TW201434495A - Solid pharmaceutical composition for buccal administration of agomelatine - Google Patents

Abstract

The invention relates to a solid buccal pharmaceutical composition comprising agomelatine intended for systemic action.

Description

Solid pharmaceutical composition for buccal administration of agomelatine

This invention relates to a novel solid pharmaceutical form for administration of agomelatine by the buccal route.

Agomelatine, or formula (I) N- [2-(7-methoxy-1-naphthyl)ethyl]acetamide: Its hydrates, crystalline forms, amorphous forms, complexes, co-crystals and addition salts with pharmaceutically acceptable acids or bases have valuable pharmacological properties: it is a melatoninergic system A selective agonist of the receptor and, on the other hand, an antagonist of the 5-HT _2C receptor. These properties provide activity in the central nervous system and, more particularly, in the treatment of severe depression, seasonal affective disorder, generalised anxiety disorder, Obsessive-compulsive disorder, bipolar disorder, sleep disorders, cardiovascular disease, digestive system disorders, insomnia and fatigue due to jet lag, appetite disorders and obesity.

Agomelatine, its crystalline form, its complex, its co-crystals, its pharmaceutically acceptable acid or base addition salts, its formulations and its use in therapy have been described in particular in patent applications EP 0 447 285, WO2005/077887, WO2007/015003, WO2007/015002, WO2007/015004, WO2010/097052, WO2010/102554, CN101955440, WO2011/050742, CN102050756, WO2011/006387, WO2011/075943, CN101774937, CN101870662, CN102030673, WO2012/046253, WO2011/113362, WO2011/113363, CN102206864, CN102503886 and CN102432490.

In all of the following, "agomelatine" is understood to mean agomelatine, its hydrate, its complex, its eutectic, its crystalline form, its amorphous form and its pharmaceutically acceptable Accepted acid or base addition salts.

Agomelatine may especially be in crystalline form II.

Agomelatine can be administered by the oral route or, more specifically, by the enteral route in the form of an immediate release lozenge swallowed with half a cup of water. These agomelatine lozenges are especially useful for the treatment of major depression, seasonal mood disorders, generalized anxiety disorder, obsessive-compulsive disorder, bipolar disorder, sleep disorders, cardiovascular disease, digestive system disorders, due to jet lag. Insomnia and fatigue, appetite disorders and obesity, and any pathology associated with circadian rhythm disorders.

Pharmacokinetic studies in humans have shown that the bioavailability of agomelatine by the oral route is lower than that of the parental route of agomelatine and is different for the same individual. And varies from individual to individual.

The low bioavailability of agomelatine and the difference in inter-individual and intra-individual concentrations thus led to the study of novel formulations that overcome these disadvantages. Thus, a solid oral pharmaceutical composition of agomelatine is developed, which is described in patent application EP 1427724, which contains agomelatine and particles consisting of lactose and starch, which are Atomized and dried and sold under the name STARLAC ^® . This pharmaceutical composition makes it possible to obtain a tablet having excellent disintegration ability in the oral cavity and more specifically in the sublingual cavity, which meets the criteria for oral dissolution. The solubilized ingots make it possible to deliver the active ingredient into the oral cavity and, more specifically, into the sublingual cavity in less than three minutes. The dissolution of the active ingredient in saliva and subsequent absorption through the oral mucosa and, more specifically, the sublingual mucosa, and rapid entry into the blood make it possible to avoid pre-system decomposition and first-pass effects. Therefore, bioavailability is significantly improved with less variability in the active ingredients in the blood and rapid emergence.

However, it is readily apparent that this formulation has the disadvantage of causing a significant irritating sensation in the oral mucosa due to the active ingredient used (agomelatine).

