WO2015001359A1 - Combinaison de médicaments et son utilisation dans la thérapie de l'obésité - Google Patents

Combinaison de médicaments et son utilisation dans la thérapie de l'obésité Download PDF

Info

Publication number
WO2015001359A1
WO2015001359A1 PCT/GB2014/052049 GB2014052049W WO2015001359A1 WO 2015001359 A1 WO2015001359 A1 WO 2015001359A1 GB 2014052049 W GB2014052049 W GB 2014052049W WO 2015001359 A1 WO2015001359 A1 WO 2015001359A1
Authority
WO
WIPO (PCT)
Prior art keywords
obesity
product
compound
weight
pyridinyloxy
Prior art date
Application number
PCT/GB2014/052049
Other languages
English (en)
Inventor
Peter Richardson
Bruce Campbell
Original Assignee
Proximagen Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Proximagen Limited filed Critical Proximagen Limited
Publication of WO2015001359A1 publication Critical patent/WO2015001359A1/fr

Links

Classifications

    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • This invention relates to a drug combination, its composition and its use in the treatment of over-weight or obesity.
  • Obesity is now recognized as a chronic disease and a critical global health issue (Fiegal et al, 1998, Int. J. Obesity 22:39-47, Mokdad et al, 1999, JAMA 282:1519-1522; Halford, 2006, Appetite, 46, 6-10).
  • the "identifiable signs and symptoms" of obesity include an excess accumulation of fat or adipose tissue, an increase in the size or number of fat cells (adipocyte differentiation), insulin resistance, increased glucose levels (hyperglycemia), increased blood pressure, elevated cholesterol and triglyceride levels and decreased levels of high-density lipoprotein.
  • Obesity is associated with a number of comorbidities including a significantly elevated risk for type 2 diabetes, coronary heart disease, stroke, hypertension, various types of cancer and numerous other major illnesses, and overall mortality from all causes (Must et al, 1999, JAMA 282:1523-1529, Calle et al, 1999, N. Engl. J. Med. 341 :1097- 1 105).
  • indirect sympathomimetic drugs such as phentermine have been reported to reduce appetite, and although widely used have the side effect of raising blood pressure which severely restricts their use in obese patients, many of whom already suffer from hypertension. In addition these agents have other side effects including tachycardia (increased heart rate), pulmonary hypertension, heart valve damage, and drug dependency (addiction).
  • An indirect sympathomimetic is defined herein as an agent that has physiological effects which mimic activation of the sympathetic nervous system.
  • Indirect sympathomimetic agents include inhibitors of noradrenaline reuptake such as amphetamine and tyramine.
  • the patient's blood pressure is reduced by greater than 4mmHg within 14 days of starting treatment. In an embodiment the patient's blood pressure is reduced by greater than 5mmHg within 14 days of starting treatment. In an embodiment the patient's blood pressure is reduced by greater than 6mmHg within 14 days of starting treatment. It is expected that this surprising initial reduction in blood pressure will then be followed by a more gradual reduction as a consequence of weight loss.
  • an indirect sympathomimetic has the effect of increasing blood pressure. This increase in blood pressure is especially hazardous in patients already suffering from hypertension.
  • obese hypertensive patients who experience an increase in blood pressure when treated with an indirect sympathomimetic are expected to experience a reduced increase in blood pressure, or even a reduction in blood pressure, when treated with a combination of a compound of formula (I) or vabicaserin and the indirect sympathomimetic.
  • the claimed combination is expected to be useful for treatment of over-weight or obesity in patients suffering from hypertension.
  • the initial reduction in systolic blood pressure will be about 1 to 20 mmHg, preferably from 3 to 15 mmHg such as from 5 to 12 mmHg, from 5 to 10 mmHg, or from 7 to 9 mmHg. In an embodiment the initial reduction in blood pressure is at least 8mmHg. It is expected that the initial reduction in blood pressure will occur within 14 days of commencing treatment
  • Suitable 5HT 2 c agonists of formula (I) for use in the present invention are disclosed in WO00/76984, where they are defined in claims 1 to 41 .
  • the pharmaceutically acceptable salt is the L-malate.
