WO2014125052A1

WO2014125052A1 - Pharmaceutical composition for oral administration comprising fexofenadine and process for preparing thereof

Info

Publication number: WO2014125052A1
Application number: PCT/EP2014/052869
Authority: WO
Inventors: Georges Daste; Benjamin DEROUET; Marie RENOUARD
Original assignee: Sanofi SA
Current assignee: Sanofi SA
Priority date: 2013-02-14
Filing date: 2014-02-14
Publication date: 2014-08-21
Anticipated expiration: 2015-08-14
Also published as: UY35329A; TW201440808A; AR094761A1

Abstract

The present invention relates to pharmaceutical compositions for oral administration, said compositions comprising high(methyl)pectin, glycerol,water and fexofenadine,or a pharmaceutically acceptable salt thereof. The invention also relates to the uses of these compositions as a medicament and to the process for preparing said compositions.

Description

PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION COMPRISING FEXOFENADINE AND PROCESS FOR PREPARING THEREOF

The present invention relates to a formulation of fexofenadine or a pharmaceutically acceptable salt thereof. More particularly, it relates to a pharmaceutical composition for oral administration comprising high(methyl)pectin, glycerol, water and fexofenadine or a pharmaceutically acceptable salt thereof. The present invention also concerns a process for preparing the pharmaceutical composition and the use of said pharmaceutical composition as a medicament. Fexofenadine is a well-known antihistamine compound with a selective peripheral H1 -receptor antagonist activity. Fexofenadine as a substance is usually used in the form of fexofenadine hydrochloride represented by formula (I) below:

Formula (I)

The process for preparing fexofenadine hydrochloride is known from US 6,1 13,942. Moreover, fexofenadine hydrochloride is commercially available under the trade name ALLEGRA®. ALLEGRA is a coated tablet suitable for oral administration. Because of some properties of fexofenadine hydrochloride, tablets containing so are big enough. Indeed, the total content of fexofenadine hydrochloride in a tablet cannot exceed 30% by weight (wt) of the total tablet weight. Thus, some patients, especially elderly patients and children, may have difficulty in swallowing the rather large tablet. Additionally, the administration of a tablet usually requires the ingestion of a liquid in order to facilitate the swallowing. In everyday life, patients do not have always liquids at hand. These issues can result in poor compliance or non-compliance with the treatment. Other formulations of fexofenadine have been further proposed.

WO 03/041683 discloses an orodispersible tablet containing fexofenadine. While orodispersible formulations can be more easily swallowed, taking them may be considered unpleasant by some patients.

WO 00/21510 discloses a liquid formulation of fexofenadine, suitable for nasal or ophthalmic administration. These two types of administration may be of interest in some specific local treatments, with a limited bioavailability. However, fexofenadine is highly active when orally administered. This explains why this last way of administration is usually preferred.

Thus, there is still a need for new fexofenadine formulations, suitable for oral administration, which is convenient for most patients, especially including the elderly and children. In particular, such a formulation should be easy to swallow and preferably be ingested without liquid.

The present invention thus relates to a pharmaceutical composition for oral administration comprising:

1 -3.5% wt, preferably 1 .5-3% wt, of high(methyl)pectin, - 40-68% wt, preferably 48-62% wt, of glycerol,

16-29% wt, preferably 20-25% wt, of water,

0-1 % wt, when present, preferably 0.1 -0.5% wt, of at least one surfactant,

3-5 % wt, preferably 3.5-4.5% wt, of fexofenadine, or a pharmaceutically acceptable salt thereof,

12-24 % wt, preferably 15-20% wt, of a pharmaceutical excipient able to complex with the fexofenadine or its pharmaceutically acceptable salt thereof,

0-5% wt, when present, preferably 0.5-2.5% wt, of at least one other ingredient selected in the group consisting of: sugar substitutes, flavouring agents and/or colouring agents, the weight percentages being relative to the total weight of the composition, and the pH of the composition being within the range of about 2.8 to about 3.2.

It should be noted that throughout the present application, ranges are intended limits inclusive.

