination half-life of sumatriptan is about 2 hours. Sumatriptan may be given orally or subcutaneously as the succinate, and intranasally as the base. Doses are expressed in terms of the base; sumatriptan succinate. 70 mg is equivalent to about 50 mg of sumatriptan.
  • the recommended dose in the UK is 50 mg, although some patients may require 100 mg. Not more than 300 mg may be taken in any 24-hour period. In the USA a lower dose of 25 mg may be used, although some patients require 50 or 100 mg. This may be followed by a second dose of up to 100 mg provided that the total daily dose does not exceed the recommended maximum of 200 mg.
  • patients aged 18 years and over may be given a single dose of 20 mg into one nostril, although 10 mg may be effective in some patients. In the USA, a dose of 5, 10, or 20 mg may be used. Not more than 40 mg should be used in a 24-hour period.
  • sumatriptan may be self-administered by subcutaneous injection in a single dose of 6 mg. Not more than 12 mg should be given in a 24-hour period. In the USA, it may also be used in single doses of 4 mg if adverse effects are dose-limiting. Sumatriptan may be given for the treatment of acute migraine in children and adolescents. Although not licensed for oral paediatric use in the UK, the BNFC suggests that a single oral dose of 25 mg may be given to children aged 6 to 10 years and 50 mg to those aged 10 to 12 years; older children may be given the usual adult dose.
  • intranasal sumatriptan is licensed for use in adolescents aged 12 to 17 years in a dose of 10 mg into one nostril; not more than 20 mg should be used within a 24-hour period.
  • the BNFC suggests that either this dose or an unlicensed dose equivalent to the usual adult dose may be used in those aged 12 years and over.
  • Almotriptan Malate after oral doses, peak plasma-almotriptan concentrations are obtained in about 1 to 3 hours. The plasma elimination half-life is about 3.5 hours in healthy subjects. Almotriptan is given orally as the malate, and doses are expressed in terms of the base; almotriptan malate. 8.75 mg is equivalent to about 6.25 mg of almotriptan. The usual dose of almotriptan is 12.5 mg in the UK and 6.25 or 12.5 mg in the USA. No more than 2 doses should be taken in a 24-hour period.
  • Eletriptan Hydrobromide peak plasma concentrations are attained within 1.5 hours. The plasma elimination half-life is about 4 hours. Eletriptan is given orally as the hydrobromide, but doses are expressed in terms of the base; eletriptan hydrobromide. 24.2 mg is equivalent to about 20 mg of eletriptan. The usual dose is 40 mg. No more than 2 doses should be taken in a 24-hour period.
  • Frovatriptan after oral doses, peak plasma-frovatriptan concentrations are attained in 2 to 4 hours. Food may delay the time to peak plasma concentrations by about 1 hour. The plasma elimination half-life of frovatriptan is about 26 hours. Frovatriptan is given orally as the succinate although doses are expressed in terms of the base; frovatriptan succinate. 3.9 mg is equivalent to about 2.5 mg of frovatriptan. The recommended dose is 2.5 mg. The maximum dose of frovatriptan in 24 hours is 5 mg in the UK although, in the USA, a maximum daily dose of 7.5 mg is allowed. Naratriptan Hydrochloride: after oral doses, peak plasma-naratriptan concentrations occur at 2 to 3 hours.
  • naratriptan hydrochloride 1.1 1 mg is equivalent to about 1 mg of naratriptan.
  • the recommended dose of naratriptan in the UK is 2.5 mg, and in the USA it is 1 or 2.5 mg.
  • the maximum dose of naratriptan is 5 mg in any 24-hour period.
  • Rizatriptan Benzoate after oral doses, peak pi as ma- rizatriptan concentrations are obtained in about 1 to 1.5 hours or 1.6 to 2.5 hours depending on the formulation. Food may delay the time to peak plasma concentrations of the tablet formulation by about 1 hour. The plasma half-life is about 2 to 3 hours.
  • Rizatriptan is given as the benzoate, and doses are expressed in terms of the base; rizatriptan benzoate. 14.53 mg is equivalent to about 10 mg of rizatriptan.
  • the usual dose in the UK of rizatriptan is 10 mg orally. In the USA a dose of 5 or 10 mg is used.
  • the recommended maximum dose in 24 hours is 20 mg in the UK and 30 mg in the USA.
  • Zolmitriptan peak plasma concentrations are achieved in about 1.5 to 3 hours after oral doses, depending on the formulation, and in about 3 hours with the intranasal spray. The elimination half-life is 2.5 to 3 hours. The recommended dose in the UK is 2.5 mg orally. The maximum dose of zolmitriptan in 24 hours is 10 mg. Recommended doses in the USA are somewhat lower; the dose is 1.25 or 2.5 mg with a maximum dose of 10 mg in 24 hours. When used intranasally, the usual dose is 5 mg as a single dose into one nostril, up to a maximum of 10 mg daily.
  • a method of preventing, treating, or ameliorating obesity and/or a condition or disorder associated with obesity which comprises administering a 5-HT 2c receptor agonist, or a pharmaceutically acceptable salt thereof, and a triptan, or a pharmaceutically acceptable salt thereof, to a subject in need of such prevention, treatment, or amelioration.
  • a combination of the invention, or a composition of the invention for use in the prevention, treatment, or amelioration of obesity and/or a condition or disorder associated with obesity.
  • the invention also provides use of a combination of the invention, or a composition of the invention, in the manufacture of a medicament for the prevention, treatment, or amelioration of obesity and/or a condition or disorder associated with obesity.
