"COMPOSITION AND CONTAINER, KIT, METHOD OF USE’’

The present invention regards a single-dose composition, a container or a heat-sealed sachet comprising such single-dose composition, a kit comprising said single-dose composition, and a method of use of a kit comprising the aforementioned single-dose composition.

Mannitol (CAS N° 69-65-8; otherwise referred to as "D-mannitol” or "mannite”) is a chiral alditol, with six hydroxyl groups on an aliphatic chain consisting of six saturated carbon atoms.

At room temperature, mannitol appears as a white, odourless and non-hygroscopic solid. Mannitol is used as a sweetener in foods for diabetic people due to the fact that it is poorly absorbed by the bowel.

Over the years, mannitol has been widely used in the pharmaceutical industry and in the gastroenterological field due to its osmotic diuretic characteristics and by virtue of the fact that it is an ancient remedy for constipation. The sweet taste of mannite makes its use particularly appreciated by children.

Mannose, an oxidation product of mannitol, has also proven to be particularly suitable for use in paediatrics, since it acts as a prebiotic for bacterial strains of the gut flora.

A use of mannitol that has been investigated in the past is its use in emptying the colon prior to endoscopic examinations, carried out by ingesting high doses of mannitol pre-dissolved in water. In particular, the action of emptying the colon occurs in 4 or 5 hours after ingesting mannitol pre-dissolved in water. The use of mannitol pre-dissolved in water has a number of advantages over other known substances having the function of emptying the colon (for example Macrogol ^® , based on polyethylene glycol). As a matter of fact, Macrogol ^® , having a slower induction, requires at least one first intake the day before, and a second intake on the day of the examination. Furthermore, the taste of some of such known substances is markedly worse, being very bitter, with respect to the taste of mannitol.

Nevertheless, the use of mannitol solutions reveals some limitations and drawbacks. As a matter of fact, in the past there have been cases of bowel explosion in patients who had been subjected to gastric emptying by ingesting mannitol pre-dissolved in water. These explosions have been attributed to incomplete cleansing of the colon, with permanence - in the bowel - of methane-producing bacteria, or hydrogen- reducing producers (see for example the technical problem of the prior art document EP3015102A1 , paragraphs [0002]-[0012]). Specifically, following some cases, it was observed that a portion of mannitol that remained undissolved in the solution taken by the patient had reduced the ingested dose that would have been required for proper bowel cleansing and, as discussed above, only a partial dissolution of mannitol in solution can be a contributing cause of explosion.

According to a further aspect, in cases where the user of the preparation is an elderly person, this could limit the shaking required for the full dissolution of mannitol in solution due to various factors, by way of example, due to pain in the joints, distraction, lack of patience, or the like.

Moreover, an incomplete intake of mannitol in solution, and therefore an incomplete cleansing of the bowel could also limit the possibilities of a correct diagnosis, which may not be useful in a statistically larger number of patients.

It is therefore extremely important that, for this specific use, mannitol be completely dissolved in solution, so that it can be administered effectively, completely and reproducibly.

Thus, the present invention falls within the preceding context, aiming at providing a single-dose composition, a preferably single-dose container, a kit for the use of a kit comprising a single-dose composition and a method capable of: (1) obtaining a quantitative dissolution of mannitol, uniformly reproducible in substantially all cases of administration prior to the performance of colonoscopy; (2) reducing up to eliminating the presence of the mannitol precipitate in the solution prior to administration thereof to a patient, and, thus, (3) allowing a simple, safe and effective administration of mannitol to any patient under normal conditions of use of the latter. Moreover, the manufacture, handling and packing of the present powder composition, in an extremely fine granulometric state, represents a major technological challenge.

Such objectives are achieved by means of a single-dose composition according to claim 1 , by means of a preferably single-dose container according to claim 4, by means of a kit comprising a single-dose composition according to claim 6, and by means of a method of use of a kit according to claim 9. The claims dependent on the aforementioned claims show preferred embodiments of the present invention.

The present invention will now be described based on the attached drawings, provided solely by way of non-limiting example, wherein:

- figure 1 shows a container subject of the present invention, according to a first embodiment, wherein the sealing element is spaced from the container compartment;

- figure 2 shows a schematic view of a kit subject of the present invention, according to a possible embodiment, wherein the container is shaped differently with respect to figure 1;

- figures 3, 4 show a dissolving container according to a first embodiment, respectively in an at least partially collapsed configuration and in an expanded configuration;

- figures 5, 6 show a dissolving container according to a second embodiment, respectively in an at least partially (for example: completely) collapsed configuration and in an expanded configuration;

- figures 7, 8 show a container and dissolving container assembly according to another embodiment, respectively in a lateral view and in a cross section at the plane VIII-VIII schematised in figure 7;

- figure 9 shows a plan view of a heat-sealed sachet 1 subject of the present invention, according to a possible embodiment.

It should be observed that the dimensional ratios shown in the previous figures do not represent limitations to the present invention.