Pectin is represented by general formula (II) below:

Formula (II)

In pectin, which is extracted normally, more than 50% of the acid units are esterified. This pectin is usually classified and known as "high methyl ester pectin" or "high(methyl)pectin". The percentage of ester groups is known as the degree of esterification (DE). Preferably, according to the invention, high(methyl)pectin has a DE from about 50 to about 80, more preferably, from about 65 to about 75. High(methyl)pectin is an important ingredient of the composition. Indeed, high(methyl)pectin allows one to obtain a composition, which, once formed, can be grasped. Additionally, with high(methyl)pectin, the gelling of the composition is easily controlled, occurs rapidly, i.e. in less than 2 hours, and doesn't require heating the composition to a temperature above 90°C, thus avoiding any potential degradation of other ingredients, in particular, fexofenadine, or its pharmaceutically acceptable salt thereof.

In the composition according to the invention, glycerol is introduced as a sort of co-agent of the pectin, which allows, with the presence of water and the adjustment of the pH, the gelling of the composition. Additionally, the presence of glycerol avoids the use of sucrose in the compositions, sucrose being caloric and cariogenic. One particular advantage of the pharmaceutical composition according to the invention is that said composition is sugar free. Preferably, water introduced into the composition is purified water according to the U.S. and E.U. pharmacopeias.

The composition according to the invention may comprise at least one surfactant, the presence of which is only required in some particular embodiments. For example, the presence of the surfactant may be required depending on the process for preparing the pharmaceutical composition. In particular, in the latter process according to the invention disclosed hereafter, the step (i) of mixing fexofenadine or a pharmaceutically acceptable salt thereof, the pharmaceutical excipient, glycerol and water may comprise the addition of a surfactant, depending on the particular embodiment of this step (i) (see below). In this case, the surfactant is used to disperse the fexofenadine, or a pharmaceutically acceptable salt thereof, and the pharmaceutical excipient.

When present, the surfactant is preferably a non-ionic surfactant. Advantageously, the surfactant is chosen among the group consisting of: ethylene propylene oxide copolymers, such as those sold under the trademark POLOXAMER, polysorbates, such as those sold under the trademark TWEEN. Preferably, the surfactant is a polyoxyethylene (20) sorbitan monooleate (or polysorbate 80) such as sold under the trade name TWEEN 80.

Fexofenadine introduced into the composition is preferably a salt of fexofenadine, more preferably, fexofenadine hydrochloride as represented by formula (I) above. Fexofenadine hydrochloride exists under three forms, depending on the degree of hydration of the salt. Preferably, fexofenadine hydrochloride is in form I, i.e. anhydrous.

Fexofenadine, or a pharmaceutically acceptable salt thereof is known to be difficult to solubilize. The composition according to the invention comprises a pharmaceutical excipient that can form a complex with the fexofenadine or its pharmaceutically acceptable salt. Indeed, in a preferred embodiment, the pharmaceutical excipient is β-cyclodextrin.

Additionally, the composition according to the invention may comprise at least one other ingredient selected in the group consisting of: sugar substitutes, flavouring agents and/or colouring agents.

By sugar substitute, it is meant a food additive that replicates the taste of sugar. Preferably, said sugar substitutes are artificial sweeteners such as sucralose, saccharine and/or potassium acesulfame. The flavouring agents are preferably selected in the group consisting of lime, lemon, strawberry and apple. By colouring agents, it is meant dyes, lakes and/or opacifying agents. Examples of such colouring agents are red iron oxide, yellow iron oxide, Ti0₂, carmine E120, FD&C blue no. 1 Aluminium Lake, etc.

To gel the composition, the pH of the composition must be adjusted within a range of about 2.8 to about 3.2, preferably, within the range of about 2.9 to about 3.1 . Said adjustment is performed by adding an acid to the composition. Preferably, the acid is chosen among the group consisting of citric acid, tartaric acid, phosphoric acid and/or lactic acid, and is more preferably, citric acid.

The pharmaceutical composition according to the invention has a water activity of less than 0.61 .

The « water activity » represents the water availability (i.e. free water) which can be used by the microorganisms for their growth within the sample. The water activity may be measured by methods known in the art.

Preferably, the water activity is less than 0.60, more preferably, less than 0.59 and still more preferably less than 0.58. This low water activity is of particular interest because it renders the addition of preservatives to the composition, such as parabens, unnecessary.

It may be noted that once gelled, the pharmaceutical composition according to the invention forms a solid which is chewable. Moreover, for patients having few or no teeth, said solid composition can also be sucked. This pharmaceutical composition can thus be easily ingested by all patients, particularly by the elderly and the children. The pharmaceutical composition may also have an agreeable appearance and a pleasant taste:

- the taste of the composition can be modified by the addition of suitable sugar substitute(s) and flavouring agent(s), and

- colouring agent(s) may render the chewable composition more attractive.

