WO2024047555A1

WO2024047555A1 - Method and apparatus for making solid medicines

Info

Publication number: WO2024047555A1
Application number: PCT/IB2023/058575
Authority: WO
Inventors: Fabrizio Pucci; Fiorenzo Parrinello
Original assignee: Sacmi Cooperativa Meccanici Imola Societa' Cooperativa
Priority date: 2022-08-31
Filing date: 2023-08-30
Publication date: 2024-03-07

Abstract

A method for making a solid medicine, wherein the solid medicine comprises a solid dispersion which includes at least one polymeric matrix in which at least one active ingredient is dispersed, comprises the steps of: - extruding at least one polymeric material in an extrusion stage (2), the polymeric material being intended to form the polymeric matrix of the solid medicine; - adding the active ingredient to the polymeric material, thereby obtaining a compound comprising at least the polymeric material and the active ingredient; - pressing the compound to obtain the solid medicine. The active ingredient is added to the polymeric material after having cooled the polymeric material downstream of the extrusion stage (2).

Description

Method and apparatus for making solid medicines

The invention relates to a method and an apparatus for making solid medicines, for example pastilles, pills, tablets or lozenges, of any shape or size. Alternatively, the solid medicines made with the method and the apparatus according to the invention may be suppositories.

The method and the apparatus according to the invention are particularly suitable for making solid medicines in a compressed state.

The solid medicines made by means of the method and the apparatus according to the invention are intended for oral or rectal administration.

Plants are known for the continuous production of a medicine in the form of pastilles, which comprise an extruder which is fed with a synthetic polymeric material. The latter is plasticised inside the extruder. While the polymeric material flows inside the extruder, other substances are added to it, in particular at least one active ingredient and one or more additives if necessary, depending on the desired medicine composition. In this way a compound in the fluid state is obtained, which is injected into suitable moulds to obtain the pastilles.

The plants described above operate continuously and allow high productivity to be achieved. However, they have several defects which limit their use.

For example, inside the extruder relatively high temperatures are reached, which are necessary to bring the polymeric material to the fluid state and keep it in that state. Not all active ingredients and/or additives are able to withstand such high temperatures. Some active ingredients and/or additives degrade at the temperatures which are reached inside the extruder, and are no longer able to act effectively.

For this reason, known plants of the type described above are only able to process a limited number of active ingredients and/or of additives and consequently can only work with a limited group of pharmaceutical formulations.

An object of the invention is to improve the apparatuses and the methods for making solid medicines in a compressed state, for example pastilles, pills, tablets, lozenges or suppositories, of any shape or size.

A further object is to provide a method and an apparatus for making solid medicines, in which the risks of damaging the active ingredients and/or the other additives while the medicines are being made are reduced.

Another object is to provide a method and an apparatus which are able to make many different types of solid medicines in the compressed state, that is to say, which have good flexibility.

A further object is to provide a method and an apparatus which guarantee a wide degree of freedom in the formulation of solid medicines. In particular, it is desirable to make available to pharmaceutical companies a wide possibility of choice in terms of the type of active ingredients, but also in terms of the type and the quantity of additives which can be used in the formulation of the medicine.

Another object is to provide a method and an apparatus for making solid medicines which have good productivity.

According to a first aspect of the invention, a method is provided for making a solid medicine, the solid medicine comprising a solid dispersion which includes at least one polymeric matrix in which at least one active ingredient is dispersed, wherein the method comprises the steps of:

- extruding at least one polymeric material in an extrusion stage, obtaining a continuous flow of polymeric material intended to form the polymeric matrix of the solid medicine;

- adding the active ingredient to the continuous flow of polymeric material, thereby obtaining a compound comprising at least the polymeric material and the active ingredient;

- pressing the compound to obtain the solid medicine, wherein the active ingredient is added to the continuous flow of polymeric material after having cooled the polymeric material downstream of the extrusion stage.

Owing to this aspect of the invention, it is possible to make a solid medicine without damaging the active ingredient. In fact, before adding the active ingredient, the polymeric material which has been plasticised in the extrusion stage is cooled to a temperature lower than the extrusion temperature of the polymeric material in the extrusion stage, but at which the polymeric material can in any case be formed by pressing, to obtain the solid medicine. In this way the temperature of the polymeric material may be brought to a value which the active ingredient can withstand without degrading. In this way a medicine is obtained whose therapeutic properties are not compromised.

By lowering the temperature of the polymeric material before adding the active ingredient or the active ingredients, it is also possible to use many different active ingredients, which can be chosen depending on the desired therapeutic effect. That makes the method according to the first aspect of the invention particularly versatile.

Moreover, a wide degree of choice is ensured in terms of the type and the quantity of any additives, that is to say, substances able to support the action of the polymeric material or adjuvants of the active ingredient. By lowering the temperature of the polymeric material downstream of the extrusion stage, it is in fact possible to use additives which would degrade if they were to be added to the polymeric material in the extrusion stage.

By cooling the polymeric material before adding the active ingredient, it is possible to widen the workability window for making the solid medicine, even with active ingredients which do not easily degrade.

