WO2008090076A1 - Oral pharmaceutical compositions in the form of stabilised aqueous solutions - Google Patents

Abstract

The invention relates to a liquid pharmaceutical composition, in the form of a suspension containing a micronised powder of an active ingredient in a physiological liquid medium acceptable for oral administration, which is stable in time.

Description

 ORAL PHARMACEUTICAL COMPOSITIONS IN THE FORM OF STABILIZED AQUEOUS SUSPENSIONS

The present invention relates to novel pharmaceutical compositions for oral administration, in the form of an aqueous suspension of a micronized powder of active principle.

Oral medication is the preferred route, thanks to its easy setting. Most of the time the drug is given as a tablet. There are however cases where the compressed form is not the most practical. For example, if the dosage is to be finely adapted to the subject being treated, for example in the case of pediatric or veterinary medicinal products, or if it is difficult to swallow a tablet, in the case of children, animals, persons with inflammation throat. The liquid form may then be more suitable. However, if the active ingredient is not soluble, it may be necessary to provide a suspension of the powder in a dispersion medium that does not have a poor appetite. The aqueous medium is the medium of choice for dispersing the active ingredient powder and obtaining an easily administrable suspension (low viscosity, neutral taste, absence of intrinsic toxicity).

The preparation of aqueous suspensions of powders presents difficulties that are often difficult to overcome. One of them is the colloidal stability of the suspension. It is indeed necessary to avoid as much as possible that the suspension sediment, and if sedimentation appears, the resuspension must be as fast as possible by simple manual shaking of the bottle. Otherwise, the risk of misdiagnosis during use is great, which is unacceptable for a drug. On the other hand, the suspension is often dosed using a dropper or a dosing syringe. The suspension must therefore be fluid enough to flow freely from the metering device. In addition, it is preferable to avoid for practical reasons that the solution wets too much the walls of the container and the measuring device, to prevent too large quantities remain on the walls (wrong dosage, loss of product, etc. .). Finally, it is necessary to avoid that the product does not foam, which would make the dosage not precise and uncertain.

Among the drugs that can benefit from a presentation in liquid form are anti-inflammatory drugs. Their dosage must be precise, it must be adapted to the weight of the subject treated, and if they are given in the case of inflammation of the upper oral sphere, it is difficult to swallow a solid form. On the other hand, most anti-inflammatory molecules are poorly soluble in water. The preparation of an aqueous liquid form of anti-inflammatory compounds therefore requires the preparation of stabilized aqueous suspensions from micronized powder of an anti-inflammatory active principle, and is subject to the difficulties mentioned above. The anti-inflammatory molecules that can benefit from the present invention are, for example, nonsteroidal anti-inflammatory drugs (NSAIDs).

Several strategies are known to those skilled in the art to obtain such suspensions or dispersions of stable powders. It should be kept in mind that a suspension of powder in a liquid is thermodynamically unstable, and that only the kinetics of sedimentation can be modified. It is therefore always a pseudo-stability. Four parameters can be used to slow down the sedimentation rate: the size profile of the powder, the difference in density between powder and dispersion medium, the interactions between particles and the viscosity of the dispersion medium.

The size specifications of a powder are often given by the proportion below a particle size threshold. Thus it can be read that a stable suspension of an anti-inflammatory principle such as meloxicam is obtained from the active ingredient having at least 90% of particles smaller than 50 microns in size. Such an approach is too much simplification of reality, and generally leads to disappointments. A number of other parameters must be considered. At first glance, the size of the particles affects the sedimentation rate by the effect of Brownian motion, which is all the more effective when the particles are fine. Other phenomena are to be considered, in particular the depletion interactions (Bibette J. et al., Phys Rev. Lett., 65, 2470 - 2473 (1990)) which intervene as soon as the population of the particles is not homogeneous, and especially if it is bimodal. It is therefore preferable to specify the size profile of the particle population, rather than a simple threshold value or an average. In addition, the shape of the particles must be taken into account. The interactions between particles will be different depending on whether the particles are spheroids or have a marked anisotropy. Often the non-taking into account of the shape of the particles leads to erroneous measurements of size profile, in particular if one uses a method of diffusion of the light, since the intensity diffused by a particle depends inter alia on the factor of size. form.

