WO2003070149A1

WO2003070149A1 - Process for the preparation of compositions and apparatus embodying the process

Info

Publication number: WO2003070149A1
Application number: PCT/IB2003/000606
Authority: WO
Inventors: Giuseppe Motta; Silvano Valtancoli
Original assignee: Tecnea Engineering S.R.L.
Priority date: 2002-02-22
Filing date: 2003-02-18
Publication date: 2003-08-28
Also published as: BR0303191A; AU2003246872A1; ITBO20020094A0; ITBO20020094A1

Abstract

A process for the preparation of a composition (1) comprising one or more excipients and at least one active ingredient comprises at least the following steps: feeding along a feed line (A) a first film web (2), exhibiting at least high heat-resistant and non-stick properties and having at least one cavity (3); filling the cavity (3) with a predetermined does of the composition (1); unwinding along the feed line (A) a second film web (4), exhibiting at least high heat-resistant and non-stick properties in such a way as to lay it over the first film web (2) to form a partly closed cavity (3) with the dose in it; forming a closed pack (C) of the composition (1) in stable, compact form by applying an electromechanical force to the cavity (3) for a set time period and at a frequency falling within a predetermined range.

Description

PROCESS FOR THE PREPARATION OF COMPOSITIONS AND APPARATUS EMBODYING THE PROCESS

Technical field

The present invention relates to a process for the preparation of compositions, in particular compositions constituting pharmaceutical forms, and to an apparatus that embodies the process.

In the present specification, reference is made, purely by way of example and without thereby restricting the scope of the invention, to pharmaceutical forms with controlled release of the active ingredient. More specifically, these pharmaceutical forms permit the slow or rapid release of the active ingredient (hence the term "controlled") , where the slow or rapid release is obtained by mixing the drug (or drugs) with an appropriate excipient (or excipients) or by suitably treating the product.

Background art

At present, to obtain a pharmaceutical form of this type, the mixture of ingredients is subjected to various processes, such as compacting by compression, granulation, extrusion and filming, all of which are well within the knowledge of experts m the trade.

All of these processes, however, present drawbacks.

Dry compacting of the product, for example, is possible only with suitable materials, requires specific excipients which are not always compatible with the possible therapeutic uses of the drug, and is comparatively complex and requires expensive equipment .

The wet granulation process exposes the drug and the excipients to the harmful action of a diluent and heat, and besides being lengthy and expensive, requires the use of binders that may interfere with the bio-availability of the drug.

The filming process also exposes the active ingredients and excipients to the harmful action of heat, water and other solvents. It too is lengthy and expensive. Lastly, extrusion is possible only with ingredients that have a plastic consistency when hot, which means that active ingredients and excipients are subjected to prolonged heating that potentially impairs the correct functioning of the drug.

To avoid these drawbacks (assuming that many active ingredients are highly heat-sensitive) , prior art has devised several methods whereby these controlled release pharmaceutical forms are obtained by applying a mechanical or electromechanical action for a well-defined period of time and at a well-defined frequency. Thus, patent EP 675.710, describes how, by applying a mechanical or electromechanical force at frequencies within a defined range to a mixture comprising an active ingredient and one or more selected excipients, it is possible to obtain a pharmaceutical form suitable for administration in a desired manner.

In practice, for oral, topical or parenteral applications, the pharmaceutical form comprises a mixture of one or more excipients with one or more active ingredients compatible with each other, this mixture being subjected to mechanical or electromechanical action at a frequency of between 1 kHz and 2 MHz for a set period of time, to give a matrix, a tablet or a single or multi-layered film that releases the active ingredient in the stomach or intestine or by contact with the skin or in a body fluid in a slow or rapid but always controllable manner. In practice, the mixture is subjected to the action of an ultrasound energy source which, thanks to its ability to act in a very short time period, changes the state of the product from crystalline to amorphous without having any negative effects on the active ingredient but, on the contrary, giving it the form most suited to use with controlled release.

From the point of view of end result, the pharmaceutical forms thus made fulfil their purpose but the method and means developed to prepare them present some disadvantages linked directly to the fact that the product subjected to the treatment has a very sticky consistency which tends to adhere to any surface it comes into contact with. Thus, on account of the heat generated by the ultrasound means, small quantities of the product cling to the working parts of the production apparatus during the production process.

The production apparatus therefore necessitates periodic cleaning cycles using mechanical means or chemicals (for example solvents) to remove all traces of the product from the working parts in order to maintain required standards of hygiene (for example when changing over to another product) , not to mention the fact that the gram weight of the resulting pharmaceutical form may not always be accurate. The cleaning procedures slow down the entire production process which involves not only the production line where the pharmaceutical forms themselves are prepared but also the packaging lines downstream. To avoid this general slowdown and keep productivity at a high level, it is necessary to increase the number of cleaning stations.

