WO2014122405A1

WO2014122405A1 - Solid pharmaceutical composition for oral delivery of agomelatine

Info

Publication number: WO2014122405A1
Application number: PCT/FR2014/050231
Authority: WO
Inventors: Patrick Genty; Jean-Manuel Pean; Fabien RIOULT; Patrick GENISSEL
Original assignee: Les Laboratoires Servier
Priority date: 2013-02-08
Filing date: 2014-02-07
Publication date: 2014-08-14
Also published as: FR3001894A1; AR095152A1; TW201434495A; UY35294A

Abstract

The invention relates to a solid oral pharmaceutical composition containing agomelatine intended for systemic action.

Description

SOLID PHARMACEUTICAL COMPOSITION FOR BUCCAL ADMINISTRATION OF AGOMELATIN

The present invention relates to a new solid pharmaceutical form for oral administration of agomelatine.

Agomelatine or N- [2- (7-methox-1-naphthyl) ethyl] acetamide of formula (I)

as well as its hydrates, crystalline forms, amorphous form, complexes, co-crystals, and addition salts with a pharmaceutically acceptable acid or base, has interesting pharmacological properties: it is a selective agonist of the melatoninergic system receptors and on the other hand a 5-HT _2C receptor antagonist. These properties give it an activity in the central nervous system and more particularly in the treatment of major depression, seasonal depression, generalized anxiety disorder, obsessive-compulsive disorder, bipolar disorders, sleep disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to time differences, appetite disorders and obesity.

Agomelatine, its crystalline forms, its complexes, its co-crystals, its addition salts with a pharmaceutically acceptable acid or base, its preparation and its therapeutic use have been described, inter alia, in applications EP0447285, WO2005 / 077887, WO2007 / 015003, WO2007 / 015002, WO2007 / 015004, WO2010 / 097052, WO2010 / 102554, CN101955440, WO2011 / 050742, CN102050756, WO201 1/006387, WO2011 / 075943, CN101774937, CN101870662, CN102030673, WO2012 / 046253 , WO2011 / 113362, WO2011 / 113363, CN102206864, CN102503886, and CN 102432490.

In what follows, "agomelatine" is understood to mean agomelatine as well as its hydrates, its complexes, its co-crystals, its crystalline forms, its amorphous form, and its addition salts with an acid or a pharmaceutically acceptable base acceptable. In particular, agomelatine may be in crystalline form II.

Agomelatine can be administered orally or more specifically enterally in the form of immediate release tablets to be swallowed with half a glass of water. These agomelatine tablets are useful, especially for the treatment of major depression, seasonal depression, generalized anxiety disorder, obsessive-compulsive disorder, bipolar disorder, sleep disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to time differences, appetite and obesity disorders, and all pathologies related to a disruption of circadian rhythms. Pharmacokinetic studies in humans have shown that the bioavailability of oral agomelatine is low compared to the parenteral route and varies for the same individual and from one individual to another.

Also, the low bioavailability of agomelatine as well as variations in inter and intra-individual concentrations have led to the search for a new formulation that makes it possible to overcome these disadvantages. A solid pharmaceutical composition orodispersible agomelatine described in the patent application 427724 EPI has been developed comprising agomelatine and granules consisting of lactose and starch dried by co-atomisation and marketed as STARLAC ^®. This pharmaceutical composition makes it possible to obtain tablets having a very good ability to disintegrate in the oral cavity and more specifically in the sublingual cavity, while respecting the orodispersibility criteria. The orodispersible tablets make it possible to deliver the active ingredient into the oral cavity, and more specifically into the sublingual cavity, in less than three minutes. Dissolution of the active ingredient in saliva and then absorption by the mucous membranes of the oral cavity, and more specifically by the sublingual mucosa, and rapid passage through the blood allow the presystemic degradation and the first-pass hepatic effect to be contorted. Thus, the bioavailability is very much improved with much lower variability and a rapid appearance of the active ingredient in the blood.