All these features make the compliance with the treatment easier for the patient.

The pharmaceutical composition according to the invention can be used as a medicament, in particular as an antihistamine and/or a bronchodilator, and is particularly suitable for the treatment of an allergy and/or urticaria. Furthermore, the pharmaceutical composition according to the invention can be used in a method of treatment of an allergy and/or urticaria, said method comprising the administration of the pharmaceutical composition of the invention to a patient.

The pharmaceutical composition, under solid form, can be divided into units, each unit comprising a dose of fexofenadine or a pharmaceutically acceptable salt thereof. As an example, a unit of 0.75g, 1 .5g and 3g can comprise respectively a dose of 30, 60 and 120mg of fexofenadine or a pharmaceutically acceptable salt thereof. As mentioned above, the pharmaceutical composition according to the invention may form units, which are graspable. In particular, a 1 .5g unit of the pharmaceutical composition has a hardness above 30g, preferably comprised in the range from 40g to 200g, more preferably from 50g to 150g, when measured by a texture analyser. Measurements by a texture analyser are known in the art. An example of such a measurement is more specifically described in the example.

The present invention further relates to a process for preparing a pharmaceutical composition according to the invention, comprising the following steps: i) Mixing fexofenadine or a pharmaceutically acceptable salt thereof, the pharmaceutical excipient, glycerol and water,

ii) After heating, adding the high(methyl)pectin,

iii) Adding the sugar substitute(s), flavouring agent(s) and/or colouring agent(s), if any

(i) Heating the resulting mixture of step (ii) to a temperature ranging from about 60°C to about 90°C, preferably at a temperature of about 70°C, iv) Adjusting the pH with an acid,

v) Forming and cooling the composition until gelling occurs.

One aim of step (i) of the process is to solubilize fexofenadine, or a pharmaceutically acceptable salt thereof, by complexing it with the pharmaceutical excipient, and to disperse said resulting complex in glycerol and water. According to the invention, this solubilization and dispersion can be performed according to different embodiments. In a first embodiment, step (i) is performed as followed: a) Mixing fexofenadine, or a pharmaceutically acceptable salt thereof, and the pharmaceutical excipient with water,

b) Adding glycerol and the surfactant to the resulting mixing of step (a). More particularly, step (a) comprises several sub-steps:

The pharmaceutical excipient is first mixed with a part of water in order to obtain a mixing having a pasty consistency;

A part of fexofenadine or a pharmaceutically acceptable salt thereof is added to the mixture having a pasty consistency followed by another part of water;

Finally, the rest of fexofenadine, or a pharmaceutically acceptable salt thereof, is added followed by the rest of water.

In this step (a), a surfactant is added to disperse the different ingredients. However, said dispersion is notably improved by the progressive addition of water and fexofenadine, or a pharmaceutically acceptable salt thereof. Additionally, in the last sub-step, the rest of water is added after a contact time of at least 45 min, preferably, at least 1 h.

Advantageously, step (a) may comprise the following sub-steps:

The pharmaceutical excipient is first mixed with 50% (half) of the water in order to obtain a mixture having a pasty consistency;

About 60 to 85% of the fexofenadine or a pharmaceutically acceptable salt thereof is added to the mixture having a pasty consistency followed by another 15 to 35% of the water;

Finally, about 15 to 40% of the fexofenadine or a pharmaceutically acceptable salt thereof is added followed by the rest of water (from 15 to

35%, depending on the amount of water added in the previous sub-step).

In this embodiment, the percentages are relative to the total content of each ingredient.

In a second embodiment, step (i) is performed as follows:

I. Mixing the water with the glycerol, II. Adding the fexofenadine or a pharmaceutically acceptable salt thereof and the pharmaceutical excipient to the mixture of step (I).

More particularly, in step (II), the fexofenadine, or a pharmaceutically acceptable salt thereof, and the pharmaceutical excipient are added to the mixture of step (I) in a powder form, said powder comprising the fexofenadine or a pharmaceutically acceptable salt thereof complexed with the pharmaceutical excipient.