The sedimentation rate of course depends on the difference in density between the powder particles and the dispersion medium. If it is difficult to play on the density of the active ingredient, on the other hand one can adapt the density of the medium of dispersion to bring it closer to that of the powder. Insofar as one does not want to fundamentally modify the dispersion medium, this can be obtained by dissolving solutes. The limit is the acceptability of these solutes in pharmaceuticals, as well as the taste they can impart to the product (salty taste for example). The suspended particles interact with the solvent and with each other. If the grains are small enough, these interactions can play a role in the phenomena of aggregation and flocculation, and thus on sedimentation. This is particularly true of electrostatic interactions that have a longer range than Van der Waals interactions. The presence of electrolyte in the solution will screen the electrostatic interactions, and thus reduce the possible repulsive interactions. In practice, solubilization of electrolyte may therefore have a beneficial effect on the density, but may lead to an aggregation phenomenon, which is not desired.

The stability of the suspension will also depend on the interactions between the powder grains and the dispersion medium. The wettability of the powder and the wetting nature of the medium will make it possible to modify the colloidal stability of the suspension. While it is not always easy to modify the surface state of the powder, the wetting nature of the medium can be modified by adding surfactants. Several pitfalls can come from the use of surfactants. For example, if surfactants with too much detergency are used, foaming effects may be desirable. The choice of the surfactant and its dosage are therefore delicate. It is even often preferable to avoid the addition of such compounds in pharmaceutical compositions.

The last adjustable parameter is the viscosity of the medium. It is easily understood that an increase in the viscosity of the medium will reduce the sedimentation rate. In this regard, US Pat. No. 5,112,604 discloses, for example, a suspension in the form of a syrup comprising a 1: 1 mixture of 70% sorbitol and syrup as suspension medium, microgranules with continuous release of theophylline or of acid. salicylsalicylic whose sizes are less than 125 .mu.m, silica, a polysaccharide gum, and a surfactant or a mixture of surfactants for modifying the wettability of the powder. The addition of this dispersion medium consisting of the 1: 1 mixture of sorbitol and syrup makes it possible to increase the viscosity substantially, to maintain the suspension in stable and uniform form, and thus to limit the sedimentation phenomena for about 90 days. . However, this sharp increase in viscosity is not always desirable, since the suspension must keep practical characteristics of implementation, for example for the dosing with a drop-count or syringe. Moreover, if the increase in viscosity reduces the rate of sedimentation, it does not prevent sedimentation, but actually makes it more difficult to resuspend. Moreover, the formulation as described in US Pat. No. 5,112,604 requires the use of surfactants, such as simethicone, in order to modify the surface tension parameters of the microgranules and thereby will make it possible to improve the interaction between the powder and dispersion medium. This addition has the disadvantage of causing foam phenomena during manufacture and use, and requires the addition of compounds to prevent this formation of foam. However, the addition of surfactants is not satisfactory from a pharmaceutical point of view because the surfactants are often allergenic and irritating to the mucous membranes.

Alternatively, it has been proposed to modify the three-dimensional structure of the suspension in order to avoid phase shift or sedimentation phenomena. In this respect, US Pat. No. 6,184,220 describes the production of stable dispersions of micronized meloxicam in the presence of silicon oxide. It is then necessary, during the dispersion of the silicon oxide, to subject it to shear sufficiently large to create a three-dimensional so-called "siloid" structure which traps the grains of active principle and thus prevents sedimentation. This three-dimensional siloid structure seems to act as an effective stabilizer of sedimentation over time since the volume of this three-dimensional structure only decreases by 20% after several months of storage without the appearance of sedimentation. However, a significant disadvantage of the compositions of US Pat. No. 6,184,220 remains the need to apply significant shear forces during the dispersion of silicon oxide using a specific material, for the formation of a structure or three-dimensional siloid network. This step clearly complicates the manufacture of the product, and above all is not necessarily reproducible from one batch to another. In particular, from a pharmaceutical point of view, it is very difficult to verify the obtaining of this particular structure if it is later by its apparent consequences on the long-term stability. In addition, the parameters allowing the characterization of this three-dimensional structure, such as the network dimension, the symmetry, etc., are difficult to measure, which makes it difficult to characterize the quality and reproducibility of the pharmaceutical batches at the same time. industrial scale.

Surprisingly, it has been discovered that the selection of particular natural polysaccharide polymers used in combination with silicon oxide makes it possible to obtain excellent long-term stability of suspensions: approximately 36 months at 20 ^° C. This stability is obtained without however requiring an additional step of dispersion of silicon oxide by shear for the formation of a three-dimensional siloid structure, and surprisingly does not require either addition of surfactants. The particular natural polysaccharide polymers used according to the present invention are not modified by the addition of ether function at the side chains, and are selected from carrageenates, xanthans, guars, and derivatives of alginic acid. .