A single-dose composition according to the present invention comprises or consists of mannitol at an amount comprised from 50 to 200 grams, wherein such mannitol is in powder form. This powder has a bulk density comprised from 0,40 to 0,65 g/ml and it comprises powder particles. A percentage comprised from 90% to 100% by weight of the powder particles has particle size distribution comprised from 1 m to 500 pm, preferably from 5 pm to 400 pm, more preferably from 10 pm to 300 pm.

It should be observed that the bulk density values mentioned in this description are to be understood as being measured at ambient temperature and pressure.

As regards the terminology used in this description, the term "single-dose” is used to indicate an amount of a single dose of composition, to be used in a single use as described in greater detail hereinafter.

In this regard, it should be pointed out that the weight of mannitol in the present composition is an unusually high amount (comprised from 50 to 200 g, assuming substantially pure mannitol) for a single dose of composition in the pharmaceutical field, which has posed the inventors of the present invention to face new technological challenges. By way of example, the use of a large amount of mannitol has resulted in the unusual use and adaptation of multi-dose containers (i.e. that can be opened and closed several times) to a single use, for single-dose products.

According to an embodiment, the single-dose composition of the present invention consists of an amount comprised from 30 g to 80 g, preferably from 40 g to 70 g, more preferably from 50 g to 60 g of mannitol. According to another embodiment, the single-dose composition of the present invention consists of an amount comprised from 80 g to 120 g, preferably from 85 g to 115 g, more preferably from 90 g to 110 g, even more preferably comprised from 95 g to 105 g of mannitol.

According to a further embodiment, the single-dose composition of the present invention consists of an amount comprised from 110 g to 190 g, preferably comprised from 120 g to 180 g, more preferably comprised from 130 g to 179 g, even more preferably comprised from 135 g to 185 g. Preferably, the single-dose composition of the present invention consists of an amount comprised from 140 g to 170 g, preferably comprised from 141 g to 160 g, more preferably comprised from 145 g to 155 g of mannitol.

In this description, the expression "consisting of is used to indicate a composition in which mannitol is the essentially exclusive component, except for any impurities present therein.

According to an embodiment, the single-dose composition is devoid of pyrogenic substances and/or devoid of excipients.

More specifically, avoiding the use of excipients which favour densification and/or the flow of mannitol into the container, but which could have simultaneously slowed down the dissolution thereof, was considered a necessity and an attention toward the patient who, following ingestion of the mannitol composition previously dissolved in water, is subjected to an almost full emptying of the bowel in order not to risk administering any unnecessary and foreign component which can in any way interfere with the practices aimed at the pre-treatment and relaxation of the colon walls in order to perform a correct colonoscopy. According to another embodiment, mannitol has a percentage by weight comprised from 97% to 100%, preferably comprised from 98% to 100% or comprised from 99% to 100%, or of 100%, with respect to the total weight of such composition. By way of example, possible components other than mannitol (when present, at an amount less than 3% by weight with respect to the total weight of the composition) could comprise substances related to mannitol, such as other polyalcohols, for example sorbitol.

According to a preferred embodiment, mannitol has a percentage by weight of 99,5%, of 99,6%, of 99,7%, of 99,8%, of 99,9% or of 100% with respect to the total weight of such composition. Preferably, the mannitol contained in the composition is of a pharmaceutical grade.

It should be observed that, in each range of values mentioned in this description, the extremes of the range are to be deemed within the range (unless the context clearly indicates otherwise), same case applying to any intermediate value between the extremes, although not explicitly stated numerically.

As regards the terms "in powder form”, this expression is used to indicate mannitol in finely divided, pulverulent form, comprising a plurality of powder particles.

With regard to the expression "particle size distribution” (PSD), this term is used indicate the statistical dimensional distribution curve of the powder particles.

According to an embodiment, the powder particle size distribution could be as in Table 1 below:

Table 1

According to an embodiment, the powder particles could be substantially spherical-shaped.

This means that the particle size distribution discussed in this description could be a "particle size diameter” with the same described characteristics, preferably comprised from 1 m to 500 pm, preferably comprised from 5 pm to 400 pm, more preferably comprised from 10 pm to 300 pm, even more preferably comprised from 15 pm to 250 pm, without prejudice to possible variability (±) comprised from 1% to 15% (as discussed below). As concerns the embodiments that provide for "substantially spherical” powder particles, it should be observed that the sphericity parameter is defined by the ratio between the outer surface of a powder particle and the outer surface of an equivalent sphere (i.e. a sphere of the same volume as the powder particle).

In such context, a powder particle is deemed to be "substantially spherical” if it has a sphericity parameter comprised from 1 to 1 ,3, preferably comprised from 1 to 1 ,2, more preferably comprised from 1 to 1 , 15, even more preferably comprised from 1 to 1 ,1 or comprised from 1 to 1 ,05.

As regards the bulk density outlined above, in particular the poured bulk density, such parameter is measured according to the European Pharmacopoeia reference standard (Ph. Eur.), current edition 2.2.42, in force at the priority date of this patent application.

In the context of the present invention, the expression "bulk” implies that the powder density value is calculated in a manner formally analogous to an absolute density (such as for a solid body or for a liquid). However, since a powder has empty inter-particle spaces, the total volume occupied by the powder (i.e. its outer bulk), thus including the inter-particle spaces between the various particles, should be taken into account when evaluating bulk density.