  • Conditions or disorders associated with obesity include hypertension, shortness of breath and other respiratory problems, glucose intolerance, insulin resistance, pre-diabetes, diabetes, type 2 diabetes, diabetes insipidus, diabetic nephropathy, coronary heart disease, heart attack, stroke, hyperlipidemia, dyslipidemia (for example, high cholesterol or high levels of triglycerides), cancer, infertility, skin infection, gastric ulcers, osteoarthritis, other orthopedic problems, reflux esophagitis (heartburn), snoring, gout, gallbladder disease, gallstones, sleep apnea, menstrual irregularities, infertility, heart trouble, bulimia, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and Alzheimer's disease.
  • obesity and overweight substantially increase the risk of morbidity from hypertension, dyslipidemia, type 2 diabetes, coronary heart disease, stroke, gallbladder disease, osteoarthritis and endometrial, breast, prostate, and colon cancers.
  • Higher body weights are also associated with increases in all-cause mortality. Most or all of these problems are relieved or improved by permanent significant weight loss. Longevity is likewise significantly increased by permanent significant weight loss.
  • a method of decreasing food intake, inducing satiety, controlling weight gain, or delaying gastric emptying/motility which comprises administering a 5-HT 2c receptor agonist, or a pharmaceutically acceptable salt thereof, and a triptan, or a pharmaceutically acceptable salt thereof, to a subject in need of such decreased food intake, induced satiety, controlled weight gain, or delayed gastric emptying or motility.
  • Such methods may be used, for example for the treatment of eating disorders, such as binge eating disorder, or night eating disorder, or digestive disorders, such as rapid gastric emptying or dumping syndrome, or gastrointestinal disorders, such as dysfunction of gastrointestinal motility.
  • eating disorders such as binge eating disorder, or night eating disorder
  • digestive disorders such as rapid gastric emptying or dumping syndrome
  • gastrointestinal disorders such as dysfunction of gastrointestinal motility.
  • a combination of the invention, or a composition of the invention for use in decreasing food intake, inducing satiety, controlling weight gain, or delaying gastric emptying/motility, of a subject.
  • the invention also provides use of a combination of the invention, or a composition of the invention, in the manufacture of a medicament for decreasing food intake, inducing satiety, controlling weight gain, or delaying gastric emptying/motility, of a subject.
  • combination treatment may be employed to increase the therapeutic effect of the 5-HT 2 c receptor agonist in the treatment of obesity and/or a condition or disorder associated with obesity, or in decreasing food intake, inducing satiety, controlling weight gain, or delaying gastric emptying/motility, compared with the effect of the agonist as a monotherapy.
  • combination treatment may be employed to decrease the doses of the individual components in the resulting combinations while preventing or further reducing the risk of unwanted or harmful side effects of the individual components.
  • triptans alone do not influence feeding, unless at very high concentrations.
  • sumatriptan succinate 40mg/kg
  • the triptan is present (or is administered) at a non-anorectic dosage.
  • the 5-HT 2c receptor agonist, or pharmaceutically acceptable salt thereof is present (or is administered) at an anorectic dosage
  • the triptan, or pharmaceutically acceptable salt thereof is present (or is administered) at a non-anorectic dosage.
  • the triptan may be present (or administered) at a dosage which is within a typically prescribed dose range of the triptan for the treatment of migraine as a monotherapy.
  • the triptan may be present (or administered) at a dosage which is below a typically prescribed dosage of the triptan for the treatment of migraine as a monotherapy.
  • An anorectic dose of a 5-HT 2 c receptor agonist may be a dose of the agonist that is typically prescribed as a monotherapy for the treatment of obesity or weight loss.
  • An example of an anorectic dosage of lorcaserin, or a pharmaceutically acceptable salt thereof, in humans is 10mg once or twice per day.
  • Anorectic doses of lorcaserin in mice are described in Fletcher et al, Neuropharmacology, 2009 57(3):259-67. Suitable typically prescribed dosages for different triptan compounds for the treatment of migraine are referred to above.
  • Preferred dosages of the 5-HT 2 c receptor agonist and the triptan below the typically prescribed dose for monotherapy are doses that are up to 50%, or up to 25% of the typically prescribed dose.
  • compositions, or methods of the invention for combinations, compositions, or methods of the invention for the treatment of obesity, or for decreasing food intake, inducing satiety, controlling weight gain, or delaying gastric emptying/motility, preferably the 5-HT 2c receptor agonist, or pharmaceutically acceptable salt thereof, is present (or is administered) at a non-anorectic dosage, and the triptan, or pharmaceutically acceptable salt thereof, is present (or is administered) at a non-anorectic dosage.
  • the triptan may be present (or administered) at a dosage which is within a typically prescribed dose range of the triptan for the treatment of migraine as a monotherapy.
  • the triptan may be present (or administered) at a dosage which is below a typically prescribed dosage of the triptan for the treatment of migraine as a monotherapy.
  • Example 1 shows that therapeutic appetitive effects were observed when non- anorectic doses of a 5-HT 2 c receptor agonist and a triptan were administered in combination. Such dosages still enhance the therapeutic appetitive effect of a 5-HT 2C receptor agonist, but minimise the risk of any adverse side effects from administration of the agonist.
  • Example 2 shows that a significant reduction of the rate of gastric emptying was observed when non-anorectic doses of a 5-HT 2C receptor agonist and a triptan were administered in combination. Again, such dosages produce a therapeutic effect of a 5-HT 2C receptor agonist, but minimise the risk of any adverse side effects from administration of the agonist.