The particular combinations of these natural polysaccharide polymers and silicon dioxide without siloid three-dimensional structure according to the present invention thus make it possible to stabilize the suspensions of micronized powder of anti-inflammatory active ingredient over time, without increasing the viscosity of the suspension. . As indicated above, the use of these particular polysaccharide gums according to the invention makes it possible to avoid the addition of surfactants and / or anti-foaming compounds. In addition, the polysaccharides according to the present invention are natural, which is important in terms of safety. Indeed, avoiding the addition of compounds from chemical synthesis for which the suspicion of causing allergic reactions, for example, is becoming larger.

The present invention therefore constitutes an important advance for the preparation of micronized powder suspensions of active ingredients, since the additional step of dispersion by shearing to obtain a three-dimensional siloid structure is no longer necessary without for all that addition of surfactants is made mandatory. The suspension is, on the contrary, simply obtained by mixing or homogenization of the various constituents with stirring, and does not require any particular equipment or the application of a specific shear. It is therefore possible to control the reproducibility of pharmaceutical batches. It retains a homogeneous appearance without phase shift and sedimentation over very long periods of 18 months to 36 months at 20 ^° C.

Summary of the invention

The present invention relates to a liquid pharmaceutical composition intended for stable oral administration comprising a suspension of a micronized powder of a pharmaceutical active ingredient dispersed in a physiological medium, and 0.01 to 1% by weight of a polysaccharide polymer chosen from carrageenans, xanthanes, guars and derivatives of alginic acid, and whose viscosity of the suspension obtained is less than 30 cP (centipoise) at 20 ^° C. In addition, said compositions may contain 0.1 to 5% or 0, 1 to 2% by weight of a micronized powder of silicon oxide. The compositions according to the present invention are particularly useful for the formulation of active ingredients that are poorly soluble, such as for example those whose solubility is less than 500 mg / L in the dispersion medium at room temperature. We particularly want to talk about nonsteroidal anti-inflammatory compounds, such as the enolcarboxamide acid derivatives, and more particularly meloxicam.

The compositions according to the present invention may also comprise conventional components of pharmaceutical formulations which are not essential for obtaining the suspension according to the invention, such as preservatives or antimicrobial agents. However, the pharmaceutical compositions according to the present invention do not require the addition of surfactants or anti-foaming agents. They also have characteristics of taste and palatability so that it is not necessary to use additional aromatic agent.

The present invention also relates to a process for preparing a stable aqueous suspension of micronized powder in which the colloidal stability is obtained by adding an amount of between 0.01 and 1%, or between 0.1 and 1%. or between 0.2 and 1% of a polysaccharide polymer selected from carrageenans, xanthans, guars and alginic acid derivatives, and whose viscosity of the suspension is less than 30 cP (centipoise).

Detailed description of the invention

The invention consists of a liquid pharmaceutical composition, in the form of a suspension of a micronized powder of an active ingredient in a liquid physiological medium acceptable for oral administration, stabilized so as not to present sedimentation and this over long storage periods of not more than 36 months at 20 ^° C. The surprising effect is that the colloidal stability is obtained by the addition of a precise amount of a particular polysaccharide polymer, while retaining a acceptable viscosity of the suspension less than 30 cP, or between 18 and 30 cP (centipoise), without it being necessary to obtain a structuring in the form of a three-dimensional network by application of a large shear during the incorporation micronized powders of metal oxide and without adding surfactant compounds. The compositions according to the present invention are therefore preferably free of surfactants.

By stable or stabilized composition is meant a composition whose sedimentation rate is sufficiently low so that no sedimentation occurs during the desired shelf life, that is to say up to 36 months. Sedimentation is detected by simple visual observation of the appearance of a phase shift. Indeed, the phenomenon of sedimentation begins with the formation of a clear ring on the surface of the suspension which progresses until the observation of two distinct phases: a transparent phase and a charged phase. No phase separation or phase shift has occurred throughout the lifetime of the pharmaceutical compositions of the invention. More specifically, the pharmaceutical compositions according to the present invention are stable for the shelf life of the drug, i.e., for periods of about two to three years, or depending on the consumption of the product, ranging from a few weeks to several months, and up to three years, as shown in the Examples below.

The present invention is particularly applicable to the form of suspension of active pharmaceutical ingredients for which the oral administration of tablets is not desirable or impractical. It is particularly applicable to the active ingredients for which the dosage must be finely adapted to the patient, which can be obtained by a liquid form easily dosable. These are, for example, pediatric medicines and veterinary pharmacy, for which the weight of the subject varies in large proportions, and for which the administration of tablets is not very suitable. The suspension according to the invention obviously applies to the non-soluble active ingredients in the chosen physiological dispersion medium. Indeed solubility, even partial, of the active ingredient in the dispersion medium may cause solubilization and recrystallization depending eg temperature changes, which will change the size profile of the powder grains, which is not not desirable. In general, it can be considered that a solubility of less than 500 mg / l at room temperature is sufficiently low to prevent this phenomenon.