Forming by pressing also allows a reduction in the internal stresses and frictions generated in the compound used to form the solid medicine, which helps to keep the temperature of the compound limited.

Moreover, forming by pressing can be performed in line with extrusion of the polymeric material, which makes it possible to obtain the solid medicine with a high production speed.

The production speed is also increased because the solid medicine is formed after the polymeric material has already been partially cooled, which makes it possible to cool the solid medicine more quickly after the forming and therefore reduces the cycle time.

The active ingredient is added to the continuous flow of polymeric material while the polymeric material is fluid enough to be pressed.

In an embodiment, the polymeric material intended to form the polymeric matrix is an amorphous polymer having a glass transition temperature.

In this embodiment, the active ingredient may be added to the polymeric material after having cooled the polymeric material, downstream of the extrusion stage, to a temperature higher than the glass transition temperature of the amorphous polymer.

In particular, in the extrusion stage the amorphous polymer may be brought to an extrusion temperature at least 80 °C higher than the glass transition temperature.

The active ingredient may be added to the amorphous polymer after having cooled the amorphous polymer, downstream of the extrusion stage, to a working temperature at least 50°C higher than the glass transition temperature.

With these values of the working temperature, the viscosity of the amorphous polymer is still low enough for it to be formed by pressing.

In an alternative embodiment, the polymeric material intended to form the polymeric matrix may comprise a semi-crystalline polymer.

The semi-crystalline polymer includes a crystalline fraction and an amorphous fraction. The crystalline fraction has a melting temperature and a crystallisation temperature. The amorphous fraction has a glass transition temperature.

In the extrusion stage, the polymeric material may be heated to a temperature higher than the melting temperature of the crystalline fraction. The active ingredient may be added after having cooled the polymeric material, downstream of the extrusion stage, to a temperature higher than the crystallisation temperature of the crystalline fraction.

In an embodiment, the method comprises the step of mixing the compound, in order to evenly disperse the active ingredient in the polymeric material. The step of mixing the compound may be carried out inside a twin-screw extruder.

Owing to the combined action of the two screws included in the twin-screw extruder, it is possible to obtain a particularly even dispersion of the active ingredient in the polymeric material, thereby mixing the active ingredient with the polymeric material without there being a substantial increase in the temperature.

In an embodiment, the step of pressing the compound to obtain a solid medicine in the compressed state comprises cutting a continuous flow of the compound to obtain successive doses of compound, and compression moulding each dose in a mould to form the solid medicine in the compressed state.

By compression moulding, the compound can be formed with high productivity, without excessively stressing its components.

In an embodiment, the step of pressing the compound to obtain a solid medicine comprises forming the solid medicine by calendering.

According to a second aspect of the invention, an apparatus is provided for making a solid medicine, the solid medicine comprising a solid dispersion which includes at least one polymeric matrix in which at least one active ingredient is dispersed, wherein the apparatus comprises:

- an extrusion stage for extruding at least one polymeric material intended to form the polymeric matrix of the solid medicine;

- a cooler positioned downstream of the extrusion stage for cooling the polymeric material;

- a metering unit positioned downstream of the cooler, for adding the active ingredient to the polymeric material which has been cooled, thereby obtaining a compound comprising at least the polymeric material and the active ingredient;

- a mixer for mixing the compound;

- a pressing device for pressing the compound, so as to obtain the solid medicine.

Owing to the cooler, which cools the polymeric material coming from the extrusion stage, it is possible to add the active ingredient to a polymeric material which is already partially cooled, but is still fluid enough to be pressed. In this way, the risks of the active ingredient degrading due to the high temperatures are reduced, if not eliminated.

The apparatus provided by the second aspect of the invention is also very versatile because, by lowering the temperature at which the active ingredient is added in the polymeric material, one increases the number of active ingredients and/or additives different from each other which can be used.

Finally, the pressing device allows the compound to be formed at temperatures lower than those normally used in the injection moulding of prior art apparatuses, which helps to avoid damaging the active ingredient. The invention may be better understood and implemented with reference to the accompanying drawings, which illustrate an example, non-limiting embodiment of it, in which:

Figure 1 is a schematic top view showing an apparatus for making solid medicines;

Figure 2 is a schematic side view of the apparatus of Figure 1 ;

Figure 3 is a graph schematically showing the distribution of temperatures in the apparatus of Figure 1 , in the case in which an amorphous polymer is used;

Figure 4 is a graph like that of Figure 3, relative to a semi-crystalline polymer;

Figure 5 is a graph which shows the results of the DSC analysis on an amorphous polymer, with different scan speed values;

Figure 6 is a graph showing how the viscosity varies depending on the temperature for an amorphous polymer, with a relatively low heating/cooling speed value;

Figure 7 is a graph like that of Figure 6, relative to a higher heating/cooling speed value.

Figures 1 and 2 show an apparatus 1 for making solid medicines, for example medicines intended for oral administration, such as tablets, pastilles, pills and lozenges, of any shape or size. The apparatus 1 may also be used for making solid medicines intended for rectal administration, for example suppositories.