More precisely, according to the aforementioned regulation, a 100 ml class A graduated flask is filled and brought to volume with the powder particles, after which the bulk density is calculated as the ratio between the weight of the powder contained in the flask and the volume (100 ml) occupied by that weight of the powder particles.

According to an embodiment, the bulk density of the mannitol powder inside the container may be comprised from 0,42 g/ml to 0,64 g/ml, preferably from 0,50 g/ml to 0,62 g/ml, more preferably from 0,56 g/ml to 0,60 g/ml, even more preferably comprised from 0,57 g/ml to 0,59 g/ml.

According to another embodiment, the bulk density of mannitol powder is 0,58 g/ml.

According to an embodiment, a method that can be used for analysing the particle size distribution is discussed hereinafter: 100 g of mannitol powder are screened using 600 pm, 500 pm, 355 pm, 250 pm, 180 pm and 100 pm ASTM series sieves. All sieves except for the 100 pm sieve come from GIULIANI TECNOLOGIE S.r.l. (Via Centallo 62/18, 10156 Turin, Italy; https://www.giuliani.it/setacci-sieves). The 100 pm sieve comes from Retsch GmbH (Retsch-Allee 1-5, 42781 Haan, Germany; https://www.retsch.com/products/sieving/). Such sieves were connected to a vibrating screen made by RMU-Resistenze Meccaniche Unificate serial n° 42280, at an intensity of 10, for 13 minutes. Following screening, a particle size profile of the mannitol powder is constructed. Regarding this, see for example the particle size profiles of Table 3 or of Table 4.

As concerns the powder particle size distribution, it should be observed that the particle size distribution will be comprised from 1 pm to 500 pm, unless there is a variability (±) comprised from 1 % to 15%, preferably comprised from 1 % to 10%, more preferably comprised from 1 % to 5%, with respect to the upper limit of the range of 500 m (or 400 pm, 300 pm, 250 pm according to other embodiments).

According to a particularly preferred embodiment, the powder particles have a particle size distribution comprised from 1 pm to 250 pm, without prejudice to a possible variability (±) comprised from 1% to 15%, preferably comprised from 1% to 10%, more preferably comprised from 1% to 5%, with respect to the upper limit of the range (250 pm).

According to an advantageous embodiment, the aforementioned single-dose composition, according to any one of the illustrated embodiments, is a single-dose composition for use in the treatment of constipation, or for use as a purgative to be administered to a patient prior to a colonoscopy examination. The aforementioned objectives are also achieved through a container 1, preferably a single-dose container 1, containing a single-dose composition - according to any one of the preceding claims - in a container compartment 4 hermetically sealed by a removable sealing element 6.

The aforementioned objectives are also achieved through a heat-sealed sachet, preferably a single-dose heat-sealed sachet, containing a single-dose composition - according to any one of the preceding claims - in a container compartment 4 hermetically sealed by a removable or tearable sealing element, wherein said heat-sealed sachet is made of a polymeric material which can also possibly be compostable according to the UNI EN 13432 or ASTM D6400 standard.

In other words, such container 1 or the heat-sealed sachet (for example shown in figure 9) advantageously forms the primary casing for mannitol in powder form, with which the powder particles are directly at contact.

It should be observed that the expression "hermetically” is used to indicate the ability to at least prevent the powder from leaking out from the container compartment and/or from the inner compartment discussed hereinafter. Preferably, the expression "hermetically” in the context of the dissolving container 30 entails a substantially hermetic sealing of the inner compartment 26 of such dissolving container 30, in order to obtain the single-dose solution.

As regards the standard UNI EN 13432 or ASTM D6400 mentioned above, such standard is meant in the version valid at the priority date of the present patent application.

Preferably, the compostable polymeric material comprises or, alternatively, consists of at least one polylactic acid (PLA) film.

With reference for example to the embodiment of figure 1, the container 1 comprises a first lateral wall 2 which extends around a first main extension axis X so as to delimit the container compartment 4.

According to an embodiment, the first lateral wall 2 is connected to a first bottom wall 8 at a first axial end 12 of the container 1 and, at an opposite second axial end 14, it delimits at least one opening 16 for access to the container compartment 4.

According to another embodiment, the container 1 or the first lateral wall 2 could be substantially cylindrical-shaped or truncated-cone-shaped. According to a further embodiment, the container 1 , or the first lateral wall 2 and the optional first bottom wall 8, could be made of a polymeric material, preferably polyethylene (preferably high-density polyethylene; HDPE) or polypropylene.

According to an embodiment, the sealing element 6 can be connected to the first lateral wall 2, in particular at the second axial end 14 of the container 1, so as to hermetically seal the container compartment 4.

According to another embodiment, the sealing element 6 is made of a more flexible material with respect to the material that the container or the first lateral wall 2 is made of, said material being preferably polymeric such as low-density polyethylene (LDPE).

According to a further embodiment, the sealing element 6 and the container 1 (or the first lateral wall 2 of the latter) could be joined by a tamper-proof seal 32, preferably annular-shaped and/or in the form of a flange.

