HK1101802B - Orodispersible pharmaceutical composition for oromucosal or sublingual administration of agomelatine - Google Patents

Description

Orodispersible pharmaceutical composition for oromucosal or sublingual administration of agomelatine

Technical Field

The present invention relates to a new coated solid orodispersible pharmaceutical dosage form for the administration of agomelatine by the oral, oromucosal or sublingual route.

Background

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

and its hydrates, crystalline forms and addition salts of pharmaceutically acceptable acids or bases have valuable pharmacological properties: it is a selective agonist of receptors of the melatoninergic system, and in another aspect it is 5-HT_2CAn antagonist of a receptor, which renders it active in the central nervous system. These properties provide it with activity in the central nervous system, especially in the treatment of major depression, seasonal affective disorder, sleep disorders, cardiovascular disease, diseases of the digestive system, insomnia and fatigue due to jet lag, appetite disorders and obesity.

Agomelatine, its preparation and use in therapy have been described in european patent specifications EP 0447285 and EP 1564202.

Hereinafter, "agomelatine" is understood to mean agomelatine, its hydrates, crystalline forms and addition salts of pharmaceutically acceptable acids or bases.

Agomelatine in the form of immediate release tablets can be administered by the oral route by swallowing with half a glass of water. Such agomelatine tablets are particularly useful in the treatment of major depression, seasonal affective disorder, sleep disorders, cardiovascular diseases, digestive system diseases, insomnia and fatigue due to jet lag, appetite disorders and obesity, and all diseases associated with circadian rhythm disturbances.

Pharmacokinetic studies in humans have shown that the bioavailability of agomelatine administered by the oral route is very low compared to the parenteral route and varies both within the same body and between individuals.

The low bioavailability of agomelatine and the inter-and intra-individual concentration differences have also led to the search for new formulations that could solve these problems. Thus, a solid orodispersible pharmaceutical composition of agomelatine described in patent application EP 1427724 was developed, containing agomelatine and consisting of lactose and starch dried by co-spraying and known under the name STARLACCommercially available granules. The pharmaceutical composition makes it possible to obtain tablets which have very good disintegration properties in the mouth and at the same time meet the criteria for dispersibility in the mouth. Tablets which are dispersible in the mouth allow the active ingredient to be released in the oral cavity. The active ingredient dissolves in saliva and is then absorbed through the mucous membranes of the oral cavity and rapidly enters the blood, which makes it possible to avoid the degradation before the system. The bioavailability is very clearly improved with much less variability and rapid appearance of the active ingredient in the blood. For optimal absorption through the oral mucosa, the tablet may be placed specifically under the tongue to release the active ingredient to the sublingual mucosa, which is considered the most permeable oral mucosa.

Furthermore, because they can disappear rapidly from the oral cavity without the need for liquids and without the problem of swallowing, pharmaceutical forms that can be dispersed in the mouth are known to improve patient compliance and comfort.

However, the drawbacks that this formulation has deriving from the active ingredient agomelatine used have rapidly become evident, agomelatine causing a marked irritating sensation in the oral mucosa.

When the sublingual route is specified, the stinging effect is aggravated by the increased local concentration of agomelatine, resulting in very poor patient acceptability.

The use of taste compounds corresponding to 5 senses of sweetness, saltiness, sourness, bitterness and freshness does not alter the pain sensation of the stimulus species, because the two chemosensitive systems that elicit taste and stimulus differ anatomically and physiologically (Franck and Rabin, Nose and Throat Journal, 1989, 68, 291-. The methods known to the person skilled in the art for masking the irritating sensation caused by the dissolution of the product in saliva are very limited: (i) the use of local anesthetics (WO 9915171), (ii) the use of molecules that interact with receptors on nerve endings that cause sensory stimulation (Raisinghani and Premkumar, Pain, 2005,113123-133), (iii) desensitization of nerve endings, while maintaining controlled release (both in duration and quantity) of the stimulus product from the pharmaceutical dosage form held in the oral cavity for a duration of time (US 5762963).