Such a powder comprising the fexofenadine, or a pharmaceutically acceptable salt thereof, complexed with the pharmaceutical excipient can be prepared as follows:

The pharmaceutical excipient is first mixed with a quantity of water (the quantity representing 10 to 20% of the total weight of both components : fexofenadine or a pharmaceutically acceptable salt thereof and the pharmaceutical excipient), in order to obtain a mixture having a pasty consistency;

All of fexofenadine, or a pharmaceutically acceptable salt thereof, is added progressively to the mixture having a pasty consistency,

The resulting paste is then dried at about 60°C during at least 2 hours in order to remove the water.

The dried product is finally ground in order to obtain a powder.

It should be noted that because the water added is then removed by drying, the quantity of water mentioned in the preparation process of the powder is not taken into account in the total weight of the composition, according to the invention.

In this latter embodiment, the addition of a surfactant can be avoided.

Advantageously, the addition of the high(methyl)pectin of step (ii) is performed after heating the mixture of step (i) to a temperature within the range of about 35°C to 45°C, preferably at about 40°C.

Preferably, in step (v), the pH is adjusted with citric acid, tartaric acid, phosphoric acid and/or lactic acid, and more preferably, with citric acid.

In a first preferred embodiment, the forming step is performed by pouring the pharmaceutical composition into moulds. Advantageously, the moulds may be further lined up to form a blister pack, which may then be thermally sealed. In a second preferred embodiment, the forming step is performed by deposition of a drop of the pharmaceutical composition on a cooled belt. The drops solidify and cool as they travel along with the belt. The solidified units are then discharged at the end of the belt and collected. The cooled belt may be made of steel or another suitable material.

The present invention is further illustrated by the following example, which is not to be construed in any way as limitating, with reference to:

Figure 1 , which is a photo of a mould filled with the composition according to the invention, and - Figure 2, which is a diagram of the mould used to prepare the units of composition in example 1 .

EXAMPLE 1 : Composition and process according to the invention

1. Composition

A pharmaceutical composition according to the invention was prepared with the following ingredients:

* The percentage of each ingredient is the weight percentage with respect to the total weight of the composition. ** w/w: weight/weight. ***Qs: quantum satis.

2. Preparation process The preparation of the pharmaceutical composition is carried out as follows.

The aim of the first steps of the process is to solubilize and disperse the fexofenadine: 67.6g of β-cyclodextrin is mixed with 44g of water to form a pasty mixture. Then, 12g of fexofenadine is added to the mixture, followed by 31 g of water, the addition of the water having the purpose of avoiding the hardening of the mixture. Finally, the rest of fexofenadine is added, followed by the rest of water.

215.6g of glycerol and 0.8g of surfactant are then added to the mixture and mixed. The mixture is heated at 40°C. When the mixture has reached 40°C, 8g of high(methyl)pectin is added to the mixture. 2g of sucralose and 2g of lime flavour are added to the mixture, which is then heated to a temperature of 70°C. The pH is adjusted with a solution of citric acid 10% w/w.

The resulting mixture is the pharmaceutical composition according to the invention. Said composition is then poured into plastic or metal-laminated moulds. An example of blister pack is illustrated in Figure 2. In this figure, the blister pack 1 comprises two parallel rows of cavities 2 and is reinforced by a central rib 3. Each cavity is cup-shaped. The maximum diameter of the cup (at the surface of the blister pack 1 ) is about 20 mm and its depth is about 6.5 mm.

Each cavity is filled with 1.5g (corresponding to a dose of 60mg of fexofenadine hydrochloride) of the pharmaceutical composition 4, which is liquid. The blister pack is then thermally sealed with a foil cover sheet, and the pharmaceutical composition is cooled until the composition gels.

Once gelled, the pharmaceutical composition according to the invention can be easily turned out of the moulds to form a moulded unit and is easily grasped, as shown in figure 1 .

3. Water activity

The pharmaceutical composition according to the invention does not require the use of any preservatives. In particular, the addition of parabens can be avoided. This feature can be evidenced by measuring the water activity of the pharmaceutical composition according to the invention.

The water activity is measured by using a Rotronic Hygrolab device. This measurement is not carried out on an entire moulded unit, but on a sample portion of said unit, the sample having the following dimensions: 20mm in diameter (x) 2-3 mm in thickness. This portion is sliced from the moulded unit. The sample is then introduced into the measuring cell. After a short equilibrium time, the value can be read.