Therefore, according to such embodiment, before accessing the single-dose composition it will be necessary to tear and/or remove the tamper-proof seal 32, and to remove the sealing element 6.

According to an embodiment, the tamper-proof seal 32 could be designed so as to act as a stirrer, following the tearing or removal thereof. More precisely, the torn or removed seal could be elongated shaped, so as to be inserted into the container compartment 4 and/or into the inner compartment 26 and be actuated manually in order to facilitate the dissolution of the mannitol powder.

Preferably, the polymeric material of the container 1 (or, of the first lateral wall 2 and of the optional first bottom wall 8) is non-identical/different with respect to the polymeric material that the sealing element 6 is made of.

Preferably, the polymeric material of the sealing element 6 could be polyethylene (preferably low-density polyethylene; LDPE).

According to an embodiment, the heat-sealed sachet, preferably a heat-sealed closed sachet, preferably having 4 ends (4 sides, perimeter ends) heat-sealed for example with a square or rectangular shape. Said heat-sealed sachet (Fig. 9; 1) could comprise or, alternatively, consist of a pair of sachet walls made of said polymeric material or of another specific compostable polymer in the form of material film, said sachet walls being heat-sealed to each other along the perimeter by means of one or more heat-sealing areas (Fig. 9; 2). The embodiment of figure 9 shows the sachet wall facing upwards (the opposite wall being concealed from the view), polygonal-shaped, preferably square- or rectangular-shaped. The heat-sealed outer part 6 in Fig. 9 also represents a sealing element which can be removed for example using cutting means such as a pair of shears.

According to an embodiment, the container compartment 4 comprises a first volume fraction 18 and a second volume fraction 20. The first volume fraction 18 is occupied by the single-dose composition, and the second volume fraction 20 is devoid of the aforementioned composition. More precisely, the second volume fraction 20 could contain a gas, preferably air or at least one inert gas.

In other words, above a vacant surface 22 of the single-dose composition 1 in the container compartment 4 there is a space devoid of mannitol corresponding to the second volume fraction 20.

According to another embodiment, the first volume fraction is equal to or greater than about half of a total internal volume of the container compartment 4.

According to a further embodiment, the first volume fraction is about two-thirds of the total internal volume of the container compartment 4, the second volume fraction being consequently one-third of the total internal volume of such compartment 4.

The aforementioned objectives are further achieved by means of a kit comprising the container 1 or the heat-sealed sachet according to any one of the preceding embodiments, a dissolving container 30 at least partially permeable to light, and a funnel 24 for transferring the single-dose composition from the container 1 or from the heat-sealed sachet to the dissolving container 30.

It should be observed that, the expression "at least partially permeable to light”, is used to indicate a dissolving container 30 with at least one portion 36 at least partly transparent (for example: a completely transparent container, or a container with at least one transparent portion 36), so as to allow to see - from the outside - at least one part of an inner compartment 26 of such container, in particular without the need to open the latter. This expression will also include a container comprising at least one pair of transparent portions 36, for example diametrically opposite or contralateral.

The at least partial permeability to light has a double utility in the context of the present invention: on the one hand, seeing the inner compartment 26 allows to establish the complete dissolution of mannitol. On the other hand, in some embodiments, such characteristic allows the introduction of a water volume appropriate for dissolution, or in any case, to establish that the water volume already present in the container is sufficient for a quantitative dissolution of mannitol.

The expression "appropriate water volume” therefore refers to the volume of water present or that can be introduced into the inner compartment, appropriate for fully dissolving the mannitol in powder form.

According to a first embodiment, a water volume suitable to completely dissolve the single-dose composition contained in the container 1 or in the heat-sealed sachet is contained in the dissolving container 30.

According to a second embodiment, the dissolving container 30 comprises a level gauge 28 for a water volume that can be introduced (i.e. to be introduced) into the dissolving container 30 and suitable to fully dissolve the single-dose composition contained in the container 1 or in the heat-sealed sachet.

In other words, in these two last embodiments the dissolving container 30 could already be filled with the appropriate water volume, or such container 30 could initially be empty but provided with a level gauge 28 so that a user can, on his own account, introduce the appropriate water volume, specifically without making mistakes.

It should be observed that the term "water” has no particular limitations in the present description.

According to an embodiment, the water could comprise or consist of deionised water, demineralised water, mineral water (preferably non-carbonated), or mains water.

As a matter of fact, it was observed that any salts previously dissolved in water have no negative effects on the solvation of mannitol, which is surprising since the salts already dissolved in water should compete with mannitol due to the water solvation capacity, and thus they are expected to increase the time required for the dissolution of the mannitol powder.

On the other hand, with the mannitol powder according to the present invention dissolution was not observed to slow down, although the dissolution kinetics justifying the absence of slowing remain yet to be clarified.

According to an embodiment, the water required for the dissolution of mannitol is at a substantially neutral pH (pH 7,0 ± 0,2), or it is weakly basic, preferably at pH 8,0 ± 0,5.

With regard to the level gauge 28, in an embodiment such indicator could comprise or consist of a sign, a notch, a line or an alphanumeric character arranged on the dissolving container 30, in particular at a window or portion 36 at least partially permeable to light.