However, these various methods have disadvantages. Indeed, the use of local anesthetics or molecules that interact with receptors associated with sensory stimulation is not satisfactory because these compounds have intrinsic, unexplored pharmacological properties. Furthermore, a strategy based on desensitization is incompatible with obtaining a pharmaceutical composition that can be dispersed in the mouth (disintegration time in vitro less than 3 minutes), i.e. a pharmaceutical composition that disintegrates in the buccal cavity less than 3 minutes, preferably less than one minute.

The applicant has now developed a new pharmaceutical composition which overcomes the problem of irritation of the active ingredient and which at the same time can be used to obtain a preparation which can be dispersed in the mouth, which releases the active ingredient by the sublingual or oromucosal route and is independent of local anaesthetics or other pharmacologically active compounds.

Disclosure of Invention

The invention more particularly relates to a solid pharmaceutical composition consisting of:

^*a central core or layer comprising agomelatine and excipients making it possible to obtain a preparation dispersible in the mouth,

^*a coating dispersible in the mouth.

The pharmaceutical composition according to the invention is in particular formed by a central orodispersible core comprising agomelatine and an orodispersible coating.

One embodiment of the present invention relates to a pharmaceutical composition consisting of an orodispersible central layer comprising agomelatine and an orodispersible coating.

Preferably, the central core and the central layer of the solid pharmaceutical composition according to the invention comprise agomelatine and excipients which make it possible to obtain a mouth-dispersible formulation by a compression process using diluents, lubricants and optionally glidants and disintegrants.

More particularly, the orally dispersible formulation may be obtained with a specific diluent which is dispersible in the mouth or with a conventional diluent to which one or more disintegrants have been added. Advantageously, the orally dispersible diluent used is based on a diluent obtained by co-spraying lactose and starch and known by the name StarlacSold granules, or formed by spraying polyols such as sorbitol or mannitol or by co-spraying mixtures based on polyols, for example under the name PartekOr PharmaburstExcipients are sold.

Other diluents, optionally with disintegrants, may be used provided they have dispersible properties in the mouth and have sufficient hardness and low friability.

Suitable lubricants, glidants and disintegrants (if present) are selected from the respective classes of different excipients. The lubricant is preferably magnesium stearate or sodium stearyl fumarate.

The powder coating dispersible in the mouth according to the invention preferably consists of a diluent, a lubricant, optionally a glidant, optionally a disintegrant and optionally a desensitizing agent which is diluted in the coating.

Advantageously, the orodispersible coating according to the invention contains a desensitizing agent, such as citric acid, menthol or aspartic acid.

More particularly, an orally dispersible coating is obtained with a specific diluent that is dispersible in the mouth or with a conventional diluent to which one or more disintegrants have been added. Advantageously, the orally dispersible diluent used is based on a diluent obtained by co-spraying lactose and starch and known by the name StarlacSold granules, or formed by spraying polyols such as sorbitol or mannitol or by co-spraying mixtures based on polyols, for example under the name PartekOr PharmaburstExcipients are sold.

Other diluents, optionally with disintegrants, may be used provided they have dispersible properties in the mouth and have sufficient hardness and low friability.

Suitable lubricants, glidants and disintegrants (if present) are selected from the respective classes of different excipients. The lubricant is preferably magnesium stearate or sodium stearyl fumarate.

Among the disintegrants used in accordance with the invention, mention may be made ofThose based on sodium carboxymethyl starch, e.g. PrimojelOr ExplotabOr disintegrating agents based on polyvinylpolypyrrolidone, e.g. KollidonCL, or L-HPC (low substituted hydroxypropyl cellulose) based disintegrants.

The solid pharmaceutical composition of the present invention is a tablet prepared by a press coating method. This press coating process has been described in non-orally dispersible tablets aimed at designing sustained release dosage forms: tablets or multi-layer tablets with a central core (Abdul and Poddar, journal of Controlled Release, 2004,97，393-405)。

in the case of tablets according to the invention having a core layer, the first coating layer is pre-compressed and constitutes the bottom layer of powder on which the core layer is placed. A second coating layer overlies the central layer prior to the final step of compression.