The solid medicines made by means of the apparatus 1 may be considered to be solid medicines in a compressed state since, as will be described in more detail below, they are made by pressing.

The solid medicines made by means of the apparatus 1 may comprise a solid dispersion which includes a polymeric matrix in which one or more active ingredients are dispersed, as well as other additives if necessary.

The polymeric matrix may be in the amorphous or semi-crystalline form. In the latter case, an amorphous fraction and a crystalline fraction can be recognised in the polymeric matrix.

The polymeric matrix may comprise one or more polymeric materials, in copolymer or homopolymer form, such as for example povidone, copovidone, copolymers of methacrylic acid, poloxamer, or others.

The polymeric materials which form the polymeric matrix are usually water- soluble or in any case soluble in the organic liquids they come into contact with inside the human body, particularly in the organic liquids present in the gastrointestinal system.

The active ingredient is a pharmaceutical active ingredient, that is to say, a substance active from a pharmaceutical viewpoint to achieve, for example, a predetermined therapeutic effect.

The additives may be of various types.

In general, the formulation of the solid medicine is chosen in such a way as to modulate the speed of dissolution of the medicine itself inside the human body. More precisely, the formulation of the solid medicine is chosen in such a way as to calibrate the availability of the active ingredient over time, after the solid medicine has been introduced into the body. As mentioned above, the polymeric material may be an amorphous polymer or a semi-crystalline polymer.

Amorphous polymers have a characteristic temperature, called the glass transition temperature T_g. This temperature is the temperature at which the glass transition of the amorphous material occurs, that is to say, a solidsolid transition in which, during heating, the amorphous material passes from a glassy, rigid and fragile solid state, to a fluid solid state. In the glassy solid state, the polymeric chains of the amorphous material are substantially stationary, whilst in the fluid solid state there are short-range movements of the polymeric chains.

The glass transition occurs when, owing to the temperature increase, the rotational movements of the kinetic units of the amorphous polymeric material are unblocked. Since, in the same material, the kinetic units may be of different types, the rotational movements are unblocked in a temperature range and therefore the glass transition occurs in a temperature range and not at a specific predetermined temperature.

Once one knows - by means of differential scanning calorimetry (DSC) - the temperature range in which the rotational movements of the kinetic units of the amorphous polymeric material are unblocked, it is possible, by means of a conventional calculation, to determine the glass transition temperature Tg.

The glass transition is affected by the heating speed or cooling speed of the material considered.

That is visible in Figure 5, which shows the results of the differential scanning calorimetry (DSC) on samples of an amorphous polymeric material.

During the differential scanning calorimetry the sample was heated, kept at a constant temperature and then cooled, multiple times.

In order to study the effects, on the glass transition temperature T_g, of the sample heating or cooling speed, multiple scanning speeds were considered during heating and cooling (that is to say, heating or cooling speeds), as specified below: vi = 5 °C/minute

V2 = 20 °C/minute v3 = 50 °C/minute v4 = 80 °C/minute

In the testing relative to heating, sample behaviour was studied while the latter was heated from 0°C to 200°C, for each of the speeds indicated above. In the testing relative to cooling, sample behaviour was studied during cooling from 200°C to 0°C, for each of the preceding speeds.

Figure 5 shows the processed thermograms, obtained from the testing described above.

The results of the testing shown in Figure 5 have been outlined in Table 1 below, which shows that the glass transition temperature T_g varies with variations in the heating or cooling speed (scanning speed) used. In particular, when the sample is heated, the glass transition temperature T_g increases as the heating speed increases, passing from a value of 89.2°C for a heating speed of 5 °C/minute to a value of 99°C for a heating speed of 80 °C/minute.

In contrast, when the sample is cooled, the glass transition temperature T_g generally decreases as the cooling speed increases, passing from a value of 85.7°C for a cooling speed of 5 °C/minute to a value of 82.1 °C for a cooling speed of 80 °C/minute.

Table 1 Moreover, as can be seen from Table 2 below, the difference between the glass transition temperature, measured during sample heating for a predetermined scanning speed, and the glass transition temperature, measured during sample cooling for the same scanning speed, increases as the scanning speed increases.

Table 2

Several studies were also carried out which demonstrate how even the viscosity of an amorphous polymer is affected by the heating or cooling speed.

Figures 6 and 7 show how the viscosity of an amorphous polymeric material varies as temperature varies, for different heating or cooling speed values. In particular, the curve C1 of Figure 6 refers to the variation in viscosity in a sample which is heated from 160°C to 210°C, with a heating speed of 1 °C/minute. The curve C2 of Figure 6 in contrast refers to the variation in viscosity in a sample which is cooled from 210°C to 160°C, with a cooling speed of 1 °C/minute.

The curve C3 of Figure 7 refers to the variation in viscosity in a sample which is heated from 150°C to 220°C, with a heating speed of 10°C/minute. The curve C4 of Figure 7 in contrast refers to the variation in viscosity in a sample which is cooled from 220°C to 150°C, with a cooling speed of 10°C/minute.

