WO2003061647A1

WO2003061647A1 - Orodispersible pharmaceutical composition comprising 2-({2-methoxy-2- [3-(trifluoromethyl) phenyl]ethyl}amino) ethyl-4-(2-{ [2-(9h- fluoren-9-yl) acetyl]amino} ethyl)benzoate

Info

Publication number: WO2003061647A1
Application number: PCT/FR2003/000199
Authority: WO
Inventors: Patrick Wuthrich; Hervé Rolland; Marc Julien
Original assignee: Les Laboratoires Servier
Priority date: 2002-01-23
Filing date: 2003-01-22
Publication date: 2003-07-31
Also published as: FR2834891A1; FR2834891B1; AR038306A1

Abstract

The invention relates to an orodispersible solid pharmaceutical composition comprising 2-({2-methoxy-2- [3-trifluoromethyl) phenyl]ethyl} amino)ethyl-4-(2-{ [2-(9H- fluoren-9-yl) acetyl]amino}ethyl)benzoate (compound A). The inventive composition is characterised in that it contains compound A or one of the pharmaceutically-acceptable salts thereof and granules consisting of co-dried starch and lactose.

Description

ORODISPERSIBLE PHARMACEUTICAL COMPOSITION OF

2 - ({2-METHOXY-2- [3- (TRIFLUOROMETHYL) PHENYL] ETHYL} AMINO)

ETHYL-4- (2 - {[2- (9 ^ r-fluoren-9-YL) ETHYL} ACETYLlAMINO) BENZOATE

The present invention relates to a solid orodispersible pharmaceutical form for the oral administration of 2 - ({2-methoxy-2- [3- (trifluoromethyl) phenyl] ethyl} amino) ethyl-4- (2 - {[ 2- (9H-fluoren-9-yl) acetyl] amino} ethyl) benzoate and its pharmaceutically acceptable salts without simultaneous intake of a glass of water and without swallowing problem.

This active principle, hereinafter referred to as compound A, is a hypoglycemic agent which is both insulin-sensitive and insulin-secreting.

Compound A can be administered orally either as tablets or as a powder to be swallowed with half a glass of water. These tablets are useful for the treatment of diabetes.

The doses of compound A in the form of tartrate used range from 50 mg to 200 mg per dose, one to several times a day, in the form of immediate-release tablet or powder.

Many people find it difficult to swallow conventional tablets, which are often large. Problems related to the ingestion of drugs (choking, suffocation by obstruction of the throat) are often the cause of poor compliance with dosages, or even stopping treatment.

The pharmaceutical compositions of the present invention not only make it possible to remedy the known drawbacks of the swallowed tablet form, but also to provide a superior medical service which in particular improves the quality of life of patients.

The orodispersible pharmaceutical composition of compound A has the advantage rapid obtaining of high active principle plasma levels.

The orodispersible pharmaceutical composition according to the invention has the particularity of requiring neither water nor chewing during its administration. It disintegrates very quickly in the mouth, preferably in less than three minutes and even more preferably in less than a minute.

Many rapidly dissolving forms are described in the prior art. In general, the technologies described above have in common the use of a disintegrating agent such as Kollidon ^® CL (crosslinked polyvinylpyrrolidone), EXPLOTAB ^® the (carboxymethylated starch), AC DISOL ^® (crosslinked sodium carboxymethylcellulose).

This disintegrating agent is essential in the formulation of orodispersible tablets and must be used in conjunction with a direct compression excipient. The difficulties encountered in the manufacture of such tablets lie in the fact that it is very difficult to obtain tablets having constant and reproducible physical characteristics and compatible with the conventional handling constraints of the tablets.

Indeed, the mixtures conventionally used lead to tablets of very high hardness totally unsuitable for rapid disintegration in the oral cavity.

Other orodispersible forms can be produced by the use of lyophilization, leading to the production of very porous solid forms called "oral lyophilisate".

These forms require the use of a very specific industrial process, complicated and time-consuming, giving a medicinal form at high cost price.

The present invention overcomes these drawbacks. It relates to a solid orodispersible form of compound A containing a simple excipient, of natural origin allowing rapid disintegration, exhibiting taste neutrality and pleasant texture. This excipient plays the role of both a binder and a disintegrant. he provides a simple formulation of compound A, having an excellent ability to direct compression leading to tablets of low friability and hardness compatible with conventional handling techniques.

More particularly, the invention relates to a solid orodispersible pharmaceutical composition of compound A or of its pharmaceutically acceptable salts, characterized in that it contains:

- of compound A or one of its pharmaceutically acceptable salts,

- and granules consisting of co-dried lactose and starch.

The composition according to the invention may also contain, for manufacturing reasons, one or more lubricants and a flow agent as well as flavors, colors and sweeteners, conventionally used.

In the pharmaceutical compositions according to the invention, the compound A is preferably found in the form of tartrate.

To improve the masking of bitterness of compound A, it may possibly be associated with excipients such as cyclodextrins or coated with excipients by the use of technologies known to those skilled in the art such as for example coating in a fluidized air bed, atomization, coacervation, prilling, spray congealing.