  • the invention provides a method of preventing, treating, or ameliorating type 2 diabetes and/or a condition or disorder associated with type 2 diabetes, which comprises administering a 5-HT 2c receptor agonist, or a pharmaceutically acceptable salt thereof, and a triptan, or a pharmaceutically acceptable salt thereof, to a subject in need of such prevention, treatment, or amelioration.
  • a combination of the invention, or a composition of the invention for use in the prevention, treatment, or amelioration of type 2 diabetes and/or a condition or disorder associated with type 2 diabetes.
  • a combination of the invention, or a composition of the invention in the manufacture of a medicament for the prevention, treatment, or amelioration of type 2 diabetes and/or a condition or disorder associated with type 2 diabetes.
  • Conditions or disorders associated with type 2 diabetes include any damage to the heart (diabetic cardiomyopathy), blood vessels (diabetic microvascular and macrovascular disease), eyes (diabetic retinopathy), kidneys (diabetic nephropathy), and nerves (diabetic neuropathy) as a result of type 2 diabetes.
  • Type 2 diabetics are often referred to as insulin resistant. They often have higher than normal plasma insulin levels (hyperinsulinemia).
  • Hyperinsulinemia may be a causative factor in the development of high blood pressure, high levels of circulating low density lipo-proteins (LDLs), and lower than normal levels of the beneficial high density lipo-proteins (HDLs).
  • LDLs low density lipo-proteins
  • HDLs beneficial high density lipo-proteins
  • Insulin resistance and hyperinsulinemia have also been linked with two other metabolic disorders that pose considerable health risks: impaired glucose tolerance and metabolic obesity. Individuals with impaired glucose tolerance are considered to be at higher risk for diabetes and coronary artery disease. Insulin resistance is frequently associated with hypertension, coronary artery disease (arteriosclerosis), and lactic acidosis, as well as related disease states.
  • combination treatment may be employed to increase the therapeutic effect of the 5-HT 2 c receptor agonist in the prevention, treatment, or amelioration of type 2 diabetes and/or a condition or disorder associated with type 2 diabetes, compared with the effect of the agonist as a monotherapy.
  • combination treatment may be employed to decrease the doses of the individual components in the resulting combinations while preventing or further reducing the risk of unwanted or harmful side effects of the individual components.
  • the 5-HT 2c receptor agonist, or pharmaceutically acceptable salt thereof is present (or is administered) at an anorectic dosage
  • the triptan, or pharmaceutically acceptable salt thereof is present (or is administered) at a non- anorectic dosage.
  • the triptan may be present (or administered) at a dosage which is within a typically prescribed dose range of the triptan for the treatment of migraine as a monotherapy.
  • the triptan may be present (or administered) at a dosage which is below a typically prescribed dosage of the triptan for the treatment of migraine as a monotherapy.
  • the 5-HT 2c receptor agonist, or pharmaceutically acceptable salt thereof is present (or is administered) at a non-anorectic dosage that is sufficient to affect glucose tolerance in the subject when administered as a monotherapy
  • the triptan, or pharmaceutically acceptable salt thereof is present (or is administered) at a non-anorectic dosage.
  • the triptan may be present (or administered) at a dosage which is within a typically prescribed dose range of the triptan for the treatment of migraine as a monotherapy.
  • the triptan may be present (or administered) at a dosage which is below a typically prescribed dosage of the triptan for the treatment of migraine as a monotherapy.
  • compositions, or methods of the invention for the treatment of type 2 diabetes and/or a condition or disorder associated with type 2 diabetes preferably the 5-HT 2c receptor agonist, or pharmaceutically acceptable salt thereof, is present (or is administered) at a dosage that is less than is required to affect glucose tolerance in the subject when administered as a monotherapy, and the triptan, or pharmaceutically acceptable salt thereof, is present (or is administered) at a non-anorectic dosage.
  • the triptan may be present (or administered) at a dosage which is within a typically prescribed dose range of the triptan for the treatment of migraine as a monotherapy.
  • the triptan may be present (or administered) at a dosage which is below a typically prescribed dosage of the triptan for the treatment of migraine as a monotherapy.
  • Preferred dosages below the typically prescribed dose for monotherapy are doses that are up to 50%, or up to 25% of the typically prescribed dose.
  • Examples of dosages of different triptans, or pharmaceutically acceptable salts thereof, that are within a typically prescribed dose range for monotherapy, dosages that are less than a typically prescribed dosage for monotherapy, and dosages that are up to 50% or up to 25% of a typically prescribed dosage, are shown in the table below:
  • Example 3 shows that therapeutic glycemic effects were observed when doses of a 5-HT 2 c receptor agonist and a triptan that alone were not sufficient to influence glucose tolerance were administered in combination. Such doses enhance the therapeutic glycemic effect, but minimise the risk of any adverse side effects from administration of the agonist.
  • the 5-HT 2c receptor agonist, or pharmaceutically acceptable salt thereof, and the triptan, or pharmaceutically acceptable salt thereof may be administered simultaneously, separately, or sequentially to a subject.
  • the 5-HT 2 c receptor agonist and the triptan may be administered substantially simultaneously (for example, within about 60 minutes, about 50 minutes, about 40 minutes, about 30 minutes, about 20 minutes, about 10 minutes, about 5 minutes, or about 1 minute of each other) or separated in time by about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, or about 72 hours, or more.
  • the skilled person will be able to determine, and optimise, a suitable time course for sequential administration, depending on the particular combination of the 5-HT 2 c agonist and triptan.
  • the time course is preferably selected such that there is at least one beneficial effect, for example an enhancing of the effect of the 5-HT 2 c agonist, or a mutual enhancing of the effect of the combination components, for example a more than additive effect, additional advantageous effects, fewer side effects, less toxicity, or a combined therapeutic effect compared with a non-effective dosage of one or both of the combination components, and very preferably a synergism of the combination components.