  • the synthesis and medical use of PRX933, and salt forms thereof, is disclosed in WO00/76984 (PCT/SEOO/01017) and WO2004/000829 (PCT/SE2003/001043). The content of both documents is hereby incorporated by reference.
  • the 5HT 2 c agonist is vabicaserin (9aR,12aS)- 4,5,6,7,9,93,10,1 1 , 12,12a-decahydrocyclopenta[c][1 ,4]diazepino[6,7,1 - ij]quinoline), which has the following structural formula:
  • Vabicaserin All pharmaceutically acceptable salt forms of Vabicaserin are suitable for use in the present invention. Accordingly, the present invention makes available a product comprising a compound of formula (I) or vabicaserin and an indirect sympathomimetic as a combined preparation for simultaneous, sequential or separate use in treating over-weight or obesity.
  • the present invention makes available a compound of formula (I) or vabicaserin for use in treating over-weight or obesity wherein an indirect sympathomimetic is administered simultaneously, separately or sequentially with the compound of formula (I) or vabicaserin.
  • the present invention makes available a method of preventing or treating over-weight or obesity, comprising administering to a human or animal subject in need thereof a compound of formula (I) or vabicaserin and an indirect sympathomimetic in sufficient amounts to provide a therapeutic effect.
  • over-weight and “obesity” are taken to mean the medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems.
  • Body mass index (BMI), a measurement which compares weight and height, defines people as “over-weight” (pre-obese) if their BMI is between 25 and 30 kg/m 2 , and “obese” when it is greater than 30 kg/m 2 .
  • the indirect sympathomimetic is selected from phentermine, methylphenidate (also known as Ritalin), diethylproprion, phendimetrazine and phenmetrazine.
  • hypotension is taken to mean a persistently elevated blood pressure i.e. systolic blood pressure greater than 140mmHg and diastolic blood pressure greater than 90mmHg.
  • any suitable form of the 5HT 2 c agonist or an indirect sympathomimetic can be used. These include salts, prodrugs and active metabolites. Suitable dose ranges for the 5HT 2 c agonist or an indirect sympathomimetic are known in the art, although the synergistic effect of the combination means that the effective dose may be reduced.
  • 5HT 2 c agonist will of course depend on the usual factors, including its potency, but is preferably at least 0.01 , e.g. at least 0.02, and may be up to 1 .5 mg/ kg/day.
  • the dose of the indirect sympathomimetic is from 0.01 to 1 mg/kg/day.
  • the dose is from 0.01 to 0.2 mg/kg/day.
  • the dose is from 0.05 to 0.22 mg/kg/day.
  • the dose is from 0.1 to 0.5 mg/kg/day.
  • the dose of the 5HT 2 c agonist that is administered with an indirect sympathomimetic will of course depend on the usual factors, including its potency, but is preferably at least 0.01 , e.g. at least 0.02, and may be up to 0.5 mg/ kg/day.
  • the dose of the 5HT 2C agonist is from 0.01 to 0.3 mg/kg/day.
  • the dose is from 0.01 to 0.2 mg/kg/day.
  • the dose is from 0.05 to 0.2 mg/kg/day.
  • the dose is from 0.1 to 0.5 mg/kg/day.
  • the compounds of the invention may be administered by any available route, such as via the oral, inhaled, intranasal, sublingual, intravenous, rectal, dermal, and vaginal routes.
  • the oral route is the preferred route of administration.
  • the compounds of the invention are preferably formulated as combinations to be administered orally, for example as tablets, troches, lozenges, aqueous or oral suspensions, dispersible powders or granules.
  • Preferred pharmaceutical compositions of the invention are tablets and capsules.
  • Liquid dispersions for oral administration may be syrups, emulsions and suspensions. More preferably, the pharmaceutical composition of the combination is a pressed tablet or capsule with conventional excipients, examples of which are given below. These may be immediate release or modified, sustained or controlled release preparations
  • compositions of the combination intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the combined active ingredients in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may include but are not restricted to, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example starch gelatin, acacia, microcrystalline cellulose or polyvinyl pyrrolidone; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate, or glyceryl distearate may be employed.
  • Aqueous suspensions may contain the combined active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long- chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids, for example polyoxyethylene sorbitan monooleate.