More precisely, a second lateral wall 34 of the dissolving container could delimit such window 36.

According to another embodiment, the second lateral wall 34 of the dissolving container could delimit at least two windows 36, for example contralateral or diametrically opposite, specifically so as to allow a backlit verification of the complete dissolution of mannitol.

With reference for example to the embodiment of figure 8, the dissolving container 30 comprises the second lateral wall 34 which extends around a second main extension axis Y so as to delimit the inner compartment 26.

According to an embodiment, the second lateral wall 34 is connected to a second bottom wall 38 at a first axial end 40 of the container 30 and, at an opposite second axial end 42, it delimits at least one opening 44 for access to the inner compartment 26.

As regards the characteristics and materials that can be used for the dissolving container 30, the preferred or accessory characteristics mentioned in relation to the container 1 shall apply mutatis mutandis.

According to an embodiment, the ratio between the weight of mannitol contained in the container 1 or of the heat-sealed sachet and the water volume contained or that can be introduced up to the level gauge 28 in the dissolving container 30 are mutually selected so as to obtain - at a temperature of 25°C and at ambient pressure - a concentration of mannitol in aqueous solution comprised from 0,05 g/ml to 0,213 g/ml, preferably comprised from 0,1 g/ml to 0,19 g/ml.

According to an embodiment, the container 1 or the heat-sealed sachet is shape-coupled to, or is at least partially nested in, the dissolving container 30. According to another embodiment, the dissolving container 30 could delimit a coupling seat with the, or a housing seat 46 of the container 1 or with the heat-sealed sachet.

By way of example, the coupling seat or the housing seat 46 could comprise a recess 48 at least partially housing the container 1 or the heat-sealed sachet, for example partially, mainly or substantially fully.

With reference for example to the variant of figures 7 and 8, the second lateral wall 34 is shaped so as to identify the recess 48, being for example designed with a concavity toward the external of the dissolving container 30 (i.e. on the opposite side with respect to the inner compartment 26).

According to an embodiment, when the container 1 is associated with the coupling seat or with the housing seat 46, the main extension axes X, Y are substantially parallel to each other and advantageously non-coincident.

According to another embodiment, at least one second lateral wall 34 of the dissolving container 30 is flexible so that an inner compartment 26 of such container 30 is expandable from an at least partially collapsed configuration to an expanded configuration.

According to a first example, the second lateral wall 34 could comprise at least one bellows-like portion 50, so as to allow conversion between the aforementioned configurations.

More precisely, the second lateral wall 34 could comprise an axial alternation (with respect to the second main extension direction Y) of outer tubular or annular portions 52 arranged side by side and connected to inner tubular or annular portions 54 which form one or more bellows-like portions 50.

In this manner, in the at least partially collapsed configuration, the inner tubular or annular portions 54 are housed (specifically: radially) at least partly in the outer tubular or annular portions 52, so that the volume of the inner compartment 26 is smaller.

However, when the inner compartment 26 is converted into the expanded configuration (for example by pulling on the axial ends 40, 42 of the container), the inner tubular or annular portions 54 move axially alongside the outer tubular or annular portions 52, so that the volume of the inner compartment 26 is greater (at least with respect to the at least partially collapsed configuration).

According to a second example, the second lateral wall 34 could be made of at least one pair of material films 56, 58 joined together (for example sealed), preferably at the respective peripheral portions 60, so as to allow conversion between the aforementioned configurations.

According to such variant, the inner compartment 26 is advantageously enclosed at least by such pair of material films 56, 58.

Advantageously, the two or more material films 56, 58 are joined to each other, so as to form a self- supporting bottom 60 (for example a substantially flat bottom) in the expanded configuration.

As regards to the funnel 24, it comprises a powder-loading portion 64 and a powder-discharge portion 66, the through-flow section through such funnel being tapered at the powder-loading portion 64 toward the powder-discharge portion 66. According to an embodiment, the powder-loading portion 64 could be truncated-cone or truncated- pyramidal-shaped.

According to another embodiment, the powder-discharge portion 66 could be substantially tubular, or truncated-cone or truncated-pyramidal-shaped.

In a possible embodiment, the kit according to any one of the preceding embodiments is arranged in a secondary, preferably protective, housing.

Lastly, the aforementioned objectives are achieved by means of a method of use of the kit - according to any one of the embodiments illustrated above - comprising the following steps:

i) removing the sealing element from the container 1 or from the heat-sealed sachet (for example, tearing a portion of the heat-sealed sachet);

ii) transferring the single-dose composition from the container 1 or from the heat-sealed sachet to the dissolving container 30 using the funnel 24;

iii) completely dissolving the mannitol powder in the water volume thus obtaining a single-dose solution. According to an embodiment, the transfer step ii) could comprises the following sub-steps:

ii.a) first pouring at least one part of the appropriate water volume into the container 1 or into the heat- sealed sachet, so as to pre-dissolve the mannitol powder;

ii.b) subsequently transferring the mannitol pre-dissolution of sub-step ii.a) into the dissolving container 30. For example, sub-step ii. a) could comprise at least one (pre-)shaking and/or stirring operation. The term "(pre-)shaking” is used to indicate a pre-shaking and/or shaking operation.