In all of the situations analysed, the viscosity decreases as the temperature increases. However, if the heating/cooling speed is relatively low, as in the case in Figure 6, the viscosity variation as a function of temperature during heating can almost be superposed on the viscosity variation as a function of temperature during cooling.

If in contrast the heating/cooling speed is relatively high, as in the case of Figure 7, a significant difference is noticed between the curve showing how the viscosity varies during cooling and the curve showing how the viscosity varies during heating.

In general, if the heating/cooling speed is high enough, the viscosity measured during cooling is lower than the viscosity measured during heating, for a predetermined temperature.

For a given temperature, the difference between the viscosity measured during heating and the viscosity measured during cooling increases as the heating/cooling speed increases. Moreover, for a given temperature, during heating the viscosity increases as the heating speed increases (that is to say, the curve showing how the viscosity varies during heating shifts upwards in a graph of the type shown in Figures 6 and 7), whilst during cooling the viscosity decreases as the cooling speed increases (that is to say, the curve which shows how the viscosity varies during cooling shifts downwards in a graph of the type shown in Figures 6 and 7).

The amorphous polymeric material therefore has a hysteresis in the viscosity trend depending on the temperature, if the behaviour of the material during heating and during cooling is compared. This hysteresis is more pronounced, the higher the heating/cooling speed is.

Therefore, the more an amorphous polymeric material is rapidly cooled, the more its viscosity decreases, for a predetermined temperature.

As mentioned above, semi-crystalline polymers have an amorphous fraction and a crystalline fraction. The amorphous fraction has a glass transition temperature T_g, as previously defined. The crystalline fraction in contrast has a melting temperature Tf and a crystallisation temperature Tc.

The melting temperature Tf is the temperature at which the crystalline fraction of the semi-crystalline material, during heating, passes from the solid state to the melted state. The crystallisation temperature Tc is the temperature at which the crystalline fraction of the semi-crystalline material crystallises during cooling. The crystallisation temperature Tc is lower than the melting temperature Tf. As was previously described for the glass transition, the crystallisation and melting also do not occur at a specific temperature, but in a range of temperatures. However, it is usual practice to define a single value for the melting temperature, and for the crystallisation temperature, those values being calculated in a standardised way from the relative ranges.

For a semi-crystalline material, the crystallisation temperature of the crystalline fraction is usually significantly higher than the glass transition temperature of the amorphous fraction.

The apparatus 1 comprises an extruder 2, suitable for being fed with at least one polymeric material intended to form the polymeric matrix of the solid medicine. The polymeric material may be inserted into the extruder 2 through a hopper 3. The polymeric material may be in the form of pellets. It is also possible to insert more than one polymeric material into the extruder 2 if the composition of the solid medicine so requires.

The extruder 2 may be a single-screw extruder, that is to say, having a single extrusion screw. However, this condition is not necessary and, in place of the single-screw extruder, other types of extruder may be used.

The polymeric material is fed along a path P, initially inside the extruder 2. Simultaneously, the polymeric material is heated to obtain a polymeric material in a fluid state. The screw of the extruder 2 allows the polymeric material to be homogenised from a thermal viewpoint.

The extruder 2 defines an extrusion stage in which the temperature of the polymeric material is increased until it reaches an extrusion temperature Ti. The apparatus 1 further comprises a cooler 4, positioned downstream of the extruder 2 for cooling the continuous flow of extruded polymeric material, in such a way that the temperature of the polymeric material falls below the value of the extrusion temperature Ti reached in the extruder 2.

The cooler 4 may comprise a heat exchanger, for example a heat exchanger having an outer jacket in which a cooling fluid circulates. The heat exchanger may operate as a counter-flow heat exchanger.

In an alternative embodiment, the cooler 4 may be included in the extruder 2, in the sense that the cooler 4 may comprise a cooling section arranged in the extruder 2 downstream of the extrusion stage.

In general, in the cooler 4 the temperature of the polymeric material is reduced to a value at which the polymeric material remains fluid enough to allow the polymeric material to be subsequently formed.

More specifically, the temperature to which the polymeric material is cooled in the cooler 4 may vary depending on various factors, one of which is the type of polymeric material processed.

Figure 3 refers to the case in which the polymeric material which is processed in the apparatus 1 is an amorphous polymer and shows how the temperature of the amorphous polymer varies, shown on the y-axis, depending on the position of the amorphous polymer along the path P inside the apparatus 1 . This position is shown on the x-axis.

The amorphous polymer enters the extruder 2 at an initial temperature which may be equal to the ambient temperature TA.

The stretch P1 in Figure 3 refers to a step of heating the amorphous polymer inside the extruder 2. During this step, the temperature of the amorphous polymer is increased from the initial value, that is the temperature of the amorphous polymer upon entering the extruder 2, to the extrusion temperature Ti, which is higher than the glass transition temperature T_g.

In an example embodiment, it may happen that Ti > Tg + 70°C, for example Ti > Tg + 80°C.

At the extrusion temperature Ti, the polymeric chains of the amorphous polymer have reached sufficient mobility for the amorphous polymer to be able to be extruded.