Colloidal stability is an essential criterion for the quality of the pharmaceutical product. It has been observed, after numerous tests comparing different additives, at different concentrations, that excellent colloidal stability can be obtained. suspensions of micronized powders of pharmaceutical active ingredients, by adding precise amounts of particular polysaccharide polymers in the dispersion medium. The polysaccharides used for the preparation of the stable suspensions of powder of active principle are natural soluble polysaccharides which are not modified by ether functions at the level of the side chains. These polymers are well known in the art (ZATZ JL: Applications of gums in pharmaceuticals and cosmetic suspensions, Ind Eng Chem Prod Res Dev 1984; 23: 12-16; Bumphrey G: Extremely useful new suspending agent: Pharm J 1986; 237: 665). They belong to the families of carrageenans, xanthans, guars, and alginates. The family of xanthan gums is particularly suitable for obtaining a long-term colloidal stability for the suspensions according to the invention. Mass proportions relative to the volume of between 0.01% and 1% of the particular polysaccharide polymers according to the invention are used.

Despite the known viscosifying effect of the addition of polysaccharides, the stabilization of the suspension is not due to a noticeable increase in viscosity. Stable suspensions were obtained with viscosities not exceeding 30 cP (centipoise), between 18 cP and 30 cP (centipoise) at 20 ^° C. The measurement of the viscosity is carried out according to techniques well known to those skilled in the art. , using for example a rheoviscosimetre. Specifically, 2 ml of the pharmaceutical composition according to the present invention are introduced into the space between the flat disk and a cone 60mm in diameter. The viscosity of the composition is then determined by applying a force of between 1000 and 2000 s ^-1 at 20 ^° C.

On the other hand, as demonstrated in the examples below, other hydrophilic polymers, such as in particular cellulose ethers, commonly used to stabilize suspensions do not give the effect obtained with the polysaccharides according to the invention. Preferably, the compositions according to the present invention do not include derivatives of cellulose ethers. The polysaccharide polymers according to the present invention are distinct from cellulose ether derivatives. The pharmaceutical compositions also comprise micronized powders of metal oxides, in particular silicon, titanium or aluminum. Preferably, micronized powders of silicon oxide are used. The micronized powders of metal oxides are added by simple mixing to the suspension of the active ingredient and the polysaccharide polymer without resorting to shears. important. The micronized metal oxide powders such as silicon oxide are added by simple homogenization at about 300 to 500 rpm. The compositions according to the present invention comprise from 0.1 to 5%, from 0.1 to 2%, from 0.5 to 2%, from 1 to 2%, or from 1.5 to 2% by weight of powder. micronized silicon oxide. The latter does not have a three-dimensional siloid structure. Indeed, as previously described, the silicon oxide according to the invention is dispersed by simple homogenization without the application of significant shear forces for the formation of the structure or three-dimensional network as described inter alia in the patent US 6,184,220. The pharmaceutical compositions according to the invention are particularly applicable to the oral formulation of nonsteroidal anti-inflammatory drugs (NSAIDs). Many molecules have been developed and are used as NSAIDs. By way of examples, the following classes may be mentioned without limitation to the scope of the invention: • derivatives of propionic acid (ibuprofen, ketoprofen, carprofen, flurbiprofen, fenoprofen, fenbufen, etc.) and their salts.

• derivatives of acetic acid (diclofenac, fenclofenac, indomethacin, ibufenac, etc.) and their salts

• derivatives of fenamic acid (nifluminic, mefenamic, meclofenamic, tolfenamic and flufenamic acids) and their salts.

• derivatives of the enolcarboxamide acid (piroxicam, tenoxicam, lornoxicam and meloxicam) and their salts.

• acetyl salicylic acid and its salts.

These compounds are known to those skilled in the art, who will know how to implement them at the required dosage. In general, these compounds require dosages of the order of 25 to 500 mg per dose for an adult. The concentration of active ingredient in the suspension object of the present invention will therefore be adapted so as to provide the required dose of active ingredient in a volume of suspension acceptable for oral intake (of the order of 1 to 10 mL). In veterinary pharmacy, the dosage is usually given per kg of live weight of the animal. The dosage of these compounds ranges from 0.1 mg / kg to 10 mg / kg. Since the volume to be administered is of the order of 1 to 10 ml, the pharmaceutical compositions according to the invention may contain from 0.1 mg / ml to 10 mg / ml of the active ingredient, depending on the active principle and the type of animal. for which they are intended. These compounds are obtained in pure form in powder form. The particle size profile of the active ingredient powder can be adapted so as to obtain powders whose size profile is homogeneously unimodal and centered on a value of less than 10 μm, thus avoiding the interactions between particles of the depletion interaction type. Micronization is a well known conventional technology in the field of pharmacy (Rasenack N and Muller BW Micron-size drug particles: common and novel micronization techniques, Pharm Dev Technol 2004, 9 (I): 1-3). Preferably, the form factor is close to the isotropy, or has an anisotropy factor of less than 2 (ratio of the lengths of the main axes). This can be easily observed by optical microscopy.