  • the optimum time course will depend on the factors such as the time taken for the peak plasma concentration of the compound to be reached after administration, and the elimination half-life of each compound.
  • the time difference is less than the half-life of the first component to be administered.
  • the 5-HT 2 c receptor agonist may be administered in the morning, and the triptan administered at least once later in the day. In other embodiments, the 5-HT 2 c receptor agonist and triptan may be administered at substantially the same time. For example, it may be preferred to administer the 5-HT 2C receptor agonist, such as locaserin, or pharmaceutically acceptable salt thereof, and triptan together before a meal.
  • a suitable timing for administration may be approximately one hour before a meal.
  • locaserin and a triptan could be administered together twice daily, suitably one hour before lunch (for example 1 1am) and one hour before dinner (for example 5pm).
  • the subject may receive doses of the 5-HT 2C receptor agonist and triptan over a period of weeks, months, or years. For example, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, 5 years, or more.
  • the subject is a mammalian subject, more preferably a human subject.
  • Pharmaceutically acceptable salts include pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfiric, tartaric, oxalic, p-toluenesulfonic and the like, such as the pharmaceutically acceptable salts listed in the Journal of Pharmaceutical Science, 66, 2 (1977).
  • the acid addition salts can be obtained as the direct products of compound synthesis.
  • the free base can be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.
  • compositions of the invention may be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remington's Pharmaceutical Sciences (Mack Pub. Co., Easton, PA, 1980).
  • the 5-HT 2 c receptor agonist and/or the triptan may be provided as a controlled release or a sustained release formulation.
  • they may be provided as a combined controlled release or sustained release formulation, or as separate, discrete controlled release or sustained release formulations.
  • controlled release refers to a drug-containing formulation or fraction thereof in which release of the drug is not immediate, i.e., with a “controlled release” formulation, administration does not result in immediate release of the drug into an absorption pool.
  • controlled release includes sustained release and delayed release formulations.
  • sustained release (synonymous with “extended release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period.
  • delayed release is also used in its conventional sense, to refer to a drug formulation which, following administration to a patient, provides a measurable time delay before drug is released from the formulation into the patient's body.
  • the components of a combination of the invention, or a composition of the invention may be administered by known means, in any suitable formulation, by any suitable route.
  • the components or composition are administered orally, parenterally (including by subcutaneous, intravenous, or intramuscular injection), sublingually, transdermally, intrathecally, transmucosally, sublingually, topically, rectally, or by inhalation (including by intranasal administration).
  • intranasal administration of the 5-HT 2 c receptor agonist and/or the triptan may be particularly preferred.
  • the 5-HT 2 c receptor is expressed in high density in the brain, and is expressed in low density or is absent in peripheral tissues, intranasal administration may help to miminise the side effects resulting from administration of the 5-HT 2 c receptor agonist, particularly side effects resulting from action of the 5-HT 2 c receptor agonist at 5-HT 2A and/or 5-HT 2B receptors.
  • Suitable formulations for intranasal administration for example of sumatriptan and zolmitriptan, are known to the skilled person.
  • Suitable compositions, for example for oral administration include solid unit dose forms, and those containing liquid, e.g.
  • diluents and carriers include, for example, lactose and talc, together with appropriate binding agents.
  • the pharmaceutical formulation may be a solid, semi-solid or liquid, such as, for example, a tablet, a capsule, a caplet, a liquid, a suspension, an emulsion, a suppository, granules, pellets, beads, a powder, or the like, preferably in unit dosage form suitable for single administration of a precise dosage.
  • suitable pharmaceutical compositions and dosage forms may be prepared using conventional methods known to those in the field of pharmaceutical formulation and described in the pertinent texts and literature, e.g., in Remington: The Science and Practice of Pharmacy (Easton, Pa.: Mack Publishing Co., 1995).
  • oral dosage forms are generally preferred, and include tablets, capsules, caplets, solutions, suspensions and syrups, and may also comprise a plurality of granules, beads, powders, or pellets that may or may not be encapsulated.
  • Preferred oral dosage forms are tablets and capsules. It is especially advantageous to formulate combinations or compositions of the invention in unit dosage form for ease of administration and uniformity of dosage.
  • unit dosage forms refers to physically discrete units suited as unitary dosages for the individuals to be treated. That is, the compositions are formulated into discrete dosage units each containing a predetermined, "unit dosage" quantity of an active agent calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • unit dosage forms of the invention are dependent on the unique characteristics of the active agent to be delivered. Dosages can further be determined by reference to the usual dose and manner of administration of the ingredients. It should be noted that, in some cases, two or more individual dosage units in combination provide a therapeutically effective amount of the active agent, for example, two tablets or capsules taken together may provide a therapeutically effective dosage, such that the unit dosage in each tablet or capsule is approximately 50% of the therapeutically effective amount. Tablets may be manufactured using standard tablet processing procedures and equipment. Direct compression and granulation techniques are preferred. In addition to the active agent, tablets will generally contain inactive, pharmaceutically acceptable carrier materials such as binders, lubricants, disintegrants, fillers, stabilizers, surfactants, coloring agents, and the like.
  • inactive, pharmaceutically acceptable carrier materials such as binders, lubricants, disintegrants, fillers, stabilizers, surfactants, coloring agents, and the like.
  • Capsules are also preferred oral dosage forms for those pharmaceutical active agents that are orally active, in which case the active agent-containing composition may be encapsulated in the form of a liquid or solid (including particulates such as granules, beads, powders or pellets).