  • suspending agents for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth and
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl or n- propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, polyoxyethylene hydrogenated castor oil, fatty acids such as oleic acid, or in a mineral oil such as liquid paraffin or in other surfactants or detergents.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents, such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the combined active ingredients in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable sweetening, flavouring and colouring agents may also be present.
  • the combined pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin, or mixtures of these.
  • Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavouring and colouring agents.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, flavouring and colouring agents.
  • Suspensions and emulsions may contain a carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • a carrier for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • the 5HT 2 c agonist of formula (I) or vabicaserin in combination with an indirect sympathomimetic is to be administered via the oral route.
  • Combined compositions according to the invention may be produced using conventional formulation techniques.
  • spray-drying may be used to produce microparticles comprising the active agent dispersed or suspended within a material that provides the controlled release properties.
  • the process of milling may also be used to formulate the therapeutic composition.
  • the manufacture of fine particles by milling can be achieved using conventional techniques.
  • milling is used herein to refer to any mechanical process which applies sufficient force to the particles of active material to break or grind the particles down into fine particles.
  • Various milling devices and conditions are suitable for use in the production of the compositions of the invention.
  • the selection of appropriate milling conditions, for example, intensity of milling and duration, to provide the required degree of force, will be within the ability of the skilled person.
  • Ball milling is a preferred method.
  • a high pressure homogeniser may be used, in which a fluid containing the particles is forced through a valve at high pressure, producing conditions of high shear and turbulence.
  • Suitable homogenisers include the EmulsiFlex high pressure homogeniser, the Niro Soavi high pressure homogeniser and the Microfluidics Microfluidiser.
  • the milling process can be used to provide the microparticles with mass median aerodynamic diameters as specified above. If hygroscopic, the active agent may be milled with a hydrophobic material, as stated above.
  • the microparticles produced by the milling step can then be formulated with an additional excipient.
  • an additional excipient This may be achieved by a spray- drying process, e.g. co-spray-drying.
  • the particles are suspended in a solvent and co-spray-dried with a solution or suspension of the additional excipient.
  • Preferred additional excipients include polysaccharides. Additional pharmaceutically effective excipients may also be used.
  • compositions of the combination intended for inhaled, topical, intranasal, intravenous, sublingual, rectal and vaginal use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions.
  • Therapy according to the invention may be conducted in generally known manner, depending on various factors, such as the sex, age or condition of the patient, and the existence or otherwise of one or more concomitant therapies.
  • the patient population may be important.
  • Figure 1 shows a graph of the cumulative food intake expressed as % vehicle control after dosing with phentermine (1 mg p.o.), compound (6mg p.o) or the combination in groups of 9 rats fed ad libitum. The combination, but not the individual treatments, was significantly different from vehicle at the time points tested (p ⁇ 0.05).
  • Figure 2 shows a graph of the change in supine systolic blood pressure in patients taking (2R)-Methyl-1 - ⁇ 3-[2-(3-pyridinyloxy)ethoxy]-2- pyrazinyl ⁇ piperazine.
  • the reduction in blood pressure after 2 weeks (filled bars) and 8 weeks (hatched bars) dosing is plotted against Cmax.
  • Asterisks indicate significantly (P ⁇ 0.05) different from placebo (t test).