This tingling effect is exacerbated by the local high concentration of agomelatine when it is specifically targeted to the sublingual route, and the end result is extremely poor patient acceptance. In this case, a formulation of a sublingual dosage form has been developed and described in patent application WO2007/068829, which meets the requirements for oral dissolution and patient acceptance. An advantageous strategy is to obtain a solid pharmaceutical composition consisting of a core or central layer containing agomelatine and an excipient that provides an orally soluble formulation, and optionally an anti-irritant orally soluble coating. Such solubilized ingots make it possible to achieve rapid disintegration in less than 3 minutes and have shown an excellent ability to limit the stinging characteristics of the active ingredients.

Nonetheless, efficacy problems are found in the context of this formulation during clinical trials, which raises the thought that there may be poor compliance or compliance with a patient's medication for a part of the patient's medication (in medical prescription) Consistency with patient behavior). For example, if the patient swallows the solubilized ingot too quickly, and the active ingredient does not dissolve completely in the saliva, the active ingredient is no longer absorbed sublingually. Therefore, the active ingredient dose (between 0.5 and 3 mg) in the orally-soluble tablet is extremely low compared to the active ingredient dose (25 mg) in the oral lozenge, so in the case of the mouth-soluble ingot, if it does not pass the tongue When absorbed by the next route, no effect can be observed. It should be noted that poor compliance is even more marked in most chronic conditions that require prolonged treatment, generally as in the case of treatment of disorders of the central nervous system. The poor compliance of treatment therefore constitutes a major public health problem for clinicians, and it is necessary to find a satisfactory solution to this problem.

Applicants are now following a novel strategy consisting of developing a pharmaceutical formulation that gradually releases agomelatine in the buccal cavity. The focus of this novel formulation is that the local concentration remains sufficiently low throughout the release of the active ingredient to limit the stinging sensation and to obtain a form acceptable to the patient. formula.

Also in order to remedy the patient compliance problem, as observed in the case of prior art oral dissolution tablets, the Applicant has designed a two-layer, three-layer or central core multi-layer system for this novel formulation in which the active ingredients are concentrated In the peripheral part of the formulation. The formulation of the present invention is therefore related to: - a two-layer system "A" - "B" (where the layer "B" is thicker than the layer "A"), - a three-layer system "A" - "B" - "A", - Or a central nuclear system, where "A" is the peripheral layer and "B" is the core, wherein "A" is the "active" layer composed of the active ingredient agomelatine and excipients, and "B" is only A "placebo" layer consisting of excipients. Therefore, even if the patient does not completely disintegrate the formulation in the buccal cavity, the active ingredient contained in the outer layer will have time to dissolve into the saliva and be absorbed sublingually, and thus the ingested portion which is not absorbed by the sublingual route will Contains only excipients.

Thus, a novel pharmaceutical formulation has been developed which makes it possible to: - remedy the irritation of agomelatine, - to promote the delivery of active ingredients into the buccal cavity for the purpose of systemic action, which is a popular effect, To improve the bioavailability and variability within and between individuals in the case of lozenges administered by the oral route, while ensuring good patient compliance in the context of patient medication.

More particularly, the present invention relates to a bilayer, trilayer or central core type solid buccal preparation intended for systemic action for controlled release of an active ingredient in the oral cavity, which consists of: * one or more "active" Peripheral layer "A", which contains agomelatine and excipients, * placebo layer "B", which contains only excipients.

In an amazing and completely unexpected way, not only compared to oral (enteral) tablets, but also The purpose of the systemic effect is to increase the bioavailability of the active ingredient with respect to the same dosage of the active ingredient and the formulation containing the active ingredient in the same form as compared to the orally-dissolved oral mucosal formulation developed in the prior art. Here, and wherever used in the following description, "same form" means that the active ingredient has the same crystalline form, or is in the same form as a hydrate, complex, salt or co-crystal, and the particle size of the active ingredient the same.

The present invention is therefore directed to a solid buccal formulation intended for systemic action which allows controlled release of the active ingredient in the oral cavity to achieve the same dosage as compared to the mouth-soluble ingots described in the prior art for oral mucosal absorption. For the active ingredient and the formulation comprising the active ingredient in the same form, good acceptance with respect to taste and better absolute bioavailability are obtained. In addition it makes it possible to ensure good patient compliance in the case of patient treatment.