As a matter of fact, mannitol is a poorly flowing powder, hence this embodiment allows to avoid annoying clogging of the funnel due to the increased flowability conferred by water.

According to an embodiment, the container 1 or the heat-sealed sachet could comprise a further level gauge. In this manner, during sub-step ii. a), a part of the water volume could be poured into the container compartment 4 until it corresponds with such further level gauge.

In quantitative terms, according to an embodiment, the single-dose solution of step iii) could contain about 50 g of mannitol in at least 350 ml of water (preferably about 50 g of mannitol in 500 ml of water).

According to another embodiment, the single-dose solution of step iii) could contain about 100 g of mannitol in at least 600 ml of water (preferably about 100 g of mannitol in 700 ml of water).

According to a further embodiment, the single-dose solution of step iii) could contain about 150 g of mannitol in at least 800 ml of water (preferably about 150 g of mannitol in 900 ml of water).

In any case, the principles which should be observed in the determination of the amount of mannitol powder and the appropriate water volume are: a) the desired efficacy for the single-dose solution; and b) not exceeding the saturation concentration at the solution consumption temperature.

Preferably, the dissolving step iii) could comprise the following sub-steps:

iii. a) hermetically sealing (for example closing) the dissolving container 30; iii.b) shaking the dissolving container 30 of sub-step iii.a) until, using a portion 36 of said container at least partially permeable to light, the precipitates / sediments in the single-dose solution disappear.

With regard to sub-step iii. a), the dissolving container could comprise a cap or closure member 68, which can be reversibly connected to the dissolving container 30, for example to a container neck 70 of the latter.

By way of example, the cap or closure member 68 and the dissolving container 30 (or container neck 70) could be provided with complementary threaded means 72.

As regards the execution times of step iii. b), in an embodiment the shaking could be carried out - for a mass of single-dose composition comprised from 50 to 100 g - for a time comprised from 15 seconds to 2 minutes.

Some examples will be provided hereinafter solely by way of non-limiting example.

EXAMPLES.

Example 1 : characterisation of mannitol.

The specifications of a mannitol that can be used according to the present invention are shown in Table 2 below. The tests were conducted according to the European Pharmacopoeia reference standards in force at the priority date of the present application.

The tested product is a pharmaceutical grade mannitol named Pearlitol ^® PF, cod. 050054, manufactured by Faravelli Group S.p.A.

Table 2

Example 2: Particle size profile.

The particle size profile of three different samples, distinguished by the batch number in Table 3 below, was verified before and after sieving carried out for uniforming the in-line filling of the containers at the industrial level.

Table 3

From the previous table it can be observed that the sieving has a break-up effect with respect to the coarser grain size fractions (> 600 pm), whose fragmentation enriches by various percentages the finer grain size fractions 100-250 pm.

The grain size of the single-dose composition in a further productive batch is summarised in Table 4 below, whereas the last column on the right shows the percentage by weight of each of the fractions identified in the central column:

Table 4

Example 3: Dissolution study as a function of the pH value of water.

The solubility of the mannitol powder was then studied in the following three types of non-carbonated commercial waters:

- Sangemini: pH at source 6,2;

- Antica Fonte Boario: pH at source 7,0;

- Panna Toscana: pH at source 8,0.

The results obtained are shown in Table 5 below:

Table 5

A difficulty of dissolving 150 g of mannitol in 900 ml of water can be deduced from the table above: complete dissolution takes more than 6 minutes for water with weakly acidic or neutral pH, but this time is substantially half as much under weakly basic pH conditions.

Such circumstance is odd and still unexplained in the case of the most critical amount to be dissolved, 150 g: the experimental evidence shows that a slightly basic pH accelerates the dissolution times, even if it has no theoretical assumption since mannitol (itself slightly basic in solution), is expected to dissolve better at slightly acidic pH.

However, an acceleration of dissolution as a function of pH values cannot be observed for samples with 100 g or 50 g of mannitol.

Example 4: Procedure for filling single-dose containers.

Mannitol powder is a poorly flowing powder, which has a certain tendency, just like all fine powders, to agglomerate under pressure. A drum centrifugal sieve shaker, through which all the mass of the powder particles is passed before the mixing prior to the metering in the container, is used to break up any large powder lumps.

A mesh with a 3mm clear span, much larger than the size or particle size diameter of mannitol (preferably at least 90% with a diameter comprised from 1 m to 250 pm) was used.

Usually this step further reduces the density of the powders which quickly impact against the edges of the openings of the mesh, causing a decrease in density due to an increase in the disorderly arrangement of the particles which - based on previous evidence - can increase the volume of the material even by 30%. It has now surprisingly been observed that the use of such sieve shaker allows to accelerate the process for the in-line filling of the single-dose containers up to 50%, reducing the downtime and the onset of waste due to defective filling.

Given the size of the mannitol particles, the passing through a mesh much larger than previously indicated would not be effective in reducing the size thereof, but it shows to be extremely useful in orienting and packing the powder particles, allowing to obtain - in a short through-passing - a much greater transient density, of about 0,73 g/ml, measured in the laboratory, which considerably facilitates a faster descent of the powder into the disposable container.