In the case of tablets of the invention having a central core, the coating by compression requires the use of a central core sufficient to withstand the coating step. In the case of cores that can be dispersed in the mouth that generally exhibit a moderate resistance to extrusion and a non-negligible fragility, such coating methods are not recommended a priori. In the case of the present invention, the coating of the central core can be carried out by compression without any difficulty using a conventional industrial tablet press suitable for press coating.

The invention therefore also relates to a process for obtaining a solid orodispersible tablet having a central core, which process is characterized in that the components of the central core are mixed and then compressed, and then the components of the coating layer are mixed, the coating being carried out by compression of the obtained powder mixture around the core.

The applicant has now found that the pharmaceutical composition of the present invention retains its dispersible properties in the mouth and has a good ability to disintegrate in the mouth, which is not predictable from a rational point of view for coated pharmaceutical compositions. In particular, the pharmaceutical compositions of the present invention allow disintegration times in the oral cavity of less than 3 minutes, more particularly less than one minute, without the need for controlled release which may act on desensitization mechanisms. Surprisingly, the orodispersible pharmaceutical composition of the invention shows very good acceptability of the active ingredient by limiting its irritation properties, while at the same time dissolving the active ingredient in saliva and allowing it to pass rapidly into the blood.

The pharmaceutical compositions of the invention, administered by the sublingual route, have proved to have an excellent capacity of reducing the irritancy sensation caused by the active principle and therefore an excellent patient acceptability. Administration in this manner limits the first pass effect of the liver, so that the bioavailability of the active ingredient is increased and the inter-individual variation is reduced compared to conventional agomelatine pharmaceutical compositions for enteral administration.

The pharmaceutical compositions of the invention are preferably characterized in that they comprise, relative to the total weight of the tablet:

-from 0.02% to 5% by weight of agomelatine,

from 70% to 99.88% by weight of Starlac for direct compressionOr a mixture of the compounds of formula (I),

-from 0.1% to 3% by weight of magnesium stearate.

More particularly, the pharmaceutical composition comprises, relative to the total weight of the tablet:

from 0.02% to 5% by weight of agomelatine

-from 70% to 99.88% by weightSpecific Starlac for direct compressionOr a mixture of the compounds of formula (I),

-from 0.1 to 3% by weight of magnesium stearate,

from 0.5% to 5% by weight of a desensitizing agent, preferably citric acid, and preferably from 1% to 3%.

They optionally contain:

lubricants other than magnesium stearate, for example from 0.1 to 3% by weight of sodium stearyl fumarate, preferably from 0.5 to 1.5%.

Glidants, for example colloidal silicon dioxide, for example from 0.1 to 3% by weight, preferably from 0.2 to 1%.

-from 0.01% to 5% by weight of one or more sweeteners, preferably from 0.1% to 1%.

In addition, the pharmaceutical compositions of the invention may contain flavouring compounds, colouring substances and one or more sweetening agents, such as sucrose, aspartame, acesulfame or sucralose.

The dosage used may be adjusted according to the nature and severity of the disease, the route of administration and the age and weight of the patient. In one or more daily administrations, the dose varies between 0.1mg and 1g of agomelatine.

Detailed Description

The following examples illustrate the invention but do not limit it in any way:

example 1

Preparation: 320mg of already prepared tablets

Components	Amount (mg)
		Central core agomelatine StarlacStarlac citric acid anhydrous in form of sodium stearyl fumarate coating powderAcesulfame potassium sodium stearyl fumarate	167.651.357.5238.752.51.25

Example 2

Preparation: 350mg prepared tablet

Components	Amount (mg)
		Central core agomelatine StarlacAnhydrous citric acid Starlac as magnesium stearate coating powderAspartame acesulfame potassium magnesium stearate	148.750.2510282332

The central core is made by mixing the components followed by direct compression. The hardness of the cores of examples 1 and 2 was about 15 newtons and the brittleness was less than 1%. The components of the coating layer are mixed and the coating is carried out by compression of the obtained powder mixture around the core.