The temperature of the polymeric material is kept constant, equal to the value Ti, while the polymeric material advances inside the extruder 2, as shown by the horizontal stretch P2 in Figure 3.

In the cooler 4, the temperature of the polymeric material is reduced to a working temperature T2 higher than the glass transition temperature T_g of the amorphous polymer. More specifically, it may happen that T2 Tg + 50°C.

The temperature decrease in the cooler 4 is indicated by the stretch P3 in Figure 3. The amorphous polymer remains at a substantially constant temperature, equal to the working temperature T2, during the subsequent operation, in particular while the amorphous polymer is shaped to obtain the solid medicine, as shown by the stretch P4 in Figure 3.

Figure 4 refers to the case in which the polymeric material processed in the apparatus 1 is a semi-crystalline polymer, having predetermined values for the glass transition temperature T_g of the amorphous fraction and for the crystallisation temperature Tc and the melting temperature Tf of the crystalline fraction.

In this case, the semi-crystalline polymer is heated, in the extruder 2, to an extrusion temperature T1 higher than the melting temperature Tf of the crystalline fraction, as indicated by the stretch P1. The semi-crystalline polymer remains at the temperature T1, as indicated by the stretch P2, until it enters the cooler 4.

In a first example embodiment, in the cooler 4 the semi-crystalline polymer is cooled until it reaches a working temperature T2(A), which is higher than the crystallisation temperature Tc of the crystalline fraction, but lower than its melting temperature Tf. This is indicated by the stretch P3(A) in Figure 4, whilst the next stretch P4(A) indicates that the temperature of the semicrystalline polymer after cooling in the cooler 4 remains substantially constant, until the solid medicine is formed.

In a second example embodiment, the semi-crystalline polymer may be cooled in the cooler 4 until it reaches a working temperature T2(B) which, although being lower than the temperature T1 of the material at the outfeed of the extruder 2, is still higher than the melting temperature Tf of the crystalline fraction. This is indicated by the stretch P3(B) in Figure 4, whilst the next stretch P4(B) indicates that the temperature of the semi-crystalline polymer after cooling in the cooler 4 remains substantially constant, until the solid medicine is formed. In both of the embodiments shown in Figure 4, the working temperature reached by the semi-crystalline polymer at the outfeed of the extruder 2 is significantly higher than the glass transition temperature of the amorphous fraction, since that temperature is well below the crystallisation temperature. The inclination of the stretch P3 in Figure 3, like that of the stretches P3(A) and P3(B) in Figure 4, indicates the cooling speed of the polymeric material in the cooler 4 and, in the case of an amorphous polymer, is correlated with the apparent viscosity.

Downstream of the cooler 4, the apparatus 1 has an adding zone 5 for adding to the continuous flow of polymeric material one or more active ingredients, in particular pharmaceutical active ingredients which may be intended to perform a therapeutic action in the final solid medicine. The adding zone 5 may comprise a metering unit 6, of the known type, for inserting the active ingredient in a precision measured way into the flow of polymeric material. The active ingredient may be in powder, liquid or another form.

In the metering unit 6, or in another metering unit placed near the metering unit 6, it is possible to also add other additives to the flow of polymeric material. Alternatively, the additives may be added to the polymeric material upstream of the metering unit 6, for example in the extruder 2, or even downstream of the latter.

The apparatus 1 also comprises a mixer 7 for mixing the continuous flow of polymeric material, to which the active ingredient and any additives have been added, so as to obtain a chemically and thermally homogeneous compound.

The mixer 7 may comprise a twin-screw extruder 8, that is to say, an extruder provided with two screws rotatable about respective parallel axes, for example horizontal axes, capable of evenly mixing the compound.

The twin-screw extruder 8, in addition to guaranteeing a particularly effective mixing action owing to the combined action of the two screws, allows processing of the compound without excessively stressing it, so that the temperature of the compound is kept substantially constant, that is to say, significant heat increases are avoided.

In an alternative embodiment, the mixer 7 may be of a type different from the twin-screw extruder. For example, the mixer 7 could comprise a singlescrew extruder or another type of mixer.

The adding zone 5 may be arranged in an initial portion of the mixer 7 relative to an advancement direction of the compound in the apparatus 1 .

The mixer 7 defines a mixing stage for mixing the compound comprising at least the polymeric material, the active ingredient and possibly the additives. The mixer 7 may be thermally conditioned, for example with oil or another fluid, to keep the temperature of the compound substantially constant.

In an embodiment, the cooling stage and the mixing stage may be integrated in the extruder 2, that is to say, may be in the form of respective cooling and mixing sections which are arranged downstream of an extrusion stage of the extruder 2.

The temperature of the compound inside the mixer 7 may remain constant, for example substantially equal to the value of the temperature of the polymeric material at the outfeed of the cooler 4, as shown by the stretch P4 in Figure 3 or by the stretches P4(A) or P4(B) in Figure 4.