Dispersion media are well known to those skilled in the art. These media are chosen for their safety and acceptability in terms of taste and texture. These are generally physiological and inert media, that is to say that they do not affect the chemical stability of the active ingredient, whether by hydrolysis or by oxidation or by any other form of degradation. By way of examples, mention may be made of aqueous-based media such as water and demineralised water, added for example with polyol-based mixtures.

In the case of water-based medium, the pH may be adjusted to avoid solubilization of the active ingredient, but also to prevent degradation. Simple considerations of differences between chemistry in a homogeneous medium and in a heterogeneous medium suggest to those skilled in the art that the environments in which the active ingredient is very sparingly soluble are less conducive to causing its degradation.

Since many of the active ingredients mentioned are acid derivatives, their solubility depends on the pH of the medium. This adjustment is well known in the art and can be achieved by the use of acceptable buffers for oral pharmaceutical applications, for example phosphate, citrate, glycine, borate or phthalate buffers. In a particular embodiment, the compositions comprise meloxicam as the active principle, and the pH is adjusted to a pH of between 2 and 4, between 2 and 3, or between 3 and 4, by means of a phosphate buffer or a citrate buffer or a mixture of both for example.

Other compounds may be added to the compositions according to the invention, among the compounds conventionally used to adapt the physical and chemical properties of the pharmaceutical compositions. The compositions according to the present invention may optionally contain other compounds intended to improve the texture, to ensure microbial preservation, to reduce the effects of oxidation and / or to ensure the chemical stability of the active ingredient and to prevent its dissolution. It is well known to add in the medium, significant proportions of nonaqueous polar solvents, or nonionic solutes, such as sugar derivatives. Thus it can be added to the formulation of solutes such as glucose, fructose, mannitol, sorbitol, or liquids such as glycerol or xylitol, without this list being limiting. Non-aqueous polar liquids of up to 50% of the dispersion medium are generally used, or even 70%. Similarly solutes can be introduced in proportions of up to 20 or 30% by weight of the total. The pharmaceutical compositions according to the invention have a very satisfactory palatability that is entirely compatible with oral administration, and therefore do not require the addition of an aromatic agent.

Furthermore, the compositions according to the present invention do not require the addition of surfactant and / or antifoam agent, which constitutes an important additional advantage. They may therefore be devoid of surfactant and / or anti-foaming agent.

Given the components of the pharmaceutical composition according to the invention, and considering that it is administered orally, it will be used for several days from the same packaging, it is essential to protect the composition against the growth of microbial flora . Many compounds are used in pharmaceutical compositions to achieve this goal. By way of example, mention may be made of the derivatives of formic, sorbic, benzoic or propionic acids. Sodium benzoate is particularly well suited for this purpose. It is used in low proportion, less than 1% in general, or between 0.1 and 1% by weight, and shows excellent safety.

According to a preferred embodiment, the present invention relates to a stabilized pharmaceutical composition of meloxicam. According to this embodiment, the composition preferably comprises a polysaccharide of xanthan gum type. In addition, the stable liquid meloxicam composition comprises micronized metal oxide, particularly colloidal silica or silicon oxide. The meloxicam compositions according to this embodiment may optionally include other pharmaceutical ingredients for improving texture, chemical stability and microbial preservation. In particular aqueous suspensions have a pH of between 2 and 4, between 2 and 3, and between 3 and 4, adjusted for example by a buffer phosphate and or citric. Preferably, the compositions contain from 0.05 to 1% of meloxicam, from 0.01 to 1% of xanthan gum, from 0.5 to 2% of colloidal silica, from 0.1 to 1% of sodium benzoate as preservative, glycerol, xylitol and sorbitol in an overall proportion of between 50 and 70%, the proportions being expressed in percentages by weight, fully fall within the scope of the invention. Meloxicam can be used in proportions between 0.05 and 1%, between 0.1 and 0.75%, between 0.1 and 0.5%, between 0.1 and 0.4%, between 0 and 1 and 0.3%, or between 0.1 and 0.2%, and preferably in a proportion of about 0.15%. Xanthan gum can be used in proportions between 0.1 and 1%, between 0.2 and 0.8%, between 0.2 and 0.7%, between 0.2 and 0.6%, between 0.2 and 0.5%, between 0.2 and 0.4%, or between 0.2 and 0.3%, and preferably in a proportion of about 0.25%. Despite the high proportions of xanthan used in the compositions according to the invention, they retain a viscosity that is stable over time, namely over 18 months or 36 months at 20 ^° C., which does not exceed 50 cP or 30 cP at 2O ⁰ C. The colloidal silica may be used in proportions of between 0.5 and 2%, between 1 and 2%, between 1.5 and 2%, and preferably in an amount equal to about 2%. The preservative sodium benzoate can be used in proportions between 0.1 and 0.8%, between 0.1 and 0.6%, between 0.1 and 0.4%, or between 0.1 and 0.2%, and preferably in a proportion of about 0.15%. Moreover, it is remarkable that the quality of the suspension leads to an appetizing product without the need to add a flavor, as is generally done.