The water activity as measured is: 0.58. This result is below a water activity of 0.61 , which represents the upper limit, above which a preservative is required. 4. Hardness

As mentioned above, the moulded units are easily grasped. To evaluate this feature, the hardness of said units has been measured with a texture analyser.

Method:

The texture analyser is a TA.XT.plus Texture Analyser, from Stable Micro Systems® equipped with a 6 mm diameter cylinder probe with a 5kg load cell.

The parameters of the texturometer are as follows:

Mode: Measure force in compression

Test speed = 1 mm/s

Distance = 1 mm

Trigger type = Auto - 5.0g

The measurement is performed on a sample constituted by a moulded unit. This moulded unit is positioned so as the surface which was in contact with the cup of the blister pack is facing upwards. Once the probe has touched said surface of the sample, it penetrates it until a depth of 1 mm is reached. At this depth, the load is measured and this value represents the hardness of the sample. To assess the reproductibility of the measurement, 10 samples are tested.

The hardness measured is comprised in the range from 50 to 100g. It has been determined that a unit having a hardness below 30g is not graspable. This confirms that the moulded units of the pharmaceutical composition according to the invention are graspable.

Claims

A pharmaceutical composition for oral administration comprising :

1 -3.5% wt of high(methyl)pectin,

40-68% wt of glycerol,

16-29% wt of water,

0-1 % wt of at least one surfactant,

3-5 % wt of fexofenadine or a pharmaceutically acceptable salt thereof,

12-24 % wt of a pharmaceutical excipient able to complex with the fexofenadine or its pharmaceutically acceptable salt thereof,

0-5% wt of at least one other ingredient selected in the group consisting of: sugar substitutes, flavouring agents and/or colouring agents,

the weight percentages being relative to the total weight of the composition, and the pH of the composition being within the range of 2.8 to 3.2.

The pharmaceutical composition of claim 1 , having a water activity of less than

0.61 .

The pharmaceutical composition of claim 1 or 2, wherein the pH of the composition is adjusted by adding an acid to the composition.

The pharmaceutical composition of any one of claims 1 to 3, wherein fexofenadine is fexofenadine hydrochloride.

The pharmaceutical composition of any one of claims 1 to 4, wherein the pharmaceutical excipient is β-cyclodextrin.

The pharmaceutical composition of any one of claims 1 to 5, which is chewable.

The pharmaceutical composition of any one of claims 1 to 6, for use as a medicament.

The pharmaceutical composition of any one of claims 1 to 7, for the treatment of an allergy.

A process for preparing a pharmaceutical composition of any one of claims 1 to 8, comprising the following steps:

i) Mixing fexofenadine or a pharmaceutically acceptable salt thereof, the pharmaceutical excipient, glycerol and water,

ii) After heating, adding the high(methyl)pectin, iii) Adding the sugar substitute(s), flavouring agents and/or colouring agent(s), if any

iv) Heating the resulting mixture of step (ii) to a temperature ranging from 60°C to 90°C,

v) Adjusting the pH with an acid,

vi) Forming and cooling the composition until gelling occurs.

10. The process of claim 9, wherein step (i) is performed as followed:

a) Mixing the fexofenadine, or a pharmaceutically acceptable salt thereof, and the pharmaceutical excipient with water,

b) Adding the glycerol and the surfactant to the resulting mixture of step (a).

1 1 . The process of claim 10, wherein step (a) is performed as followed:

The pharmaceutical excipient is first mixed with a part of water in order to obtain a mixture having a pasty consistency;

A part of the fexofenadine, or a pharmaceutically acceptable salt thereof, is added to the mixture having a pasty consistency followed by another part of water;

Finally, the rest of the fexofenadine, or a pharmaceutically acceptable salt thereof, is added, followed by the rest of water.

12. The process of claim 9, wherein step (i) is performed as followed:

I. Mixing the water with the glycerol,

II. Adding the fexofenadine, or a pharmaceutically acceptable salt thereof, and the pharmaceutical excipient to the mixture.

13. The process of claim 12, wherein in step (II), the fexofenadine, or a pharmaceutically acceptable salt thereof, and the pharmaceutical excipient are added to the mixture under a powder form, said powder comprising the fexofenadine, or a pharmaceutically acceptable salt thereof, complexed with the pharmaceutical excipient.