The present invention has for an aim to overcome the above mentioned disadvantages by providing a process for the preparation of compositions, such as, for example, pharmaceutical forms, that is extremely fast, safe and accurate in making the compositions, and that guarantees the high efficiency of the production line.

Another aim of the invention is to provide an apparatus that embodies this process for the preparation of compositions and that is structurally simple, rapid and economical.

Disclosure of the invention

The above mentioned aims are achieved in a process for the preparation of compositions, a machine embodying the process and a product prepared in accordance with the process; the composition comprising at least one excipient and at least one active ingredient, the process comprising at least the following steps: feeding along a feed line a first film web exhibiting at least high heat-resistant and non-stick properties and having at least one cavity; filling the cavity with a predetermined dose of mixture constituting the composition; unwinding along the feed line a second film web, exhibiting at least high heat-resistant and non-stick properties in such a way as to lay it over the first film web to form a partly closed cavity with the dose in it; forming a closed pack of the composition in stable, compact form by applying an electromechanical force to the cavity for a set time period and at a frequency falling within a predetermined range .

Brief description of the drawings

The technical characteristics of the invention, with reference to the above aims, are clearly described in the claims below and its advantages are apparent from the detailed description which follows, with reference to the accompanying drawings which illustrate a preferred embodiment of the invention provided merely by way of example without restricting the scope of the inventive concept, and in which:

Figure 1 is a schematic side representation of the process for the preparation of compositions according to the present invention;

Figure 2 is a schematic perspective view, with some parts cut away to better illustrate others, of an apparatus embodying the process according to the present invention for the preparation of compositions;

Figures 3 and 4 are schematic perspective views illustrating scaled-up details of a zone B of the apparatus of Figure 2.

Detailed description of the preferred embodiments of the invention With reference to the accompanying drawings, in particular

Figure 1, the process according to the invention is used to prepare compositions.

These compositions, labelled 1, comprise at least one excipient and at least one active ingredient . Traditional excipients may be substituted with starches or starch derivatives to obtain the desired compositions.

The active ingredient may be one of many different types of substances: for example, a purely pharmacological extract, an enzyme, a vitamin, etc.

For convenience of description, the compositions prepared using the process according to the invention will hereinafter be referred to as pharmaceutical forms but without thereby restricting the scope of the inventive concept.

As shown in Figure 1, the process comprises the following main steps :

- feeding along a feed line A a first film web 2, exhibiting at least high heat-resistant and non-stick properties and having at least one cavity 3 in it;

- filling the cavity 3 with a predetermined dose of the composition constituting the pharmaceutical form 1 to be made;

- unwinding along the feed line A a second film web 4, exhibiting at least high heat-resistant and non-stick properties, in such a way that it is laid over the first film web 2 to form a partly closed cavity 3 with the dose in it;

- forming a closed pack C of the dose constituting the pharmaceutical form 1 in stable, compact form by applying an electromechanical force to the cavity 3 for a set time period and at a frequency falling within a predetermined range.

In addition to the main steps listed above, the process preferably further comprises a step of making the cavity 3, before the step of unwinding the first film web 2, and a step of compressing the dose of mixture after the step of filling the dose into the cavity 3 and before the step of unwinding the second film web 4.

Figure 1 also shows that the step of forming the closed pack C is followed by a further step of opening the closed cavity 3 in order to enable the pharmaceutical product 1 made to drop off the feed line A.

More specifically, this opening step comprises a step of separating the first and second film webs 2 and 4 by moving the second and first film webs 4 and 2 away from each other (see also Figures 3 and 4) .

Up to now, mention of at least one cavity 3 has been made but it is obvious that there may be a continuous succession of cavities 3 since (as also shown in Figure 2) the first and second film webs 2 and 4 are unwound from first and second reels of film 2a and 4a.

The aforementioned step of forming a closed pack C to make the product 1 is performed by the action of an ultrasound energy source 5 (a customary sonotrode) at a frequency ranging from 1 kHz to 2 MHz.

To specify the step of obtaining the pharmaceutical product whereby the mixture changes from a crystalline to an amorphous state, examples of this step are given below purely by way of further description of the process according to the invention and without restricting the scope of the inventive concept.

To obtain indomethacin, for example, weighing one gram, including excipients or starches, the mixture can be treated with ultrasounds for a time period of between 2 and 8 seconds, at an energy level of between 3000 and 4000 Joules and at a frequency of between 1 kHz and 2 Mhz.