Abstract

La présente invention concerne un produit comprenant: (i) de la (2R)-méthyl -1- {3- [2- (3-pyridinyloxy) éthoxy] -2-pyrazinyle} pipérazine ou de la vabicasérine, et (ii) un agent sympathomimétique indirect sous la forme d'une préparation combinée pour une utilisation simultanée, séquentielle ou séparée dans le traitement du surpoids ou de l'obésité.
PCT/GB2014/052049 2013-07-05 2014-07-04 Combinaison de médicaments et son utilisation dans la thérapie de l'obésité WO2015001359A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB1312129.8 2013-07-05
GBGB1312129.8A GB201312129D0 (en) 2013-07-05 2013-07-05 Drug combination and its use in therapy

Publications (1)

Publication Number Publication Date
WO2015001359A1 true WO2015001359A1 (fr) 2015-01-08

Family

ID=49033420

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2014/052049 WO2015001359A1 (fr) 2013-07-05 2014-07-04 Combinaison de médicaments et son utilisation dans la thérapie de l'obésité

Country Status (2)

Country Link
GB (1) GB201312129D0 (fr)
WO (1) WO2015001359A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000076984A2 (fr) * 1999-05-21 2000-12-21 Biovitrum Ab Nouveaux composes, et utilisation et preparation de ces derniers
US20080255093A1 (en) * 1999-06-14 2008-10-16 Tam Peter Y Compositions and methods for treating obesity and related disorders

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000076984A2 (fr) * 1999-05-21 2000-12-21 Biovitrum Ab Nouveaux composes, et utilisation et preparation de ces derniers
US20080255093A1 (en) * 1999-06-14 2008-10-16 Tam Peter Y Compositions and methods for treating obesity and related disorders

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Biovitrum initiates clinical Phase IIb study of anti-obesity treatment", 1 January 2003 (2003-01-01), XP055136477, Retrieved from the Internet <URL:http://reports.huginonline.com/898022/115545.pdf> [retrieved on 20140826] *
NANNA H. JENSEN ET AL: "Therapeutic Potential of 5-HT2C Receptor Ligands", THE SCIENTIFIC WORLD JOURNAL, vol. 10, 1 January 2010 (2010-01-01), pages 1870 - 1885, XP055134709, DOI: 10.1100/tsw.2010.180 *

Also Published As

Publication number Publication date
GB201312129D0 (en) 2013-08-21

Similar Documents

Publication Publication Date Title
EP1807083B1 (fr) Utilisation de pirlindole pour traiter des maladies caracterisees par une proliferation de lymphocytes t et/ou une hyperproliferation de keratinocytes, en particulier une dermatite atopique et un psoriasis
AU2010332495C1 (en) Therapeutic combinations of theobromine and an antihistamine
KR20230173743A (ko) 트라디피턴트에 의한 치료 방법
BR112015010703B1 (pt) uso de uma composição farmacêutica e composição farmacêutica
US10660865B2 (en) Cannabidiol for the prevention and treatment of graft-versus-host disease
WO1995017889A1 (fr) Composition therapeutique utile pour traiter l&#39;hyperparathyroidie d&#39;un patient en dialyse artificielle
WO2016011254A1 (fr) Combinaisons d&#39;antihistaminiques et d&#39;antagonistes anti-leucotriène et procédés d&#39;utilisation associés
CN110996987A (zh) 用于调控应激障碍中激素级联的组合物和方法
TW200946108A (en) Use of dronedarone or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for regulating the potassium level in the blood
BG104568A (bg) Фармацевтичен състав, съдържащ сибутрамин и орлистат
BG107185A (bg) Метод за получаване на лекарствено средство за лечение на сексуална дисфункция с апоморфин при определени нива на плазмена концентрация
TW201313679A (zh) 吲哚氫胺酸和吲哚啉氫胺酸於治療心臟衰竭或神經損傷的用途
JP2003528927A (ja) 腎機能障害の処置
TW200951117A (en) Combination of dronedarone with at least one diuretic, therapeutic application thereof
JPWO2006003910A1 (ja) メニエール病の予防および／または治療剤
WO2015001359A1 (fr) Combinaison de médicaments et son utilisation dans la thérapie de l&#39;obésité
WO2015001357A2 (fr) Association de médicaments et son utilisation en thérapie
TW201521786A (zh) 胺碘酮類似物（ｂｕｄｉｏｄａｒｏｎｅ）調配物
WO2021137224A1 (fr) Esters d&#39;acide cannabidiolique pour le traitement de la dystrophie musculaire
WO2015001358A1 (fr) Combinaison de médicaments et son utilisation pour traiter l&#39;obésité et le diabète de type ii
JPWO2010087150A1 (ja) 胃酸分泌抑制剤及びカリウムチャンネル阻害剤
TWI794847B (zh) 用於減少代謝症候群之組合物及其應用
EA009127B1 (ru) Комбинированное применение фибрата и орлистата для лечения ожирения
US20060128738A1 (en) Treatment of interstitial cystitis using cannabinoid analogs
TWI735658B (zh) 用於減少代謝症候群之組合物及其應用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14736949

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14736949

Country of ref document: EP

Kind code of ref document: A1