  • Suitable capsules may be either hard or soft, and are generally made of gelatin, starch, or a cellulosic material, with gelatin capsules preferred.
  • Two-piece hard gelatin capsules are preferably sealed, such as with gelatin bands or the like. See, for example, Remington: The Science and Practice of Pharmacy, which describes materials and methods for preparing encapsulated pharmaceuticals.
  • Oral dosage forms may, if desired, be formulated so as to provide for controlled release of the 5-HT 2 c receptor agonist and/or the triptan.
  • the present formulations are controlled release oral dosage forms.
  • the dosage forms provide for sustained release, i.e., gradual, release of the 5-HT 2 c receptor agonist and/or the triptan from the dosage form to the patient's body over an extended time period, typically providing for a substantially constant blood level of the component(s) over a time period in the range of about 4 to about 12 hours, typically in the range of about 6 to about 10 hours.
  • sustained release dosage forms are formulated by dispersing the active agent within a matrix of a gradually hydrolyzable material such as a hydrophilic polymer, or by coating a solid, drug-containing dosage form with such a material.
  • Hydrophilic polymers useful for providing a sustained release coating or matrix include, by way of example: cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, acrylic acid alkyi esters, methacrylic acid alkyi esters, and the like, e.g.
  • Preparations according to this invention for parenteral administration include sterile aqueous and non-aqueous solutions, suspensions, and emulsions.
  • Injectable aqueous solutions contain the active agent in water-soluble form.
  • non-aqueous solvents or vehicles include fatty oils, such as olive oil and corn oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, low molecular weight alcohols such as propylene glycol, synthetic hydrophilic polymers such as polyethylene glycol, liposomes, and the like.
  • Parenteral formulations may also contain adjuvants such as solubilizers, preservatives, wetting agents, emulsifiers, dispersants, and stabilizers, and aqueous suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, and dextran.
  • Injectable formulations are rendered sterile by incorporation of a sterilizing agent, filtration through a bacteria-retaining filter, irradiation, or heat. They can also be manufactured using a sterile injectable medium.
  • the active agent may also be in dried, e.g., lyophilized, form that may be rehydrated with a suitable vehicle immediately prior to administration via injection.
  • the active agent may also be administered through the skin using conventional transdermal drug delivery systems, wherein the active agent is contained within a laminated structure that serves as a drug delivery device to be affixed to the skin.
  • the drug composition is contained in a layer, or "reservoir,” underlying an upper backing layer.
  • the laminated structure may contain a single reservoir, or it may contain multiple reservoirs.
  • the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery.
  • the drug-containing reservoir and skin contact adhesive are present as separate and distinct layers, with the adhesive underlying the reservoir which, in this case, may be either a polymeric matrix as described above, or it may be a liquid or hydrogel reservoir, or may take some other form.
  • Transdermal drug delivery systems may in addition contain a skin permeation enhancer.
  • the active agent may be formulated as a depot preparation for controlled release of the active agent, preferably sustained release over an extended time period.
  • sustained release dosage forms are generally administered by implantation (e.g., subcutaneously or intramuscularly or by intramuscular injection).
  • compositions will generally be administered orally, parenterally, transdermal ⁇ , or via an implanted depot, other modes of administration are suitable as well.
  • administration may be transmucosal, e.g., rectal or vaginal, preferably using a suppository that contains, in addition to the active agent, excipients such as a suppository wax.
  • Transmucosal administration also encompasses transurethral administration, as described, for example, in U.S. Pat. Nos. 5,242,391 , 5,474,535, and 5,773,020 to Place et al.
  • Formulations for nasal or sublingual administration are also prepared with standard excipients well known in the art.
  • the combinations or pharmaceutical compositions of the invention may also be formulated for inhalation, e.g., as a solution in saline, as a dry powder, or as an aerosol.
  • kits of the invention may be recorded on a suitable recording medium or substrate.
  • the instructions may be printed on a substrate, such as paper or plastic.
  • the instructions may be present in the kits as a package insert, in the labeling of the container of the kit or components thereof (i.e., associated with the packaging or sub- packaging).
  • the instructions are present as an electronic storage data file present on a suitable computer readable storage medium, e.g. CD-ROM, diskette.
  • Some or all components of the kits of the invention may be packaged in suitable packaging to maintain sterility.