According to a preferred embodiment, the stabilized pharmaceutical compositions comprise a stabilized suspension of meloxicam whose therapeutic effects are well known to those skilled in the art, and are therefore useful as medicaments. They can be administered orally, for example for the treatment of non-human animals.

Also, the present invention relates to a method of treatment comprising administering a therapeutically effective amount of the previously described pharmaceutical compositions. Finally, the subject of the present invention is the use of oral pharmaceutical compositions for the preparation of a medicinal product intended for the treatment of, for example, non-human animals.

In general, in animal therapeutics, the veterinarian or the breeder can determine the posology which he considers the most appropriate according to a preventive or curative treatment, depending on the age, the weight of the animal, and other factors specific to the subject to be treated.

Oral compositions according to the present invention may be administered directly into the oral cavity or mixed with animal feed. Assays are done through delivery and dosing systems known to those skilled in the art.

According to a second aspect, the present invention also relates to a process for preparing a stable suspension of micronized pharmaceutical powder, in which the colloidal stability is obtained by the addition of a small amount of polysaccharides, without the viscosity being reduced. 'increases beyond 30 cP, or more than 25 cP (centipoise) at 2O ⁰ C and not using surfactants. Preferably the viscosity measured at 20 ^° C. remains below 30 cP or at 20 cP, or is between 18 and 30 ° C., and is stable over time, during long periods of storage of the compositions according to the present invention up to at 18 months and 36 months, as shown in the Examples below.

It is remarkable to note that the stability of the suspensions obtained according to the invention does not require particular actions during their preparation, and in particular does not require significant shearing and formation of a three-dimensional structure. Indeed, the suspension according to the invention is obtained by simply dissolving the components with stirring successively, starting by dissolving the polysaccharide which may require a slight heating of the solubilization medium (40 ^° C. for example). It is known to those skilled in the art that the solubilization of these polymeric compounds can take a long enough time (1 to 2 hours) and can be accelerated if the powder is poured slowly into the solubilization medium stirred sufficiently to form an important vortex. This prevents the formation of powder clusters which are then long to solubilize. The addition of the various components (buffer, etc.) can be done at the beginning or at the end of operations. The addition of the micronized active ingredient and optionally the micronized metal oxide is carried out at room temperature with stirring so as to avoid the formation of lumps or lumps. It may be advantageous to accelerate the suspension and to ensure good homogeneity of the mixture of deflocculation of the suspension using an emulsifier, optionally under vacuum, which has the additional advantage of avoid the imprisonment of air bubbles. The Deflocculation is carried out with a fast stirrer equipped with a deflocculating blade, but it is not necessary to use a rotor / stator type system which induces a strong local shear, which can be detrimental to the integrity of the polymers. A simple homogenization of the micronized powders of silicon oxide at about 300 rpm is carried out. As shown in the examples below, only the suspensions produced on an industrial scale of approximately 4000L require the application of a greater force of 3000 rpm for the incorporation of the polysaccharides according to the invention, such as gum xanthan, but this is done before the incorporation of the micronized silicon oxide powders which are still homogenized with low shears of 300 rpm.

Thanks to the low viscosity of the suspension according to the invention, it is easy to use it to administer the drug, with a precise dosage, obtained for example with a dropper or a dosing syringe. The suspension having a very good homogeneity and low viscosity, and not having a wetting power of the walls of the container or the syringe too important, the dosage is particularly easy and accurate. In addition the absence of surfactants such as lauryl sulfate or polysorbates avoids any phenomenon of foam, both during manufacture and during use. It is therefore not necessary to add an anti-foam compound, such as a simethicone derivative, which is a further advantage of the invention. According to a third aspect, the subject of the present invention is a system for delivering predetermined and precise quantities of the suspensions according to the invention. These delivery systems may be for example in the form of drop-count, pump, syringe, pipette or any other means or apparatus suitable for delivering a predetermined volume of the suspensions according to the invention. These delivery means may be mechanical, automatic, electronic, programmable, or any other type of well-known operation. With these means or delivery devices, precise doses of oral suspensions can be prepared in a convenient, fast and highly reproducible manner. Examples

EXAMPLE 1 Suspension of Meloxicam Containing Carboxy Methyl Cellulose

The meloxicam suspension comprises the ingredients as listed in Table 1 below.