The temperature of the compound in the mixer 7 is lower than the degradation temperature at which the active ingredient and/or any additives start to degrade. In this way, the active ingredient and/or any additives are not damaged by the high temperatures, when they are added to the flow of polymeric material coming from the cooler 4.

In the cooler 4, the polymeric material coming from the extruder 2 may be subjected to relative high cooling speeds, for example higher than or equal to 5°C/min. In one embodiment, the cooling speed of the polymeric material in the cooler 4 may be higher than or equal to 10° C /min.

Adopting relatively high cooling speeds has important consequences, particularly in the case in which the polymeric material is an amorphous polymer. In fact, using high cooling speeds, the glass transition temperature T_g of the amorphous polymer decreases relative to that which would be achieved with lower cooling speeds, as previously described with reference to Figure 5 and to Tables 1 and 2. That means that, in the curve of Figure 3, by increasing the cooling speed in the stretch P3 (that is to say, the gradient of the stretch P3) it is possible to have lower temperatures in the stretch P4. In other words, by quickly cooling the material in the cooler 4, it is possible to decrease the glass transition temperature and consequently to decrease the working temperature T2 which the polymeric material has in the mixer 7 and while it is shaped. In fact, the working temperature T2 is a predetermined quantity higher than T_g, for example 50°C, so that a decrease in T_g also makes it possible to decrease T2.

That has advantageous effects as regards the degree of freedom in the choice of the formulation of the solid medicine, both as regards the type of active ingredient, and as regards the type and the quantity of additives.

Moreover, by adopting relatively high cooling speeds in the cooler 4, the viscosity of the polymeric material is lower than that which would be achieved if the polymeric material were to be slowly cooled, as previously described with reference to Figures 6 and 7. That allows the compound to be kept fluid enough, and therefore allows it to be formed, even if relatively low temperatures are reached in the cooler 4, and therefore even if the compound is worked at a relatively low working temperature T2.

At the outfeed of the mixer 7, an outfeed duct 9 is provided which ends with an outlet mouth, from which a continuous flow of compound comprising the polymeric material, the active ingredient (or the active ingredients) and any additives comes out, at a temperature substantially equal to the temperature T2 (or T2(A) or T2(B)).

The outlet mouth may be defined by the outfeed section of a nozzle placed at the end of the outfeed duct 9.

In the example shown, the outlet mouth is directed upwards, so that the flow of the compound comes out of the outlet mouth in a substantially vertical upward direction. However, this condition is not necessary, and the outlet mouth could be oriented differently from what is shown in Figures 1 and 2. For example, the outlet mouth could be oriented in such a way that the flow of compound comes out of the outfeed duct 9 in a substantially vertical downward direction, or in a substantially horizontal or inclined direction.

The apparatus 1 also comprises at least one separating element 1 1 or separator for separating from the continuous flow of compound coming out of the outlet mouth a dosed quantity or dose 12 of compound. The dose 12 corresponds to the quantity of compound necessary to form a solid medicine, for example to the mass or to the weight of a single pastille.

The apparatus 1 also comprises at least one conveying element 13 or conveyor for moving a dose 12 away from the outlet.

In the example shown, the separating element 1 1 is an edge of the conveying element, particularly a lower edge of the conveying element 13, which passes over the outlet mouth to scrape from the outlet mouth the quantity of compound which came out during the interval between two consecutive passes of the conveying elements 13. However, this condition is not necessary, since it is also possible to use separating elements 11 different from what is shown in Figure 1 , for example a single blade which moves independently of the conveying element 13.

The apparatus 1 also comprises a pressing device which includes at least one mould 14 for forming a solid medicine from a dose 12. The mould 14 is configured to form the solid medicine from the dose 12 by compression moulding.

The mould 14 may comprise a first half-mould 15 and a second half-mould 16, movable one relative to the other along a moulding direction D, which in the example shown is vertical, between an open position Q1 and a closed position Q2.

In the open position Q1 , the first half-mould 15 and the second half-mould 16 are at a distance from each other, so that a dose 12 of compound can be released between the first half-mould 15 and the second half-mould 16. Moreover, in the open position Q1 it is possible to remove from the mould

14 a solid medicine which has already been formed.

In the closed position Q2, the first half-mould 15 and the second half-mould 16 are near each other, in such a way that between the first half-mould 15 and the second half-mould 16 a closed forming chamber is defined, having a shape corresponding to the shape of the solid medicine.

In the example shown, the first half-mould 15 is a female half-mould having a cavity and the second half-mould 16 is a male half-mould comprising a punch. The female half-mould is positioned below the male half-mould, in such a way that the dose 12 is released into the cavity of the female halfmould. However, this condition is not necessary and, in an alternative embodiment not shown, the male half-mould could be positioned below the female half-mould, in such a way that the dose 12 is released onto an upper surface delimiting the punch.

Moreover, the first half-mould 15 and the second half-mould 16 could be positioned in such a way that the moulding direction D is not vertical. The moulding direction D could for example be horizontal, or oblique.

The conveying element 13 is movable along a closed path, for example but not exclusively circular, in such a way as to pick up a dose 12 which the separating element 11 has separated from the continuous flow of compound and to convey the dose 12 towards the mould 14.