However, it quickly became apparent that this formulation had a disadvantage from the active ingredient used, agomelatine, which causes a pronounced irritating sensation in the mucous membranes of the oral cavity.

When the sublingual route is specifically targeted, this pungent effect is exacerbated due to high local concentrations of agomelatine, which results in very poor acceptability by the patient. In this context, a formulation of sublingual tablet type has been developed and described in the patent application WO2007 / 068829, meeting the requirements of orodispersibility and acceptability by the patient. The preferred strategy was to obtain a solid pharmaceutical composition consisting of a central core or a central layer containing agomelatine and excipients making it possible to obtain an orodispersible formulation, and an orodispersible coating optionally containing an irritating counter. These orodispersible tablets make it possible to obtain a rapid disintegration of less than three minutes, and have shown an excellent ability to limit the pungent nature of the active principle.

Nevertheless, problems of effectiveness have been observed with this formulation in clinical studies and have led to the conclusion that there may be poor compliance or compliance (adequacy between the medical prescription and the patient's attitude) by the patient. patient for his drug treatment. Thus, if the patient swallows the orodispersible tablet too quickly, without waiting for the complete dissolution of the active ingredient in the saliva, the latter is no longer absorbed at the sublingual level. As a consequence, the doses of active principle being very low in the orodispersible tablet (between 0.5 and 3 mg) compared to the oral tablet (25 mg), a lack of effectiveness can be observed with the orodispersible tablet if is not absorbed by the sublingual route. It should be noted that the lack of compliance is all the more marked in most chronic diseases requiring treatment over long periods, as in the treatment of diseases of the central nervous system in general. Poor adherence to treatment is therefore a major public health problem facing the clinician, and for which it is imperative to find satisfactory solutions.

The Applicant has now followed a new strategy of developing a pharmaceutical formulation allowing a gradual release of agomelatine in the oral cavity. The important point of this new formulation is to maintain everything at the along the release of the active ingredient of local concentrations sufficiently low to limit the sensation of sharpness and to obtain a form acceptable by the patient.

In order to also overcome the problems of compliance by the patient, as could have been observed with the orodispersible tablet of the prior art, the Applicant has designed for this new formulation a multilayer system of two-layer, three-layer or core-core type, wherein the active ingredient is concentrated in the peripheral portion of the formulation. The formulation according to the invention therefore relates to:

a bilayer system "A" - "B" (where the layer "B" is thicker than the layer "A"),

- a three-layer system "A" - "B" - "A",

- or a central core system where "A" is the peripheral layer and "B" is the core,

in which "A" is an "active" layer consisting of the active ingredient agomelatine and excipients, and "B" a "placebo" layer consisting solely of excipients. Thus, even if the patient does not allow the formulation to disintegrate to the end in the oral cavity, the active ingredient contained in the outer layer (s) will have had time to dissolve in the saliva and be absorbed sublingually, and the ingested part, therefore not absorbed sublingually, will contain only excipients.

Thus a new pharmaceutical formulation has been developed allowing:

- to overcome the irritating problem of agomelatine,

- by favoring a delivery of the active principle in the oral cavity for a systemic action, the effect sought to improve the problems of bioavailability and intra and inter-individual variability encountered with the tablets administered orally,

- while ensuring good compliance by the patient for his medication.

More particularly, the present invention relates to a solid oral preparation intended for a systemic action allowing a controlled release of the active principle in the oral cavity of bilayer, trilayer or core type consisting of:

* one or more "active" peripheral layers "A" containing agomelatine and excipients,

* a "placebo" layer "B" containing only the excipients. Surprisingly and completely unexpectedly, this new formulation has led to an increase in the bioavailability of the active ingredient not only compared to the oral tablet (enteral), but also compared to orodispersible oromucosal formulations developed in the prior art for a systemic action, for formulations of the same dosage active principle and containing the active ingredient in one form. By "same form" is meant, here and whenever the expression will be used hereinafter, that the active ingredient has the same crystalline form, or is in the same hydrated form, complexed, salified or co-crystallized, and that the particle sizes of the active ingredient are the same. The present invention thus relates to a solid oral preparation intended for a systemic action allowing a controlled release of the active ingredient in the oral cavity so as to obtain a good taste acceptability and a better absolute bioavailability compared to the orodispersible tablets with oromucosal absorption described in FIG. prior art, for formulations of the same dosage active principle and containing the active ingredient in one form. It also makes it possible to ensure good compliance by the patient for his treatment.