Similarly, to obtain ketoprofene and beta-cyclodextrin, the mixture can be treated with ultrasounds for a time period of between 1 and 15 seconds, at an energy level of between 2000 and 4000 Joules and at a frequency of between 1 kHz and 2 Mhz.

The two film webs 2 and 4 may consist (purely by way of example) of polytetrafluoroethylene, known by the trade name Teflon^®, with a maximum thickness of 300 microns. The process described up to now may be implemented by an apparatus illustrated schematically in Figure 2.

This apparatus, labelled 100 in its entirety, comprises the following main stations situated along the feed line A:

- a first station 6 for feeding along the feed line A the first film web 2, exhibiting at least high heat-resistant and nonstick properties, and having at least one cavity 3 in it;

- at least one second station 7 for feeding a dose of the above mentioned mixture into the cavity 3;

- a third station 8 for feeding along the feed line A a second film web 4, exhibiting at least high heat-resistant and non-stick properties, in such a way that it is laid over the first film web 2 to form a partly closed cavity 3; - at least one fourth station 9 for compacting the dose to form the product 1 and simultaneously sealing the cavity 3, and which is equipped with the means 5 for generating an electromechanical force applied to the dose. Between the first station 6 and the second station 7 the apparatus may further comprise a station 10 for forming the open cavity 3 on the first film web 2.

Similarly, between the dose feeding station 7 and the station 8 for feeding the second film web 4, the apparatus further comprises a station 11 for pressing the dose that has been filled into the cavity 3.

Downstream of the fourth station 9 along the feed line A, as illustrated in Figure 2, there may be a further station 12 for opening the cavity 3 designed to separate the product 1 from the cavity 3 by moving the first and second film webs 2 and 4 away from each other (see also Figures 1 and 4) .

Downstream of the opening station 12 along the feed line A, there may be a station 13 for collecting the product 1 made. The collecting station 13 may simply consist of a container for the products 1, or a conveyor unit on which the products travel to other stations for further processing (for example crushing) or for temporary storage prior to use at a later stage.

Looking more closely at the constructional details, the first station 6 may comprise the aforementioned first continuous reel 2a of film 2 for feeding the film 2 along the feed line A.

The further station 10 for forming the cavity 3 in the first film web 2 may comprise a punching element 16, mounted above the first film web 2 and equipped with a punch head 17 that moves from an idle position in which it is away from the first web 2 to a working position (shown in Figure 1 by the arrow FI indicating its motion) where the head 17 is in contact with the first web 2 inside a matching matrix or moulding element 18 in such a way that the cavity 3 is formed by plastic deformation of the flat film web 2. The second station 7 may comprise a dosing unit 14 (for example a suitable hopper) designed to fill the dose of mixture into the cavity 3. The unit 14 is mounted above the film web 2 that is moving along the feed line A.

The further pressing station 11 may comprise means 19 for compressing the dose in the cavity 3, the means 19 (which are illustrated very schematically since they are of well known type) are mounted above the first film web 2 and are mobile (see arrow F2 in Figure 1) between an idle position, where the means 19 are away from the dose, and a working position (shown in Figure 1) where the means 19 are in contact with the dose inside a shaping contact element 20 in such a way as to compact the dose within the cavity 3. The pressing step applied to the dose inside the cavity may be repeated two or more times.

The second station 8 comprises a second reel 4a of film 4 for feeding the film web 4 along the feed line A in such a way as to lay it over the first film web 2. The fourth station 9 comprises the ultrasound generating means 5 (that is to say, at least one sonotrode) , which are mounted above the cavity 3 moving forward and which are mobile from an idle position, in which they are away from the cavity 3, to a working position in which the ultrasound generating means 5 are in stable contact with the two film webs 2 and 4 with the dose between them (see Figure 1 and arrow F3) . The step of applying the electromechanical force is performed inside a matrix or contact element 15 positioned under the cavity 3 and facing the ultrasound generating means 5: thus, the product 1 is made, that is to say, changed from a crystalline to an amorphous state, inside the cavity when the latter is closed and forms a sealed pack C.