This behaviour seems to stem from the orientation of the particles that pack better together. Furthermore, with a material already densified at the time of metering in the disposable container, this allows to reduce the metering times and to use smaller bottles, without further settling in the volume that would inevitably occur as the filled disposable container advances toward the labelling.

Example 5: Dissolution study as a function of the particle size distribution and the density of the mannitol powder used.

The dissolution rate of two types of powder mannitol was compared:

- Type 1 : a mannitol subject of the present invention (Pearlitol ^® PF; according to Example 1) in powder form with a bulk density comprised from 0,40 to 0,65 g/ml and the particle size profile is that of Table 6 below:

Table 6

total 98.43 98.40047986

Therefore, in Type 1 mannitol about 96.6% by weight of the powder particles has a particle size distribution comprised from 1 m to 500 pm;

- Type 2: a reference mannitol (Pearlitol ^® 500 DC, marketed by Roquette) in powder form with a bulk density of about 0,673 / 0,683 g/ml (values obtained in two different measurements) and wherein 100% by weight of the powder particles has a particle size distribution greater than 500 pm, in particular comprised from 520 pm to 850 pm. This size of the powder particles was obtained through subsequent sieving operations.

From the operational point of view, the dissolution tests were conducted following the reference analytical specifications of the finished product: "Solve the prescribed quantity of product powder in the indicated quantity of purified water. Manually stir with a stick until the dissolution is complete. Measure the time needed to complete solubilization." The distilled water used had a temperature of about 19,4°C and the tests were conducted at atmospheric pressure (1 atm), and the stirring is of the manual type carried out by an expert analyst. The results of the present dissolution study are reported in Table 7 below.

Table 7

Table 7 above shows that - in both conducted tests - the mannitol in powder form subject of the present invention has a dissolution rate below one minute. Considering the same conditions, Type 2 powder mannitol (with higher density and particle size distribution) takes more than 3 minutes and more than 7 minutes to dissolve.

Example 6: Stability data of mannitol in powder form subject of the present invention.

Stability of mannitol in the form of powder subject of the present invention was tested and received in a heat-sealed sachet made of compostable material. 50 grams of said powder were stored for 6 months at 40°C/75% RH (Test 1) and for 6 months at 25°C/60% RH (Test 2). Tests were conducted to verify the parameters indicated in Tables 8 and 9 below at the times T0-T6 identified as: TO = moment of insertion of the air-conditioned environment, T 1 = after one month from time TO, T2 = after two months from time TO, T3 = after three months from time TO, T4 = after four months from time TO, T5 = after five months from time TO, T6 = after six months from time TO. Table 8 . _.

Table 9

Table 8 and Table 9 above confirm that, under conditions of accelerated stability and long-term stability in the climatic area II, the measured parameters of the mannitol powder contained in the heat-sealed sachet subject of the present invention remained stable throughout the duration of the test.

Innovatively, the present invention allowed to achieve the pre-set objectives.

More precisely, the present invention allows to obtain a complete dissolution of the mannitol powder easily and under the working conditions of a final user.

Advantageously, the characteristics of the sealing element and of the container were specially designed so as to ensure good storage as well as an easy opening of the container by a user.

Advantageously, the pH values explained above allow to accelerate the dissolution rate of mannitol, and thus to make the use of the present composition easier.

Advantageously, the design of the dissolving container allows to save a large amount of space, and/or weight, hence leading to a significant logistic and productive advantage.

Advantageously, the method subject of the present invention allows to compensate for the poor flowability of the mannitol powder, whose transfer is assisted by the solvent.

Advantageously, the heat-sealed sachet containing the mannitol subject of the present invention does not reveal any difficulty of disposal as a special waste, since mannitol is a natural product that does not require particular recovery attention, and the heat-sealed sachet can be disposed of in normal municipal organic waste.

The embodiments of the aforementioned composition, container, sachet, kit and method may be subjected - by a man skilled in the art - to replacements or modifications to the described characteristics according to the contingencies. These variants are also to be considered included in the scope of protection as outlined in the claims that follow.

Furthermore, it should be observed that any embodiment may be implemented independently from the other embodiments described.

Further embodiments (FRn) of the present invention are outlined and claimed below:

FR1. A container (1), preferably a single-dose container or a single-dose heat-sealed sachet, containing a single-dose composition of mannitol in powder form; said container (1) being obtainable or obtained by means of a method comprising the following steps:

a) breaking-up a coherent mass of powder mannitol, so as to obtain a disintegrated mass from said coherent mass;

c) filling a plurality of containers with the broken-up mass of step a);

wherein step a) comprises a breaking-up with a centrifugal force, and wherein a bulk density of the coherent mass is smaller than the bulk density of the broken-up mass.

FR2. The container (1) according to FR1 , wherein said bulk density of the coherent mass is smaller than a bulk density of the broken-up mass by a percentage comprised from 1 % to 40%, preferably ranging from 1 % to 30%, even more preferably comprised from 5% to 15%, with respect to the bulk density of the broken up mass.