The oral preparation according to the invention relates more particularly to sucking tablets, sublingual tablets or gingival tablets containing agomelatine. Preferably, the oral preparation according to the invention will be a tablet to be sucked. The oral preparation according to the invention may contain diluents, binders, flow agents, lubricants, coating agents, plasticizers, flavoring agents, counter-irritants and sweeteners.

The oral preparation according to the invention is characterized by the absence of a disintegrating agent which, combined with a high compressive force allows the design of a tablet which does not disintegrate, but erodes slowly by dissolving the components at room temperature. area. The "A" and "B" layers according to the invention consist of the same components, the only difference residing in the presence ("active" peripheral layer "A") or the absence ("placebo" layer "B") of the active ingredient.

Preferably, the "placebo" layer "B" will represent from 20 to 80% of the total mass of the oral preparation. In central core formulations, the "placebo" layer "B" will advantageously represent 20 to 50% of the total mass of the oral preparation, and preferably 20%. In two-layer or three-layer formulations, the "placebo" layer "B" advantageously represents 50 to 80% of the total mass of the oral preparation, and more preferably 60 to 80%.

The invention also relates to a process for preparing the solid oral preparation according to the invention: the mixtures of the constituents of the different layers ("A" or "B") are obtained by granulation or by simple mixing. These different mixtures are then compressed using a machine adapted and specific to the manufacture of the formulations according to the invention: bilayer, trilayer or core.

The oral preparation with systemic action according to the invention has a release time of the active ingredient less than 30 minutes, and more preferably less than 15 minutes. The release of the active ingredient will be for example between 3 minutes and 30 minutes, and more preferably between 3 minutes and 15 minutes.

The tablets to be sucked are solid single dose preparations intended to be sucked in order to exert a local or systemic action. They are obtained by direct compression or by granulation and compression.

The pharmaceutical composition according to the invention will for example be a tablet to be sucked, which can be prepared by a direct compression method. The tablet to be sucked according to the invention contains agomelatine, a diluent, and optionally a binding agent, a lubricating agent and / or a flow agent and / or one or more sweetening, flavoring or counter-irritating agents. It is characterized by slow erosion in the oral cavity. The diluent used according to the invention is chosen so that it allows a use in direct compression and that it gives the pharmaceutical form a high crush strength and acceptable organoleptic properties for an oral preparation. suck. Preferably the diluent used is a polyol or a saccharide (mono-, oligo- or polysaccharide) or a combination of these various compounds such as for example glucose, sucrose, mannitol, dextrates, dextrin or isomalt A these compounds may be added silicas or disintegrants.

Among the binding agents that may be used according to the invention, mention may be made of cellulose derivatives and starch derivatives, crospovidone, maltodextrin and povidone.

The counter-irritant used optionally is a compound acting on the vanilloid receptors or on the ASIC receptors (acid-sensitizing ion channels) responsible for the sensations of irritation and pain. The counter-irritant preferentially used is citric acid.

The other excipients used are the excipients conventionally described for each of the classes in the reference works, such as, for example, the Handbook of Pharmaceutical Excipients (Rowe, Sheskey and Owen, Pharmaceutical Press).

Among the lubricating agents that may be used according to the invention, mention may be made of magnesium stearate, stearic acid, glycerol behenate, sucrose esters or sodium stearyl fumarate, and more preferentially magnesium stearate or stearyl fumarate. sodium.

Among the sweeteners optionally contemplated according to the invention, there may be mentioned aspartame, acesulfame potassium, sucralose or saccharin.