In the example shown, there is provided a plurality of conveying elements 13 which are movable along the closed path. The conveying elements 13 may be supported by a conveying carrousel 17, rotatable about an axis of rotation Y which may for example be vertical.

When the conveying element 13 is interposed between the first half-mould

15 and the second half-mould 16 of a mould 14 arranged in the open position Q1 , the dose 12 is released by the conveying element 13 onto the half-mould below and the conveying element 13 returns towards the outlet mouth of the duct 9 to pick up a new dose 12.

In the example shown, there is provided a plurality of moulds 14, which are movable along a closed path which may be circular. The moulds 14 may for example be mounted in a peripheral region of a moulding carrousel 18, rotatable about an axis Z which may be vertical.

During operation, one or more polymeric materials, for example in the form of pellets, are inserted into the extruder 2. Here the polymeric material is heated and melted until it reaches a maximum extrusion temperature Ti which, in the case of a semi-crystalline polymer, is higher than the melting temperature Tt of the crystalline fraction, as well as higher than the glass transition temperature T_g of the amorphous fraction. If the polymeric material is an amorphous polymer, in the extruder 2 a temperature Ti of the polymeric material is reached which is at least 80°C higher than the glass transition temperature, the temperature being intended to subsequently be lowered before adding the active ingredient.

Downstream of the extruder 2, the polymeric material is cooled in the cooler 4. The temperature of the polymeric material reached in the cooler 4 is lower than the maximum temperature which the polymeric material reached in the extruder 2, but is however higher than the glass transition temperature of the polymeric material (if amorphous) or than the crystallisation temperature of the crystalline fraction, if the polymeric material is a semi-crystalline polymer.

After having cooled the polymeric material, it is possible to add one or more active ingredients and/or one or more additives. The active ingredients and/or the additives are added to the polymeric material after the temperature of the latter has been decreased in the cooler 4, in such a way as to reduce the risks of damaging the active ingredients and/or the additives due to high temperatures.

The compound obtained by adding to the polymeric material one or more active ingredients and/or one or more additives is then mixed to make its composition homogeneous, for example in the twin-screw extruder 8.

In this way a fluid flow of compound is obtained from which it is possible to separate the doses 12, by cutting or scraping. Each dose 12 is then conveyed towards a mould 14 and released into the mould 14. Here the dose 12 can be compression moulded while the material which forms the dose 12 is at a temperature higher than the glass transition temperature, if the polymeric matrix of the solid medicine comprises an amorphous polymer, or than the crystallisation temperature of the crystalline fraction, if the polymeric matrix of the solid medicine comprises a semi-crystalline polymer. More specifically, the compound which forms the dose 12 is shaped between the first half-mould 15 and the second half-mould 16, which remain in the closed position Q2 until the solid medicine obtained has reached a consistency adequate for being handled without being damaged. At this point, the mould 14 is brought into the open position Q1 for extraction of the solid medicine and to receive a new dose 12.

The apparatus 1 and the related operating method guarantee manufacturers of solid medicines a wide degree of freedom in the choice of formulation of the solid medicines which can be made. In fact, by cooling the polymeric material before adding the active ingredient or the additives, it is possible to use active ingredients which degrade at relatively low temperatures and which could not be used if they were added to the polymeric material in the extruder 2, as is the case in the prior art. It is therefore possible to increase the flexibility in the choice of active ingredients which can be used for making the solid medicine.

A similar reasoning is applicable to the additives. By adding the additives after the polymeric material has been cooled, the range of additives usable is broadened, since it is even possible to use heat-sensitive additives which would be damaged if added to the polymeric material while the latter is heated to a high temperature, as is the case in the extruder 2.

The apparatus 1 and the related operating method also increase the flexibility in the formulation of the solid medicine as regards the quantity of additives used. For example, one of the most widely used additives in the pharmaceutical sector is the plasticiser, which may even be used to avoid reaching temperatures which are too high during extrusion. By cooling the polymeric material in the cooler 4 before adding the active ingredient and/or the additives, it is possible to reduce the quantity of plasticiser or even to avoid its use. In fact the cooling to which the polymeric material is subjected in the cooler 4 makes the temperatures reached in the extruder 2 substantially unimportant, in terms of the risk of damaging the active ingredients and/or the additives.

In the apparatus 1 , the solid medicine is obtained by forming the compound by pressing. During pressing, high pressures are reached, which render the presence of the plasticisers non-essential. This too increases freedom in the formulation of the solid medicine.

The apparatus 1 and the related operating method make it possible to operate in a particularly wide range of temperatures, which helps to increase flexibility for making the solid medicine.

In an alternative embodiment not shown, the compound coming from the mixer 7 may be pressure formed by calendaring forming, rather than by compression moulding. In this case, a pair of calendering rollers may be used in place of the moulds 14. Alternatively, it is also possible to use a calendering roller in combination with a belt.