The buccal formulation of the present invention is more particularly directed to absorbent lozenges, sublingual lozenges and gingival lozenges comprising agomelatine. Preferably, the buccal formulation of the invention will be an absorbent lozenge.

The buccal preparation of the present invention may contain a diluent, a binder, a flow agent, a lubricant, a coating agent, a plasticizer, a flavoring agent, an anti-irritant, and a sweetener.

The buccal formulation of the present invention is characterized by the absence of a disintegrant which, in combination with high compressive strength, makes it possible to obtain a tablet which does not disintegrate but which slowly erodes by dissolution of the components on the surface.

The layers "A" and "B" of the present invention are composed of the same components, the only difference being the presence of the active ingredient ("active" peripheral layer "A") or the absence of the active ingredient ("placebo" layer "B").

Preferably, the "placebo" layer "B" constitutes from 20% to 80% of the total weight of the buccal formulation. In the central core formulation, the "placebo" layer "B" advantageously constitutes from 20% to 50%, preferably 20%, of the total weight of the buccal formulation. In a two- or three-layer formulation, the "placebo" layer "B" advantageously constitutes from 50% to 80%, more preferably from 60% to 80%, by total weight of the buccal formulation.

The invention also relates to a method for preparing a solid buccal formulation of the invention: A mixture of components of the same layer ("A" or "B") is obtained by granulation or simple mixing. These different mixtures are then compressed by means of a suitable machine for the manufacture of the formulations of the invention: a double layer, a triple layer or a central core.

The systemic effect of the present invention is that the active ingredient release time of the buccal formulation is less than 30 minutes, more preferably less than 15 minutes. For example, active ingredient release will occur between 3 minutes and 30 minutes, more preferably between 3 minutes and 15 minutes.

The lozenge to be absorbed is a solid unit dosage formulation intended to be absorbed for local or systemic action. It is obtained by direct compression or by granulation followed by compression.

For example, the pharmaceutical compositions of the present invention will be absorbent tablets which can be prepared by a direct compression process. According to the invention, the absorbent lozenge comprises agomelatine, a diluent and, optionally, a binder, a lubricant and/or a flow agent and/or one or more sweeteners, flavoring agents or anti-irritants. It is characterized by slow erosion in the oral cavity. The diluents which can be used according to the invention are selected such that they allow for direct compression and provide a pharmaceutical form with high crush resistance and acceptable organoleptic properties for the buccal formulation to be absorbed. The diluent used is preferably a polyol or a sugar (monosaccharide, oligosaccharide or polysaccharide) or a combination of various compounds such as glucose, sucrose, mannitol, glucose binder, dextrin or isomaltose. Cerium oxide or a disintegrant may be added to the compounds.

Among the binders which can be used according to the invention, mention may be made of cellulose compounds and starch compounds, crospovidone, maltodextrin and povidone.

The anti-irritant used as the case may be a compound which acts on a vanillin receptor or an ASIC (acid-sensitive ion channel) receptor which causes a feeling of irritation and pain. The anti-irritant used preferentially is citric acid.

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

Among the lubricants which can be used according to the invention, mention may be made of magnesium stearate, stearic acid, Glycerol phthalate, sucrose ester and sodium stearyl fumarate, more preferably magnesium stearate or sodium stearyl fumarate.

Among the sweeteners envisioned according to the present invention, mention may be made of aspartame, potassium sulfamate, sucralose and saccharin.

Flavoring agents contemplated in accordance with the present invention may optionally comprise any compound that is intended to have an effect on the taste descriptors (salty, sweet, bitter, sour, umami).

Sublingual and gingival lozenges are solid unit dose preparations which, for the purpose of systemic action, are intended to be applied separately to the space below the tongue and between the gums and the cheeks. It is produced by compressing a mixture of powders or granules in order to obtain a lozenge that is shaped to match its intended use.