A subject of the invention is also the use of granules consisting of co-dried lactose and starch for the preparation of solid orodispersible pharmaceutical compositions of compound A.

The term "orodispersible" is understood to mean solid pharmaceutical compositions which disintegrate in the oral cavity in less than 3 minutes, and preferably in less than a minute.

Said granules included in the solid pharmaceutical compositions according to the invention correspond to the compositions described in patent application EP 00 / 402159.8. These granules are characterized by a spherical structure and an advantageous compressibility and are marketed under the name STARLAC ^® .

The disintegrating properties of said granules are known for tablets placed in large volumes of liquids, with stirring. It is particularly surprising that such granules used for the manufacture of orodispersible forms can give particularly satisfactory results in terms of disintegration in the mouth, for two reasons.

The first is based on the observation that the least water-soluble excipients are the most suitable for the formulation of orodispersible tablets (the solubilization, resulting in an increase in water viscosity, is a brake on its penetration into the tablets ). However, said granules comprise a large fraction of lactose very soluble in water. In addition, the starch included in said granules is not a "super disintegrating" agent as used and described in the orodispersible forms of the prior art.

The second is based on the observation that the disintegration properties of an excipient (used in a tablet) evaluated in water by conventional methods cannot be extrapolated to the behavior of the same tablet in vivo, in saliva. In fact, the disintegration rates in water are measured (according to the European Pharmacopoeia) in a quantity of water large enough not to reach saturation in terms of solubilization, while in vivo, due to the small volume of saliva , the excipients are at saturation. In addition, the agitation to which the tablets are subjected during the usual test does not reflect the disintegration in the mouth. The Applicant has thus found during comparative tests that certain excipients known as good disintegrants were not suitable for the preparation of orodispersible forms. Conversely, certain excipients which disintegrate moderately in water may have advantageous properties in vivo.

The Applicant then found that the said granules surprisingly gave the tablets very good capacity to disintegrate in the mouth, and this for a wide range of tablet hardnesses, while retaining low friability, which is particularly remarkable. In fact, most of the orodispersible forms of the prior art which disintegrate quickly in the mouth are very brittle, which results in the need to use specific packaging and in risks of disintegration of the tablet as soon as it is handled and removed from its packaging.

It is particularly noteworthy that the aforementioned orodispersibility and low friability criteria are met for a wide range of tablet hardness, that is to say for tablets having a hardness of between 15 and 30 Newtons.

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

from 10% to 50% by weight of compound A or of a pharmaceutically acceptable salt thereof, and even more preferably from 20% to 40%,

- from 45% to 88% by weight of STARLAC ^® .

They will optionally contain from 0.1% to 3% by weight of lubricating agents such as sodium stearyl fumarate or magnesium stearate, preferably from

0.5% to 1.5%, and from 0.1% to 3% by weight of a flow agent such as colloidal silica, preferably from 0.5% to 1.5%.

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

Orodispersible tablets of compound A EXAMPLE 1:

Formulation; 200 mg finished tablet;

EXAMPLE 2:

Formulation; 500 mg finished tablet

The tablets are prepared by mixing the constituents followed by direct compression. The hardness of the tablets of Examples 1 and 2 is approximately equal to 20 Newtons.

In order to evaluate the disintegration time in the mouth, the orodispersible tablets of compound A described in examples 1 and 2 were placed in the mouth. During these tests, it turned out that for each of the formulations tested, the disintegration time in the mouth was less than 1 minute.

Claims

1- Solid orodispersible pharmaceutical composition of 2 - ({2-methoxy-2- [3- (trifluoromethyl) phenyl] ethyl} amino) ethyl-4- (2- {[2- (9H-fluoren-9-yl) acetyl ] amino} ethyl) benzoate (compound A) or a pharmaceutically acceptable salt thereof, characterized in that it comprises:

- of compound A or one of its pharmaceutically acceptable salts,

- granules consisting of co-dried lactose and starch.

2- A pharmaceutical composition according to claim 1 characterized in that it comprises, relative to the total weight of the composition: - from 10% to 50% by weight of compound A or of a pharmaceutically acceptable salt thereof,

- from 45% to 88% by weight of granules consisting of co-dried lactose and starch.

3- Pharmaceutical composition according to claim 2 characterized in that it comprises from 20% to 40% by weight of compound A or one of its pharmaceutically acceptable salts.

4- Pharmaceutical composition according to claim 1 characterized in that it also comprises one or more lubricants, and a flow agent.

5- Pharmaceutical composition according to claim 1 characterized in that it is in the form of tablet.

6- Tablet according to claim 5 characterized in that it is obtained by direct compression.

7- Tablet according to claim 6 characterized in that its hardness is between 15 and 50 Newtons. 8- Tablet according to claim 7 characterized in that its hardness is approximately equal to 20 Newtons.

9- Use of granules consisting of lactose and co-dried starch in the manufacture of solid orodispersible compositions of compound A or of a pharmaceutically acceptable salt thereof, disintegrating in the mouth in less than three minutes and preferably in less than one minute.

10. A solid orodispersible pharmaceutical composition of compound A or of a pharmaceutically acceptable salt thereof, according to claim 1, useful for the treatment of diabetes.