  • a combination, composition, or package of the invention comprises any of the following: lorcaserin, or a pharmaceutically acceptable salt thereof, and sumatriptan, or a pharmaceutically acceptable salt thereof; lorcaserin, or a pharmaceutically acceptable salt thereof, and naratriptan, or a pharmaceutically acceptable salt thereof; lorcaserin, or a pharmaceutically acceptable salt thereof, and zolmitriptan, or a pharmaceutically acceptable salt thereof; lorcaserin, or a pharmaceutically acceptable salt thereof, and rizatriptan, or a pharmaceutically acceptable salt thereof; lorcaserin, or a pharmaceutically acceptable salt thereof, and eletriptan, or a pharmaceutically acceptable salt thereof; lorcaserin, or a pharmaceutically acceptable salt thereof, and almotriptan, or a pharmaceutically acceptable salt thereof; lorcaserin, or a pharmaceutically acceptable salt thereof, and avitriptan, or a pharmaceutically acceptable salt thereof; lorcaserin, or a pharmaceutically acceptable salt thereof, and
  • a combination, composition, or package of the invention may comprise any of the following dosages of lorcaserin, or a pharmaceutically acceptable salt thereof, and a triptan, or a pharmaceutically acceptable salt thereof: i) 10-50mg lorcaserin, or a pharmaceutically acceptable salt thereof, and 25-300mg sumatriptan, or a pharmaceutically acceptable salt thereof; ii) 10-50mg lorcaserin, or a pharmaceutically acceptable salt thereof, and 1-5mg naratriptan, or a pharmaceutically acceptable salt thereof; iii) 10-50mg lorcaserin, or a pharmaceutically acceptable salt thereof, and 1.25-10mg zolmitriptan, or a pharmaceutically acceptable salt thereof; iv) 10-50mg lorcaserin, or a pharmaceutically acceptable salt thereof, and 5-30mg rizatriptan, or a pharmaceutically acceptable salt thereof; v) 10-50mg lorcaserin, or a pharmaceutically acceptable salt thereof,
  • a combination, composition, or package of the invention may comprise any of the following dosages of lorcaserin, or a pharmaceutically acceptable salt thereof, and sumatriptan, or a pharmaceutically acceptable salt thereof, suitable for intranasal administration: i) 10-50mg lorcaserin, or a pharmaceutically acceptable salt thereof, and 5-40mg sumatriptan, or a pharmaceutically acceptable salt thereof; ii) 10-50mg lorcaserin, or a pharmaceutically acceptable salt thereof, and 0.01 - ⁇ 5mg sumatriptan, or a pharmaceutically acceptable salt thereof; iii) 0.01- ⁇ 10mg lorcaserin, or a pharmaceutically acceptable salt thereof, and 5-40mg sumatriptan, or a pharmaceutically acceptable salt thereof; or iv) 0.01- ⁇ 10mg lorcaserin, or a pharmaceutically acceptable salt thereof, and 0.01- ⁇ 5mg sumatriptan, or
  • FIG 1 shows an experimental flowchart for feeding studies in mice
  • Figure 2 shows the effect of WAY161503 alone on food intake in mice (**p ⁇ 0.01 , Data are presented as Mean +/- SEM);
  • Figure 3 shows the effect of sumatriptan succinate alone on food intake in mice (for sumatriptan succinate 40mg/kg, p ⁇ 0.05, Data are presented as Mean +/- SEM);
  • Figure 4 shows the effect of combining WAY161503 with sumatriptan succinate on food intake in mice (*p ⁇ 0.05, Data are presented as Mean +/- SEM);
  • FIG. 5 shows an experimental flowchart for gastric emptying studies in mice
  • Figure 6 shows the effect of combining WAY161503 with sumatriptan succinate on gastric emptying in mice (**p ⁇ 0.01 , Data are presented as Mean +/- SEM);
  • FIG 7 shows an experimental flowchart for a glucose tolerance test in high fat diet- induced obese (DIO) mice;
  • Figure 8 shows the effect of WAY161503 alone on glucose tolerance in DIO mice (Data are presented as Mean +/- SEM);
  • Figure 9 shows the effect of sumatriptan succinate alone on glucose tolerance in DIO mice (Data are presented as Mean +/- SEM);
  • Figure 10 shows the effect of combining WAY161503 with sumatriptan succinate on glucose tolerance in DIO mice (Data are presented as Mean +/- SEM);
  • Figure 11 shows the effect of lorcaserin on 5 hour food intake in male mice (* p ⁇ 0.05 compared to vehicle; Data are presented as Mean +/- SEM);
  • Figure 12 shows the effect of naratriptan on 5 hour food intake in male mice (* p ⁇ 0.05 compared to vehicle; Data are presented as Mean +/- SEM);
  • Figure 13 shows the effect of combined lorcaserin and naratriptan on 5 hour food intake in male mice (* p ⁇ 0.05 compared to all other treatment groups; Data are presented as Mean +/- SEM);
  • Figure 14 shows the effect of lorcaserin on food intake in female mice (Data are presented as Mean +/- SEM);
  • Figure 15 shows the effect of sumatriptan on food intake in female mice (Data are presented as Mean +/- SEM);
  • Figure 16 shows the effect of combined lorcaserin and sumatriptan on food intake in female mice (* p ⁇ 0.05 compared to all other treatments; Data are presented as Mean +/- SEM);
  • Figure 17 shows the effect of WAY161503 on (A) DIO male mice 3 hour intake of calorie dense HFD and (B) MC4R null male mice 3 hour intake of chow diet (Data are presented as Mean +/- SEM);
  • Figure 18 shows the effect of sumatriptan succinate on (A) DIO male mice 3 hour intake of calorie dense HFD and (B) obese MC4R null male mice 3 hour intake of chow diet (* p ⁇ 0.05; Data are presented as Mean +/- SEM);
  • Figure 19 shows the effect of combined WAY161503 and sumatriptan succinate on (A) DIO male mice 3 hour intake of calorie dense HFD or (B) obese MC4R null male mice 3 hour intake of chow diet (** p ⁇ 0.01 , ***p ⁇ 0.001 compared to all other treatment groups; Data are presented as Mean +/- SEM);
  • Figure 20 shows the effect of lorcaserin on 3 hour food intake in male rats (* p ⁇ 0.05, *** p ⁇ 0.001 compared to vehicle; Data are presented as Mean +/- SEM);
  • Figure 21 shows the effect of sumatriptan succinate on 3 hour food intake in male rats (Data are presented as Mean +/- SEM);
  • Figure 22 shows the effect of combined lorcaserin and sumatriptan succinate on 12 hour chow intake in male rats (*p ⁇ 0.05 compared to lorcaserin, ** p ⁇ 0.01 compared to vehicle and sumatriptan; Data are presented as Mean +/- SEM);
  • Figure 23 shows the effect of combined lorcaserin and sumatriptan succinate on body weight gain in male rats (*p ⁇ 0.05 compared to vehicle, ** p ⁇ 0.01 compared to all other treatment groups; Data are presented as Mean +/- SEM);
  • Figure 24 shows the effect of 5-HT 2 c receptor agonist lorcaserin on glucose tolerance in DIO male mice (Data are presented as Mean +/- SEM);
  • Figure 25 shows the effect of combined lorcaserin and sumatriptan succinate on glucose tolerance in 8 month old chow fed male mice (Data are presented as Mean +/- SEM);
  • Figure 26 shows the effect of combined WAY161503 and sumatriptan succinate on insulin tolerance in male DIO mice (Data are presented as Mean +/- SEM).