Table 1

After a week of storage on a vibrating table, two separate phases appear in the suspension.

EXAMPLE 2 Suspension of Meloxicam Containing Xanthan Gum

The meloxicam suspension comprises the ingredients as listed in Table 2 below.

Table 2

Les suspensions telles que listées dans les Tableaux 1 et 2 sont obtenues par le procédé de fabrication comprenant les étapes 1 à 6 suivantes:

The suspensions as listed in Tables 1 and 2 are obtained by the manufacturing method comprising the following steps 1 to 6:

Step 1: Sodium benzoate and xylitol are added to the mixture of glycerol, sorbitol, and water by mixing at 300 rpm with a helicoidal mixer for 10 min;

Step 2: The mixture obtained is then heated to 30 ^° C. and the sodium carboxymethylcellulose or the xanthan gum is added gently with stirring at 300 rpm using a helicoidal mixer and homogenized in a turbine mixer. for 30 minutes; Step 3: After homogenization of sodium carboxymethylcellulose or xanthan gum, citric acid is added;

Step 4: The meloxicam and the silicon dioxide are then added with stirring at 300 rpm using a propeller mixer and a turbine mixer for 10 minutes; Step 5: The final volume of the suspension is adjusted and mixed for 30 minutes; and Step 6: The suspension is adjusted to a volume of 30OmL with deionized water and homogenized for 10 minutes at 3000 rpm.

Long-term stability has shown that the suspension comprising the ingredients as listed in Table 2 shows no phase shift after one week of storage when placed on a vibratory table system, and remains stable over time, even on longer periods of several months, up to 36 months at 20 ^° C., in storage in flasks.

Example 3: Stability Studies

Three batches of the meloxicam suspension according to Example 2 were tested for stability for long periods of storage in glass vials. The results are given in Table 3 below. Table 3

The results as shown in Table 3 clearly show that the meloxicam compositions according to the present invention retain excellent stability over long storage periods of up to 18 months and 36 months without the occurrence of any phase shift phenomena. They also retain a very satisfactory homogeneous appearance for the duration of storage at 20 ^° C.

Example 4: Stabilized meloxicam suspensions The meloxicam suspensions include the ingredients as listed in Table 4 below. Table 4

The suspensions as listed in Table 4 are obtained by the manufacturing method comprising the following steps 1 to 6:

Step 1: Sodium benzoate and xylitol are added to the mixture of glycerol, sorbitol, and water by mixing at 300 rpm using a helical blender for

10 minutes;

Step 2: The mixture obtained is then heated to 30 ^° C. and the xanthan gum is added slowly with stirring at 300 rpm using a helicoidal mixer and homogenized in a turbine mixer for 30 minutes;

Step 3: After homogenization of the xanthan gum, the citric acid is added;

Step 4: The meloxicam and the silicon oxide are then added with stirring at 300 rpm using a propeller mixer and a turbine mixer for 10 min;

Step 5: The final volume of the suspension is adjusted and mixed for 30 minutes; and

Step 6: The suspension is adjusted to a volume of 30OmL with demineralised water and homogenized for 10 minutes at 3000 rpm.

Example 5: Stabilized meloxicam suspensions

The meloxicam suspension comprises the ingredients as listed in Table 5 below. Table 5

The suspensions as listed in Table 5 are obtained by the manufacturing method comprising the following steps 1 to 6: Step 1: Sodium benzoate and xylitol are added to the mixture of glycerol, sorbitol, and water by mixing at 300 rpm using a helical mixer for

10 minutes;

Step 2: The mixture obtained is then heated to 30 ^° C. and the xanthan gum is added gently with stirring at 300 rpm using a helicoidal mixer and homogenized in a turbine mixer for 30 minutes. ;

Step 3: After homogenization of the xanthan gum, the citric acid is added;

Step 4: The meloxicam and the titanium or aluminum oxide are then added with stirring at 300 rpm using a propeller mixer and a turbine mixer for 10 minutes; Step 5: The final volume of the suspension is adjusted and mixed for 30 minutes; and