Among the flavoring agents according to the invention optionally envisaged, any compound intended to act on the descriptors of the taste (salty, sweet, bitter, acid, umami) will be understood.

Sublingual and gingival tablets are solid single-dose preparations respectively intended to be applied under the tongue and in the gingivo-jugal space, with a view to a systemic action. They are manufactured by compression of mixtures of powders or granules so as to obtain tablets of a shape adapted to the intended use.

The sublingual and gingival tablets according to the invention will comprise the same ingredients as the tablets to be sucked. They have similar release profiles. They differ from the tablets to be suckled only by the route of administration. The tablets to be sucked are intended for administration by the oromucosal route, that is to say that the absorption of the active ingredient is via the whole of the mucous membranes of the oral cavity, while the Sublingual tablets are applied specifically sublingually, that is to say under the tongue, and gingival tablets specifically gingival, that is to say by the gums.

The solid oral preparation intended for a systemic action according to the invention, after administration, has shown excellent acceptability of the active principle by the patient. Indeed, the formulation developed according to the invention allows a gradual dissolution of agomelatine, thus a slow and controlled release avoiding a particularly irritating massive intake of the active substance.

The Applicant has also carried out pharmacokinetic studies in humans and has been able to demonstrate in a totally unexpected and surprising manner a much better bioavailability for a solid oral pharmaceutical composition according to the invention compared to the orodispersible tablets with oromucosal absorption described in FIG. the prior art, for formulations of the same dosage active principle and containing the active ingredient in one form.

Finally, the presence of a "B" or "placebo" layer or nucleus containing no active principle has made it possible to obtain very good patient compliance, thereby overcoming the negative effects observed with the orodispersible tablets of the patient. prior art.

The pharmaceutical composition according to the invention has thus made it possible to very significantly increase the bioavailability of the active ingredient, thereby reducing intra- and inter-individual variability, while offering the patient a very well-accepted formulation, for which a very good compliance is noted.

The invention therefore relates to a solid oral pharmaceutical composition containing agomelatine, intended for a systemic action resulting in an increase in the bioavailability of the active principle compared in particular to an orodispersible form administered sublingually or oromucosally. More particularly, the pharmaceutical composition according to the invention makes it possible to achieve an absolute bioavailability of the active ingredient greater than 25%, and preferably greater than 30%, corresponding to a gain of a factor close to 1.5 to 2 compared with orodispersible sublingual or oromucosal formulations of the prior art, when comparing formulations of same dosage active principle and where the active ingredient is in the same form.

The pharmaceutical compositions according to the invention are preferably characterized in that they contain, relative to the total weight of the composition from 0.01% to 20% by weight of agomelatine, more particularly from 0.01% to 10%, and still more preferably from 0.01% to 5%.

The pharmaceutical compositions according to the invention preferably contain a diiuting agent having a very good compressibility while conferring an erodible character to the formulation. Among the diluents according to the invention include saccharides and polyols, and more preferably sucrose. The useful dosage is adaptable according to the nature and severity of the condition, the route of administration and the age and weight of the patient. This dosage varies from 0.1 mg to 25 mg of agomelatine per day in one or more doses, and preferably from 0.1 mg to 10 mg of agomelatine per day in one or more doses, and even more preferably of 0, 1 to 5 mg agomelatine daily in one or more doses. The following examples illustrate the invention but do not limit it in any way:

EXAMPLE 1: Core Core Formulation

The constituents of the central core "B" are weighed, mixed and sieved. The mixture is then lubricated and then subjected to compression. The central cores obtained are then mixed with the constituents of the outer layer "A" and then subjected to compression.

EXAMPLE 2: Bilayer Formulation

The constituents of layer "A" are weighed, mixed and sieved. The mixture is then lubricated. The same procedure is followed with the constituents of layer "B". Blends "A" and "B" are superimposed and then compressed.

EXAMPLE 3: Tricouche Formulation

The different layers are prepared as in Example 2, then superimposed and subjected to compression.