The sublingual and gingival lozenges of the present invention will comprise the same ingredients as the absorbent tablets. It has similar release characteristics. It differs from the absorbent tablet only in the route of administration. Absorbent tablets are intended for administration via the oral mucosal route, in other words, absorption of the active ingredient is carried out via the entire buccal mucosa, whereas sublingual lozenges are specifically administered by the sublingual route, in other words, under the tongue, and Gingival lozenges are specifically administered by the gum route, in other words via the gums.

The solid buccal formulation intended for systemic action according to the present invention exhibits excellent patient active ingredient acceptance after administration. Formulations developed in accordance with the present invention actually cause the agomelatine to gradually dissolve, and thus slow and controlled release, avoiding the introduction of particularly large amounts of active substances that are particularly irritating.

Applicants also performed pharmacokinetic studies in humans and were able to exhibit in completely unexpected and surprising ways, with the same dose of active ingredient and containing the same as the orally dissolved ingots described in the prior art for oral mucosal absorption. The bioavailability of the solid pharmaceutical compositions for buccal administration of the present invention is much better in the formulation of the active ingredients.

Finally, the presence of a "placebo" layer or core "B" that does not contain the active ingredient makes it possible to obtain very good compliance with a part of the patient's treatment, thereby remedying the prior art The negative effect observed in the case of the ingot.

The pharmaceutical compositions of the present invention thus make it possible to significantly increase the bioavailability of the active ingredient, and thus reduce intra- and inter-individual variability, while providing a highly acceptable formulation for the patient, in the case of the formulation, finding the pole Good level of compliance.

The present invention is therefore directed to a solid buccal pharmaceutical composition comprising agmelatine for systemic action, particularly in an oral form which is administered by the sublingual or oral mucosal route, which results in an active ingredient Increased bioavailability. More particularly, the pharmaceutical compositions of the present invention make it possible to obtain greater than 25%, preferably greater than 30%, of the absolute bioavailability of the active ingredients when comparing formulations having the same dosage of active ingredients in which the active ingredients are in the same form. This corresponds to an increase of approximately 1.5 to 2 times compared to the sublingual or oral mucosal morbid formulation compared to prior art.

The pharmaceutical composition of the present invention is preferably characterized in that it contains 0.01% to 20% by weight of agomelatine, more particularly 0.01% to 10%, and even more preferably 0.01% to 5% by weight based on the total weight of the composition. .

The pharmaceutical compositions of the present invention preferably comprise a diluent which has excellent compression capabilities while imparting an erosive character to the formulation. Among the diluents of the present invention, mention may be made of sugars and polyols, more preferably sucrose.

The applicable dosage may vary depending on the nature and severity of the condition, the route of administration, and the age and weight of the patient. The dose is changed from 0.1 mg to 25 mg of agomelatine daily in one or more administrations, and preferably from 0.1 mg to 10 mg of agomelatine, and even better, in one or more administrations per day. The daily change from 0.1 mg to 5 mg agomelatine is administered in one or more administrations.

The following examples illustrate the invention but are not intended to limit the invention in any way:

Example 1: Central Nuclear Formulation

The components of the central core "B" are weighed, mixed and sieved. The mixture is then lubricated and compressed. The central core obtained is then mixed with the components of the outer layer "A" and subsequently compressed.

Example 2: Two-layer formulation

The components of layer "A" are weighed, mixed and sieved. The mixture is then lubricated. The same procedure is carried out in the case of the components of layer "B". The mixtures "A" and "B" were placed on top of each other and then compressed.

Example 3: Three-layer formulation

The different layers were prepared as in Example 2, then placed on top of each other and compressed.

Example 4: Pharmacokinetics

Single drug pharmacokinetic studies were performed in healthy male volunteers. The oral dissolution formulation according to the prior art (more particularly as described in WO2007/068829) is compared to the dual core, double layer and triple layer absorbent tablets according to the invention.