The components of the apparatus 1 are easily cleanable. For example, the twin-screw extruder 8 can be easily opened, disassembled and cleaned to remove from it any residues of materials used to make the solid medicine. The extruder 2 and the cooler 4 are also easily cleanable. That allows careful cleaning of the apparatus 1 when production of one type of solid medicine has ended and a new type of solid medicine is to be made. This ensures that in the apparatus 1 there are no remaining residues of the components of the previous solid medicine, which could contaminate the solid medicine subsequently made.

The apparatus 1 and the related operating method allow solid medicines to be made with high productivity.

In particular, in the apparatus 1 the solid medicines are made in line with production of the compound, since the mixer 7 in which the compound is created by mixing the polymeric material with the active ingredients and/or the additives is positioned in line with the pressing device. In this way, the compound is directly fed to the pressing device, without being cooled to ambient temperature in advance. The pressing device may comprise a moulding carrousel as in the case shown in Figures 1 and 2, or a plurality of moulds positioned with a linear or matrix arrangement, or even a single mould in a fixed position.

Claims

1. A method for making a solid medicine, the solid medicine comprising a solid dispersion which includes at least one polymeric matrix in which at least one active ingredient is dispersed, wherein the method comprises the steps of:

- extruding at least one polymeric material in an extrusion stage (2), the polymeric material being intended to form the polymeric matrix of the solid medicine;

- adding the active ingredient to the polymeric material, thereby obtaining a compound comprising at least the polymeric material and the active ingredient;

- pressing the compound to obtain the solid medicine, wherein the active ingredient is added to the polymeric material after having cooled the polymeric material and decreased temperature thereof downstream of the extrusion stage (2).

2. The method according to claim 1 , wherein the polymeric material intended to form the polymeric matrix comprises an amorphous polymer having a glass transition temperature (T_g), and wherein the active ingredient is added to the polymeric material after having cooled the polymeric material, downstream of the extrusion stage (2), to a working temperature (T2) higher than the glass transition temperature (T_g) of the amorphous polymer.

3. The method according to claim 2, wherein the working temperature (T2) is at least 50°C higher than the glass transition temperature (T_g) of the amorphous polymer.

4. The method according to claim 2 or 3, wherein in the extrusion stage (2), the amorphous polymer is heated to an extrusion temperature (T1) which is at least 80°C higher than the glass transition temperature (T_g) of the amorphous polymer.

5. The method according to claim 1 , wherein the polymeric material intended to form the polymeric matrix comprises a semi-crystalline polymer which includes an amorphous fraction and a crystalline fraction, and wherein the active ingredient is added to the polymeric material after having cooled the polymeric material, downstream of the extrusion stage (2), to a temperature higher than or equal to the crystallisation temperature (Tc) of the crystalline fraction.

6. The method according to claim 5, wherein in the extrusion stage (2), the semi-crystalline polymer is heated to an extrusion temperature (Ti) which is higher than the melting temperature (Tt) of the crystalline fraction.

7. The method according to any preceding claim, and furthermore comprising the step of mixing the compound obtained by adding said at least one active ingredient to the polymeric material.

8. The method according to claim 7, wherein the step of mixing the compound occurs in a twin-screw extruder (8).

9. The method according to any preceding claim, wherein the polymeric material is cooled downstream of the extrusion stage with a cooling speed higher than or equal to 5°C/minute, preferably higher than or equal to 10°C/minute.

10. The method according to any preceding claim, wherein the step of pressing the compound to obtain the solid medicine comprises cutting a continuous flow of the compound to obtain a dose (12) of compound, and forming the dose (12) by compression in a mould (14) to form the solid medicine.

11 . The method according to any one of claims 1 to 9, wherein the step of pressing the compound to obtain a solid medicine comprises obtaining the solid medicine by calendering.

12. The method according to any preceding claim, wherein at least one additive is added to the polymeric material after having cooled the polymeric material downstream of the extrusion stage (2).

13. An apparatus for making a solid medicine, the solid medicine comprising a solid dispersion which includes at least one polymeric matrix in which at least one active ingredient is dispersed, wherein the apparatus comprises:

- an extrusion stage (2) for extruding at least one polymeric material intended to form the polymeric matrix of the solid medicine;

- a cooler (4) positioned downstream of the extrusion stage (2) for cooling the polymeric material;

- a metering unit (6) positioned downstream of the cooler (4) for adding the active ingredient to the polymeric material which has been cooled, thereby obtaining a compound comprising at least the polymeric material and the active ingredient;

- a mixer (7) for mixing the compound;

- a pressing device (18) for pressing the compound, so as to obtain the solid medicine.

14. The apparatus according to claim 13, wherein the mixer (7) comprises a twin-screw extruder (8).

15. The apparatus according to claim 13 or 14, wherein the pressing device (18) comprises a mould (14) for obtaining the solid medicine by compression moulding.

16. The apparatus according to claim 15, and furthermore comprising a separating element (11 ) for separating a dose (12) of compound from a continuous flow of compound coming from the cooler (4).

17. The apparatus according to claim 16, and furthermore comprising a conveying element (13) movable along a path for conveying the dose (12) towards the mould (14).