EXAMPLE 4 Pharmacokinetics

A single dose pharmacokinetic study in healthy male volunteers was performed. Orodispersible formulations according to the prior art, and more particularly as described in WO2007 / 068829, are compared with sucking tablets according to the dual-core, bilayer and trilayer invention.

Plasma samples are taken just before the treatment and then regularly from 2 minutes to 24 hours after the administration of the tablet and the following pharmacokinetic parameters are measured: C _max (maximum concentration observed after administration) and AUC (absorption-elimination balance of the active principle). administered). The results obtained show that the formulation developed according to the present invention makes it possible to increase the pharmacokinetic parameters obtained with the orodispersible formulations described above by a factor of 1.5 to 2. The AUC, directly correlated to the bioavailability, shows that this new formulation makes it possible to significantly increase the bioavailability obtained with respect to the orodispersible tablet.

EXAMPLE 5: Compliance study

A clinical study was conducted in DSM-IV major depressive patients who were administered a simple single-layer oral pharmaceutical composition, and an oral pharmaceutical composition containing exactly the same ingredients but in a core, bilayer or trilayer formulation according to the 'invention.

The results obtained showed that the patients were much better exposed with the central core, bilayer or trilayer formulation according to the invention than with the monolayer formulation.

Claims

1-solid bilayer-type, three-layer or core-core oral pharmaceutical composition intended for a systemic action containing agomelatine or one of its hydrates, complexes, co-crystals, crystalline forms, amorphous form, addition salts with an acid or a pharmaceutically acceptable base, characterized in that it consists of:

one or more "active" peripheral layers "A" containing agomelatine and excipients,

a "placebo" layer "B" containing only the excipients.

2- solid oral pharmaceutical composition according to claim 1 characterized in that it contains:

a bilayer system "A" - "B",

- a three-layer system "A" - "B" - "A",

in which "A" is an "active" layer consisting of the active ingredient agomelatine and excipients, and "B" a "placebo" layer consisting solely of excipients.

3- solid oral pharmaceutical composition according to one of claims 1 or 2 characterized in that it does not contain a disintegrating agent.

4- solid oral pharmaceutical composition according to one of claims 1 to 3 characterized in that it contains one or more excipients selected from diluents, binders, flow agents, lubricants, coating agents, plasticizers, flavoring agents, counter-irritants and sweeteners. 5- solid oral pharmaceutical composition according to one of claims 1 to 4 characterized in that it contains a diluent having a very good compressibility and conferring an erodible character.

6- solid oral pharmaceutical composition according to claim 5 characterized in that the diluent is a polyol or a saccharide.

7- solid oral pharmaceutical composition according to one of claims 1 to 6 which is a tablet to be sucked.

8- solid oral pharmaceutical composition according to one of claims 1 to 7, characterized in that it allows to obtain a slow release of the active ingredient and an absolute bioavailability greater than 25%.

9- solid oral pharmaceutical composition according to one of claims 1 to 7, characterized in that it allows to obtain a slow release of the active ingredient and bioavailability greater than that obtained for an orodispersible oromucosal aborption tablet containing the active ingredient agomelatine in the same form and dosage.

10- solid oral pharmaceutical composition according to one of claims 1 to 9 characterized in that the active ingredient used for its preparation is obtained in crystalline form II.

1-solid oral pharmaceutical composition according to one of claims 1 to 10 characterized in that the "placebo" layer "B" represents between 20 and 80% of the total weight of the pharmaceutical composition.

12- solid oral pharmaceutical composition according to one of claims 1 to 11 characterized in that it comprises from 0.1 to 10 mg of agomelatine.

13- solid oral pharmaceutical composition according to claim 12 characterized in that it comprises from 0.1 to 3 mg of agomelatine. 14- solid oral pharmaceutical composition according to any one of claims 1 to 13, useful for the treatment of major depression, seasonal depression, generalized anxiety disorder, obsessive-compulsive disorder, bipolar disorder, sleep disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet lag, appetite and obesity disorders and all pathologies related to a disruption of circadian rhythms.