Plasma samples were taken regularly from 2 minutes to 24 hours immediately after treatment, and then after administration of the tablets, and the following pharmacokinetic parameters were measured: _Cmax (maximum concentration observed after administration) and AUC (sum of absorption-elimination of the active ingredients administered).

The results obtained demonstrate that the formulations developed by the present invention make it possible to increase the pharmacokinetic parameters obtained by the previously described orally soluble formulations by a factor of 1.5 to 2. The AUC, which is directly related to bioavailability, demonstrates that this novel formulation makes it possible to significantly increase the bioavailability obtained compared to oral lozenges.

Example 5: Compliance Study

Conducting clinical studies in patients diagnosed with major depression according to DSM-IV, providing patients with a simple single-layer buccal pharmaceutical composition and containing the same components but presenting a central core, double or triple layer according to the present invention A buccal pharmaceutical composition of the formulation.

The results obtained demonstrate that it is substantially better for the patient to be exposed to a central core, bilayer or trilayer formulation according to the present invention than to a monolayer formulation.

Claims (14)

A bilayer, trilayer or central core solid buccal pharmaceutical composition for systemic action comprising agomelatine or a hydrate thereof, a complex, a co-crystal, a crystalline form, a non- One of a crystalline form, or a pharmaceutically acceptable acid or base addition salt, characterized in that it consists of one or more peripheral "active" layers "A" containing agomelatine and Excipient, "Placebo" layer "B", which contains only excipients. The solid buccal pharmaceutical composition of claim 1, which comprises: a two-layer system "A" - "B", a three-layer system "A" - "B" - "A", or a central nuclear system, wherein "A "B" is the core, and "B" is the "active" layer composed of the active ingredient agomelatine and excipients, and "B" is composed only of excipients. The "placebo" layer. A solid buccal pharmaceutical composition according to claim 1 or claim 2, which does not contain a disintegrant. A solid buccal pharmaceutical composition according to claim 1 or 2, which comprises one or more selected from the group consisting of a diluent, a binder, a flow agent, a lubricant, a coating agent, a plasticizer, a flavoring agent, an anti-irritant, and a sweetener. An excipient for the flavoring agent. A solid buccal pharmaceutical composition according to claim 1 or 2, which comprises a diluent having excellent compressibility and imparting aggressive characteristics. A solid buccal pharmaceutical composition according to claim 5, wherein the diluent is a polyol or a sugar. A solid buccal pharmaceutical composition according to claim 1 or 2 which is an absorbent lozenge. A solid buccal pharmaceutical composition according to claim 1 or 2, wherein it makes it possible to obtain Sustained release of the active ingredient and greater than 25% absolute bioavailability. The solid buccal pharmaceutical composition of claim 1 or 2, wherein it makes it possible to obtain a sustained release of the active ingredient and higher than the absorption of the oral mucosa of the active ingredient in the same form and at the same dose of agomelatine The bioavailability of the person obtained in the case of an orally dissolved ingot. A solid buccal pharmaceutical composition according to claim 1 or 2, wherein the active ingredient for its formulation is obtained in crystalline form II. The solid buccal pharmaceutical composition of claim 1 or 2 wherein the "placebo" layer "B" comprises from 20% to 80% by weight of the total pharmaceutical composition. A solid buccal pharmaceutical composition according to claim 1 or 2, which comprises 0.1 to 10 mg of agomelatine. A solid buccal pharmaceutical composition according to claim 12, which comprises 0.1 to 3 mg of agomelatine. A solid buccal pharmaceutical composition according to claim 1 or 2 for use in the treatment of major depression, seasonal affective disorder, generalised anxiety disorder, obsessive-compulsive disorder, bipolar disorder, sleep Disorders, cardiovascular disease, digestive system lesions, insomnia and fatigue due to jet lag, appetite disorders and obesity, and any lesions associated with circadian rhythm disorders.