Step 6: The suspension is adjusted to a volume of 30OmL with demineralised water and homogenized for 10 minutes at 3000 rpm. Example 6 Preparation of stabilized meloxicam suspensions in 4000L industrial batches

Suspensions of meloxicam in 4000L industrial batches are prepared and include the ingredients as listed in Table 6 below. Table 6

The industrial suspensions (4000L) as listed in Table 6 are obtained by the manufacturing process comprising the following steps 1 to 6:

Step 1: Sodium benzoate and xylitol are added to the mixture of glycerol, sorbitol, and water by mixing at 300 rpm with a helicoidal mixer for 10 min;

Step 2: The mixture obtained is then heated to 30 ^° C. and the xanthan gum is added slowly with stirring at 3000 rpm using a helicoidal mixer and homogenized in a turbine mixer for 30 minutes; Step 3: After homogenization of the xanthan gum, the citric acid is added;

Step 4: The meloxicam and the silicon oxide are then added with stirring at 300 rpm using a propeller mixer and a turbine mixer for 10 min; Step 5: The final volume of the suspension is adjusted and mixed for 30 minutes; and Step 6: The suspension is adjusted to a volume of 30OmL with deionized water and homogenized for 10 minutes at 3000 rpm.

For the preparation of industrial batch suspensions of about 4000L, xanthan gum is incorporated with a high shear force ie at about 3000 rpm, but this is achieved prior to incorporation of the silicon oxide that is incorporated by simple homogenization at 300 rpm which does not modify the three-dimensional structure of the suspension.

Claims

1. liquid pharmaceutical composition intended for oral administration, comprising a suspension of a micronized powder of pharmaceutical active ingredient dispersed in a physiological medium, 0.01 to 1% by weight of a polysaccharide polymer chosen from carrageenans, xanthanes, guars and derivatives of alginic acid, and 0.1 to 2% by weight of a micronized powder of silicon oxide. 2. A pharmaceutical composition according to claim 1, characterized in that the viscosity of said slurry is less than 30 cP at 2O ⁰ C. 3. Liquid pharmaceutical composition according to claim 1 or 2, characterized in that it further comprises 50 to 70% of a mixture of polyols. 4. Pharmaceutical composition according to any one of the preceding claims wherein the active ingredient has a solubility of less than 500 mg / L in the dispersion medium at room temperature. 5. Pharmaceutical composition according to any one of the preceding claims wherein the active pharmaceutical ingredient is a nonsteroidal anti-inflammatory drug. The pharmaceutical composition according to any one of the preceding claims wherein the polysaccharide is a xanthan gum. 7. Pharmaceutical composition according to any one of the preceding claims wherein the pharmaceutical active ingredient is micronized so as to have a unimodal size profile, centered on a mean value of less than 10 microns. 8. Pharmaceutical composition according to any one of the preceding claims wherein the active ingredient is a nonsteroidal anti-inflammatory compound selected from enolcarboxamide acid derivatives. 9. Pharmaceutical composition according to any one of the preceding claims, characterized in that the active ingredient is meloxicam. 10. Pharmaceutical composition according to claim 9 wherein the meloxicam is between 0.05 and 1% by weight, preferably 0.05% or 0.15%. 11. Pharmaceutical composition according to any one of claims 8 to 10 characterized in that the dispersion medium comprises an aqueous buffer of pH between 2 and 4. 12. Pharmaceutical composition according to any preceding claim further comprising a mixture of polyols selected from glycerol, mannitol, sorbitol, xylitol. 13. Pharmaceutical composition according to any one of the preceding claims further comprising a sweetener and an antimicrobial preservative. 14. Pharmaceutical composition according to any one of the preceding claims, characterized in that it does not comprise additional surfactant. 15. Pharmaceutical composition according to any one of the preceding claims, characterized in that it does not comprise additional anti-foaming agent. 16. Pharmaceutical composition according to any one of the preceding claims, characterized in that it does not comprise any additional aromatic agent. 17. Pharmaceutical composition according to any one of the preceding claims, characterized in that it is devoid of cellulose ether derivatives. 18. Composition according to any one of the preceding claims as a medicament. 19. A method for preparing a stable aqueous suspension of micronized powder of active ingredient by addition to the active ingredient in suspension in physiological dispersant in an amount of between 0.01 and 1% by weight of a polysaccharide polymer chosen from carrageenans, xanthans, guars and derivatives of alginic acid, and 0.1 to 2% by weight of a micronized powder of silicon oxide. Means for delivering a predetermined volume of the composition according to any one of claims 1 to 18. 21. The means of claim 20, characterized in that said means is a dropper, a syringe, a pipette, a dosing pump, or any other means for mechanical operation, automatic, electronic or programmable.