The coated tablets of examples 1 and 2 had a target hardness of 40 newtons and a friability of about 1%. The disintegration time in vitro is less than 3 minutes (european pharmacopoeia).

Example 3

Preparation: 320mg of already prepared tablets

Components	Amount (mg)
		Mannitol magnesium stearate coated powder anhydrous citric acid for direct compression with central agomelatine for direct compression	168.30.77.52352.52.52.5

Example 4

Preparation: 320mg of already prepared tablets

Components	Amount (mg)
		Center layer Agomelatine StarlacMagnesium stearate coating (2 outer layers of 125mg each) powdered anhydrous citric acid StarlacSucralose magnesium stearate	267.650.357.5238.752.51.25

The components of the different layers are mixed using a mixer by rolling and the powder mixture obtained is then placed in the hopper of a tabletting machine comprising a plurality of compression stations. The first layer of the coating (125mg) was pre-compressed, constituting the bottom layer of powder, on top of which the central layer was placed. The second layer of the coating covers the central layer before the final step of pressing. The resulting coated tablets possessed a target hardness of 40 newtons and a friability of about 1%. The disintegration time in vitro is less than 3 minutes (european pharmacopoeia).

Example 5

Acceptability of

Acceptability studies were conducted in 12 healthy male volunteers by administering a single dose of a conventional orodispersible composition containing 3% citric acid and 1% agomelatine (320mg of a prepared uncoated orodispersible tablet) or a 320mg prepared orodispersible tablet having a central core and containing 1mg agomelatine in the core and 3% citric acid in the coating.

Studies carried out have shown that 67% of volunteers prefer coated orodispersible tablets to a moderate extent, compared to only 50% of conventional orodispersible preparations.

Claims (13)

1. A pharmaceutical composition of agomelatine in the form of a coated solid dispersible in the mouth, characterized in that it comprises:

-a central core or central layer comprising agomelatine and excipients making it possible to obtain a formulation dispersible in the mouth, said excipients comprising a diluent, named asBy co-spraying lactose and starch,

-canAn orodispersible coating comprising a diluent, said diluent being under the nameAnd a desensitizing agent citric acid.

2. Pharmaceutical composition according to claim 1, characterized in that agomelatine is in crystalline form II.

3. Pharmaceutical composition according to claim 1, characterized in that it contains a central core.

4. Pharmaceutical composition according to claim 1, characterized in that it comprises a central layer.

5. Pharmaceutical composition according to claim 1, characterized in that the central core or central layer comprises a diluent and a disintegrant.

6. Pharmaceutical composition according to claim 1, characterized in that it comprises, relative to the total weight of the composition:

-from 0.02% to 5% by weight of agomelatine,

-from 70% to 99.88% by weight

-from 0.1 to 3% by weight of magnesium stearate,

-from 0.5% to 5% by weight of a desensitizing agent,

wherein the sum of the weight percentages of all components is 100%.

7. Pharmaceutical composition according to claim 1, characterized in that it contains one or more lubricants and also glidants, and one or more sweeteners.

8. Pharmaceutical composition according to claim 1, characterized in that it is in the form of a tablet having a central core.

9. Pharmaceutical composition according to claim 1, characterized in that it is in the form of a trilayer tablet.

10. Process for obtaining a pharmaceutical composition according to claim 8, characterized in that the components of the core are mixed and then compressed by direct compression, and then the components of the coating layer are mixed and the coating is carried out by compression of the obtained powder mixture around the core.

11. Use of granules consisting of lactose and starch and citric acid co-spray dried for the preparation of a coating for a solid orodispersible composition having a central core or layer of agomelatine according to claim 1, disintegrating in the mouth in less than three minutes.

12. The use of claim 11, wherein the composition disintegrates in the mouth in less than one minute.

13. Solid orodispersible pharmaceutical composition with a central core or layer of agomelatine according to any one of claims 1 to 9 for the treatment of major depression, seasonal affective disorder, sleep disorders, cardiovascular diseases, digestive diseases, insomnia and fatigue due to jet lag, appetite disorders and obesity, as well as all diseases related to circadian rhythm disturbances.