  • Example 1 This example describes the effect of a 5-HT 2 c-receptor agonist (WAY161503) and sumatriptan succinate, alone or in combination, on food intake in mice.
  • the mice were male mice.
  • mice For food intake studies, a fasting re-feeding paradigm has been used to increase motivation to eat (see the experimental flowchart in Figure 1). Mice maintained on a regular rodent diet were fasted overnight (12 hours) and subsequently administered with test compounds. 45 minutes after administration, mice were exposed to a pre-weighed amount of rodent diet and their food consumption measured after 3 and 6 hours. Effect of WAY161503 alone on food intake in mice
  • mice were male mice.
  • the brain centres that regulate ingestive behaviour are target regions of many signalling molecules released by the gastro-intestinal tract.
  • the integration of these signals allows the brain to coordinate many adaptive responses, such as the reduction of gastric emptying rate. This is a crucial component of the mechanisms that cooperate to establish satiety and the cessation of feeding.
  • This example describes the effect of a 5-HT 2 c-receptor agonist (WAY161503) and sumatriptan succinate, alone or in combination, on glucose tolerance in mice.
  • the mice were male mice.
  • High fat diet-induced obese (DIO) mice have impaired glucose disposal after a glucose load.
  • DIO mice were maintained on a high fat diet regimen for more than 10 weeks. The mice were fasted overnight (12 hours) and subsequently administered with test compounds. 45 minutes after administration, mice received a glucose load and their blood glucose levels were monitored over 120 minutes (at 0, 15, 30, 45, 60, 90, and 120 minutes) (see the experimental flowchart in Figure 7). The rate at which blood glucose levels decrease over time is an index of glucose disposal efficiency.
  • WAY161503 The effect of doses of 2.5-10 mg/kg WAY161503 was assessed in a glucose tolerance test in DIO mice as described above. The results are shown in Figure 8. The dose of 2.5mg/kg WAY161503 had no effect on glucose disposal. Doses of 5 and 10mg/kg WAY161503 produced a marked improvement of glucose tolerance. Blood glucose levels of mice treated with WAY161503 at doses of 5 and 10 mg/kg were significantly lower compared with blood glucose levels of mice that did not receive the drug (vehicle group; p ⁇ 0.05).
  • This example describes the effect of a 5-HT 2 c receptor agonist (lorcaserin) and a triptan (naratriptan), alone or in combination, on food intake in male mice.
  • Example 1 provides evidence of appetite suppression synergy following the combination of the 5-HT 2 c receptor agonist WAY161503 and the triptan sumatriptan ( Figures 2-4).
  • Example 4 now demonstrates that comparable synergy is also achieved through the combination of a different 5-HT 2 c receptor agonist (lorcaserin) and a different triptan (naratriptan; Figures 1 1-13). This shows that the synergistic effect of the combination of 5- HT 2 c receptor agonist and triptan on appetite suppression is a drug class effect and is not specifically related to a particular compound.
  • mice were fasted overnight (12 hours) and subsequently treated with test compounds administered i.p. and dissolved in distilled water. 45 minutes after the pharmacological treatment, mice were exposed to a pre-weighed amount of rodent diet and their food consumption was measured 5 hours later.
  • This example provides data related to food consumption at a different time point post- pharmacological treatment compared to Examples 1 and 4, thereby illustrating that the synergistic effect of 5-HT 2 c receptor agonist and triptan on appetite effects is achieved rapidly following pharmacological treatment.
  • mice were fasted overnight (12 hours) and subsequently treated with test compounds administered i.p. and dissolved in distilled water. 45 minutes after the pharmacological treatment mice were exposed to a pre-weighed amount of rodent diet and their food consumption measured 1 and 3 hours later.
  • This example describes the effect of a 5-HT 2 c receptor agonist (WAY161503) and a triptan (sumatriptan succinate), alone or in combination, on food intake in two mouse models representative of human obesity that is either dietary or genetically driven.
  • a 5-HT 2 c receptor agonist WAY161503
  • a triptan sumatriptan succinate
  • M4R melanocortin4 receptor
  • WAY161503 and sumatriptan succinate produced a synergistic effect on palatable high-fat food intake in DIO mice and a synergistic effect on standard chow diet intake in hyperphagic obese MC4R null mice.
  • the data shows that the combination is effective for different diets that vary in palatability and genetically driven differences in internal hunger drives. Importantly, the data demonstrates that the combination is effective in significantly suppressing appetite in obesity. Additionally, the data reveals that the mechanism of the synergistic effect of a combination of the invention on appetite suppression does not require functional MC4Rs. This is unlike the anorectic effect of 5-HT 2 c receptor agonist monotherapy (e.g.
  • former obesity treatments such as d-fenfluramine
  • functional MC4Rs to suppress appetite e.g. Heisler et al., Science 2002, 297:609-1 1 ; Xu et al., Journal of Neuroscience 2010, 30(44): 14630-4).