Obviously, the above mentioned matrices or contact elements can move towards and away from the feed line in synchrony with the corresponding means . Once the product 1 has been made according to the steps described above, the two film webs 2 and 4 are wound onto two rollers 21 and 22, which are power driven in stepping fashion, in such a way that the product 1 can also be extracted from the cavity 3. The two rollers 21 and 22 are mounted downstream of the fourth station 9 along the feed line A and at separate positions so that the feed directions of the first and second film webs 2 and 4 diverge (see arrows F4 and F5) in such a way as to separate the parts of the two film webs 2 and 4 previously sealed to each other by application of the electromechanical force and thus allowing the product 1 to fall out. More specifically (see Figures 3 and 4), the sealed parts consist of a single circular zone of the second film web 4 corresponding to the perimeter of the cavity 3 which, under the compressing action of the ultrasounds, tends to form a wrinkled surface due to the air forced out of the granules of mixture during the change from crystalline to amorphous state: this feature creates a zone where separation is facilitated (enabling the second film web 4 to be "peeled" off the first film web 2) precisely because of the smaller percentage of contact between the two film webs 2 and 4 in that zone. To facilitate extraction of the product from the cavity 3, the first film web 2, after being separated from the second film web 4, is diverted downwardly by a further roller 23 which causes the product 1 to be pushed out of the cavity 3 (see arrow F6) .

Obviously, if the pack obtained by the action of the sonotrode 5 has to be maintained, the rollers 21 and 22 are disabled in order to keep the film webs 2 and 4 together around the cavity 3.

In another embodiment of the apparatus 100, the working stations described above are enclosed in a zone with a controlled atmosphere (represented by a housing 101 drawn with a dashed line in Figure 2) . This controlled atmosphere might be obtained, for example, using an inert gas.

The process and apparatus described above may be used to prepare compositions for further processing, for example in a line for the production of medicinal preparations. However, the pack C with the product 1 inside it might equally well be left as such as it is without having to be opened for further processing.

Thus, as shown in Figure 3, the product fed out of the apparatus may be a finished product since it comprises the aforementioned composition 1, with at least one excipient and at least one active ingredient, enclosed in a stable compact form within a sealed cavity 3 made by a pair of film webs 2 and 4 exhibiting excellent heat-resistant and non-stick properties.

This means that the products can be made in multiple packs ready for despatch to other companies without necessitating repackaging or storage, all of which adds up to considerable savings on the cost of the end product.

The process and apparatus described above thus achieve the aims of the invention since they offer the possibility of changing the mixture from a crystalline state to an amorphous state without direct contact between the means that perform this change of state and the substances in the mixture itself.

This makes it possible to keep a good rate of production without negatively affecting the end quality of the product, especially in the case of pharmaceutical products, because the substances are kept in a suitable micro-environment both before and after ultrasound treatment.

Moreover, the end pack of the product thus obtained can be left as it is whether the product is a finished product or whether it is sent to another production line or to a packaging line.

It will be understood that the invention can be subject to modifications and variations without thereby departing from the scope of the inventive concept. Moreover, all the details of the invention may be substituted by technically equivalent elements.

Claims

1. A process for the preparation of a composition, the composition (1) comprising at least one excipient and at least one active ingredient, characterised in that it comprises at least the following steps : - feeding along a feed line (A) a first film web (2), exhibiting at least high heat-resistant and non-stick properties and having at least one cavity (3) in it;

- filling the cavity (3) with a predetermined dose of the composition (1); - unwinding along the feed line (A) a second film web (4), exhibiting at least high heat-resistant and non-stick properties, in such a way that it is laid over the first film web (2) to form a partly closed cavity (3) with the dose in it;

- forming a closed pack (C) of the dose constituting the composition (1) in stable, compact form by applying an electromechanical force to the cavity (3) for a set time period and at a frequency falling within a predetermined range.

2. The process according to claim 1, characterised in that the step of filling the dose of the composition involves dosing one or more excipients and at least one active ingredient of pharmacological type.

3. The process according to claim 1, characterised in that the step of feeding the first film web (2) is followed by a step of forming at least one cavity (3) in i .

4. The process according to claim 1, characterised in that between the filling step and the step of feeding the second film web (4) there is a further step of compressing the dose of the composition (1) .

5. The process according to claim 1, characterised in that the step of forming a closed pack (C) is followed by a step of opening the closed cavity (3) in such a way as to let the composition (1) drop off the feed line (A) .

6. The process according to claim 5, characterised in that the opening step comprises a step of separating the first film web (2) from the second film web (4) by moving the second film web (4) away from the first film web (2) .

7. The process according to claim 1, characterised in that the first film web (2) and the second film web (4) form part of a first continuous reel of film (2a) and a second continuous reel of film (4a) .

8. The process according to claim 1, characterised in that the step of forming a closed pack (C) to make the composition (1) is performed by the action of an ultrasound energy source (5) at a frequency ranging from 1 kHz to 2 MHz.