FR3. The container (1) according to FR1 or FR2, wherein said centrifugal force is exerted by means of a drum centrifugal sieve shaker.

FR4. The container (1) according to any one of FR1-FR3, wherein step a) comprises the following sub steps:

a.i) sieving the coherent mass of mannitol powder; and a.ii) packing the product of sub-step a.i).

FR5. The container (1) according to any one of FR1-FR4, wherein in sub-step a.ii) - the mannitol powder is forced through a mesh with a clear span comprised from 2,0 to 5,0 millimetres, preferably comprised from 2,0 to 4,0 millimetres, more preferably comprised from 2,5 to 3,5 millimetres, even more preferably of 3,0 millimetres.

FR6. The container (1) according to any of the FR1-FR5, wherein said bulk density of the mannitol powder at the end of sub-step a.ii) is comprised from 0,66 to 0,90 g/ml, preferably comprised from 0,66 to 0,84 g/ml, more preferably comprised from 0,68 to 0,78 g/ml, even more preferably comprised from 0,70 to 0,75 g/ml.

FR7. The container (1) according to any one of FR1-FR6, wherein at the end of step c), the mannitol powder in the container has a bulk density comprised from 0,40 to 0,65 g/ml.

FR8. The container (1) according to any one of FR1-FR7, wherein at the end of step c), the mannitol powder comprises an amount comprised from 90% to 100% by weight of powder particles with a particle size distribution comprised from 1 m to 500 pm, preferably comprised from 1 pm to 400 pm, more preferably comprised from 1 pm to 300 pm.

FR9. The container (1) according to any of FR1-FR8, wherein the single-dose composition is devoid of excipients and/or pyrogenic substances.

FR10. The container (1) according to any one of FR1-FR9, wherein said container (1) delimits a container compartment (4), wherein the container compartment (4) comprises a first volume fraction and a second volume fraction, and wherein - at the end of step c) - the first volume fraction is occupied by the single dose composition, and the second volume fraction of said compartment is devoid of said composition, and preferably wherein the first volume fraction is about two-thirds of a total internal volume of the container compartment (4), the second volume fraction being about one-third of the total internal volume.

FR11. The container (1) according to any one of FR1-FR10, wherein said single-dose composition comprises, or consists, of mannitol at an amount comprised from 50 to 200 grams, wherein said mannitol is in form of powder, wherein said powder has a bulk density comprised from 0,40 to 0,65 g/ml and it comprises powder particles, and wherein a percentage comprised from 90% to 100% by weight of the powder particles has a particle size distribution comprised from 1 m to 500 pm. FR12. The container (1) according to any one of FR1-FR11 , wherein the mannitol contained in said single dose composition is present at a percentage by weight comprised from 97% to 100%, preferably a percentage by weight of 100%, with respect to the total weight of said composition, wherein said bulk density of said mannitol powder is comprised from 0,50 g/ml to 0,62 g/ml, and wherein the single-dose composition is devoid of excipients and/or pyrogenic substances.

FR13. The container (1) according to any one of FR1-FR12, wherein the single-dose composition contained therein is for use in the treatment of constipation, or for use as a purgative to be administered to a patient prior to a colonoscopy examination.

FR14. The container (1), preferably a single-dose container or a single-dose heat-sealed sachet, wherein said single-dose composition according to any one of FR1-FR13, is contained in a container compartment (4) hermetically sealed by a removable sealing element (6).

FR15. The container (1) according to any one of FR1-FR14, wherein said container is a heat-sealed sachet, preferably a single-dose heat-sealed sachet, containing a single-dose composition according to any one of FR1-FR14 , in a container compartment (4) hermetically sealed by a removable or tearable sealing element, wherein said heat-sealed sachet is made of a polymeric material compostable according to the UNI EN 13432 or ASTM D6400 standard.

FR16. The container (1) according to any one of FR1-FR15, wherein the container compartment (4) comprises a first volume fraction and a second volume fraction, wherein the first volume fraction is occupied by the single-dose composition, preferably for about two-thirds of a total internal volume of said compartment (4), and wherein the second volume fraction is devoid of said composition, preferably for about one-third of the total internal volume.

FR17. Use of the single-dose composition of powder mannitol contained in said container (1), according to any one of FR1-FR16, in the treatment of constipation, or for use as purgative to be administered to a patient prior to performing an endoscopic examination. LIST OF REFERENCE NUMBERS container, preferably single-dose 40 first axial end

container 42 second axial end

first lateral wall 44 access opening

containment compartment 46 coupling seat or housing seat sealing element 48 recess

first bottom wall 50 bellows-like portion kit 52 outer tubular or annular portions first axial end 54 inner tubular or annular portions second axial end 56 material film

access opening 58 material film

first volume fraction 60 peripheral portions second volume fraction 62 self-supporting bottom vacant surface 64 powder-loading portion funnel 66 powder-discharge portion inner compartment 68 cap or closure member level gauge 70 container neck

dissolving container 72 complementary threaded means tamper-proof seal X first main extension axis second lateral wall Y second main extension axis window or portion permeable to light

second bottom wall