  • This example describes the effect of a 5-HT 2 c receptor agonist (lorcaserin) and a triptan (sumatriptan succinate), alone or in combination, on food intake in a different species (rat) and in a different hunger state (unrestricted continuous access to food).
  • This example provides data related to food consumption at a different time point post- pharmacological treatment compared to Examples 1 and 4-6, thereby illustrating that the synergistic effect of a 5-HT 2 c receptor agonist and triptan on appetite persists up to 12 hours in male rats.
  • This example describes the effect of a 5-HT 2 c receptor agonist (lorcaserin) and a triptan (sumatriptan succinate), alone or in combination, on body weight in male DIO mice with restricted access to palatable diet and in male rats with unrestricted access to standard lab chow.
  • mice were provided with unrestricted access to a HFD (60% fat, Research Diets) for at least 10 weeks. Mice were then subjected to a feeding schedule in which they had unrestricted access to HFD for 12 hours of the day and then food was withdrawn for the next 12 hours of the day. During the 12 hours of unrestricted HFD access, mice received two pharmacological treatments i.p., 6 hours apart, beginning 45 min prior to HFD presentation. Food intake and body weight was measured 24 and 48 hours later.
  • HFD 50% fat, Research Diets
  • Methods 8B ad libitum feeding paradigm in male rats
  • An unrestricted ad libitum feeding paradigm was used to mimic human food access (i.e. unrestricted).
  • Male rats were provided with unlimited access to standard lab chow. 45 minutes prior to the onset of the dark and light cycles, rats received the pharmacological treatment administered i.p. and dissolved in distilled water. Food intake and body weight was measured 24 and 48 hours later. Effect of a combination of lorcaserin and sumatriptan succinate on body weight gain in male rats
  • Example 9 This example describes the effect of a 5-HT 2 c receptor agonist (lorcaserin) and a triptan (sumatriptan succinate), alone or in combination, on glucose tolerance in male mice.
  • Example 3 provides evidence of a synergistic effect on glucose tolerance following administration of WAY161503 and sumatriptan succinate in combination to DIO mice.
  • This example now demonstrates that comparable synergy is also achieved following administration of a different 5-HT 2 c receptor agonist (lorcaserin) and sumatriptan succinate in combination.
  • a glucose tolerance test primarily measures glucose disposal. This disposal of glucose/lowering of blood glucose was monitored over 120 minutes by taking blood samples from the mouse's tail and measuring blood glucose levels. Glucose disposal after a glucose load is diminished both with prolonged high fat diet consumption and with ageing. DIO mice were maintained on HFD regimen for at least 10 weeks and were an average of 4 months old. Older mice were maintained on a standard lab chow diet and were an average of 8 months old. Both groups of mice displayed basal elevated levels of blood glucose (DIO average 7.3 mmol/l; older mice average 12.4 mmol/l). Mice were overnight fasted (12 hours) and subsequently treated with pharmacological compounds administered i.p. and dissolved in vehicle. 45 minutes after pharmacological treatment, mice received a glucose load and their blood glucose levels were monitored over 120 minutes. The rate at which blood glucose levels decrease over time is an index of glucose disposal efficiency (see experimental flowchart, Figure 7).
  • This example describes the effect of a 5-HT 2 c receptor agonist (WAY161503) and a triptan (sumatriptan succinate), alone or in combination, on insulin tolerance in male DIO mice.
  • Example 3 provides evidence of a synergistic effect on glucose tolerance following the combination of the 5-HT 2 c receptor agonist WAY161503 and the triptan sumatriptan succinate ( Figures 7-10). This example now demonstrates that a comparable synergistic effect on insulin tolerance is also achieved through combination of the same concentrations of WAY161503 and sumatriptan succinate in DIO mice.
  • ITT insulin tolerance test
  • An insulin tolerance test primarily measures insulin-stimulated uptake of glucose into tissues (also known as glucose disposal). The more insulin resistant an individual is, the less effective the insulin bolus will be at lowering blood glucose. This lowering of blood glucose over 120 minutes was recorded by taking blood samples from the mouse's tail and measuring blood glucose levels.
  • Prolonged consumption of a HFD impairs glucose disposal after an insulin load.
  • DIO mice were maintained on a HFD regimen for at least 10 weeks. Mice were overnight fasted (12 hours) and subsequently treated with pharmacological compounds administered i.p.. 45 minutes after pharmacological treatment, mice received an insulin load and their blood glucose levels were monitored over 120 minutes. The rate at which blood glucose levels decrease over time is an index of insulin-stimulated glucose disposal.

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Abstract

L'invention concerne des combinaisons thérapeutiques. Ces combinaisons comprennent : a) un agoniste du récepteur 5-hydroxytryptamine 2C (5-HT2C), ou un sel pharmaceutiquement acceptable de celui-ci ; et b) un triptan, ou un sel pharmaceutiquement acceptable de celui-ci. Ces combinaisons peuvent être utilisées pour le traitement de troubles qui peuvent être traités par agonisme des récepteurs 5-HT2C, tels que l'obésité et le diabète de type 2.
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Citations (2)

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WO2004037190A2 (fr) * 2002-10-25 2004-05-06 Collegium Pharmaceutical, Inc. Compositions de milnaciprane a liberation modifiee
WO2005016902A1 (fr) * 2003-06-20 2005-02-24 Arena Pharmaceuticals, Inc. Derives de n-phenyl-piperazine et methodes de prophylaxie ou de traitement de maladies associees au recepteur 5ht2c

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