9. An apparatus for the preparation of a composition, the composition (1) comprising at least one excipient and at least one active ingredient, characterised in that it comprises at least the following parts along a feed line (A) :

- a first station (6) for feeding along the feed line (A) at least one first film web (2) , exhibiting at least high heat- resistant and non-stick properties, the first film web (2) having at least one cavity (3) in it;

- a second station (7) for feeding a dose of the composition into at least one cavity (3) ;

- a third station (8) for feeding along the feed line (A) a second film web (4), exhibiting at least high heat-resistant and non-stick properties, in such a way that it is laid over the first film web (2) to form a partly closed cavity (3) ;

- a fourth station (9) for compacting the dose to form the composition (1) and simultaneously sealing the cavity (3), and which is equipped with means (5) for generating an electromechanical force.

10. The apparatus according to claim 9, characterised in that between the first station (6) and the second station (7) there is another station (10) for forming at least one open cavity (3) in the first film web (2) .

11. The apparatus according to claim 9, characterised in that between the second station (7) for feeding the dose and the third station (8) for feeding a second film web (4), there is another station (11) for pressing the dose in the cavity (3) .

12. The apparatus according to claim 9, characterised in that downstream of the fourth station (9) along the feed line (A), there is a further station (12) for opening the cavity (3) so as to separate the composition (1) from the cavity (3) by moving the first film web (2) and the second film web (4) away from each other.

13. The apparatus according to claim 12, characterised in that downstream of the opening station (12) along the feed line (A), there is a further station (13) for collecting the composition (1) •

14. The apparatus according to claim 9, characterised in that the first station (6) comprises a first reel (2a) of film web (2) for feeding the film web (2) along the feed line (A) .

15. The apparatus according to claim 9, characterised in that the second station (7) comprises a dosing element (14) designed to dose the composition (1) and mounted above the film web (2) moving along the feed line (A) .

16. The apparatus according to claim 9, characterised in that the third station (8) comprises a second reel (4a) of film web (4) for feeding the film web (4) along the feed line (A) in such a way as to lay it over the first film web (2) .

17. The apparatus according to claim 9, characterised in that the fourth station (9) comprises ultrasound generating means (5) which are mounted above the cavity (3) and which are mobile from an idle position, in which they are away from the cavity (3) , to a working position in which the ultrasound generating means (5) are in stable contact with the two film webs (2, 4) with the dose between them and inside a matrix or contact element (15) located under the cavity (3) and facing the ultrasound generating means (5) so that the composition (1) is made inside a sealed pack (C) by applying the electromechanical force to it.

18. The apparatus according to claim 10, characterised in that the further station (10) for forming the cavity (3) in the first film web (2) comprises a punching element (16), mounted above the first film web (2) and equipped with a punch head (17) that moves between an idle position in which it is away from the first web (2) and a working position where the head (17) is in contact with the first web (2) inside a matching matrix or moulding element

(18) in such a way that the cavity (3) is formed by plastic deformation of the flat film web (2) .

19. The apparatus according to claim 11, characterised in that the further pressing station (11) comprises means (19) for compressing the dose in the cavity (3) , mounted above the first film web (2) and mobile between an idle position, where the means

(19) are away from the dose, and a working position where the means (19) are in contact with the dose inside a shaping element

(20) in such a way as to compact the dose within the cavity (3) .

20. The apparatus according to claim 12, characterised in that the first film web (2) and the second film web (4) are unwound from corresponding reels (2a, 4a) and are moved along a feed line (A) by power-driven rollers (21, 22) on which the film webs are rewound, the rollers (21, 22) being mounted downstream of the fourth station (9) along the feed line (A) and at separate positions so that the feed direction of the first film web (2) diverges from that of the second film web (4) in such a way as to separate the parts of the two film webs (2, 4) previously sealed to each other by the electromechanical force and thus allowing the composition (1) to fall out.

21. The apparatus according to claim 9, characterised in that the first and second film webs (2, 4) consist of polytetrafluoroethylene .

22. The apparatus according to claim 9, characterised in that at least the first station (6), the second station (7), the third station (8) and the fourth station (9) are enclosed in a housing (101) defining a controlled atmosphere within which the product (1) is made.

23. The apparatus according to claim 22, characterised in that the housing (101) contains inert gas.

24. A product prepared using the process according to claim 1, characterised in that it comprises a composition (1) including at least one excipient and at least one active ingredient enclosed in a stable compact form within a sealed cavity (3) made by a pair of facing film webs (2, 4) exhibiting at least excellent heat- resistant and non-stick properties .

25. A product prepared using the process according to claim 1, characterised in that it comprises a composition (1) constituting a pharmaceutical form consisting of at least one excipient and at least one active ingredient enclosed in a stable compact form within a sealed cavity (3) made by a pair of facing film webs (2, 4) exhibiting at least excellent heat-resistant and non-stick properties.