Single use ampoule for a device to create aerosols

(54) Title: DISPOSABLE LIGHT BULB FOR USE IN AN AEROSOL GENERATOR DEVICE (30) Unionist Priority: 11/23/2007 DE 102007056462.9 (73) Holder (s): Pari PharmaGmbh (72) Inventor (s): Mihaela Lõnner, Thomas Gallem, Uwe Hetzer (57) Abstract: DISPOSABLE AMPOULE FOR USE IN AN AEROSOL GENERATOR DEVICE. Disposable ampoule to be used in a device used to generate aerosol, comprising: a medicament container that contains a medicament and is formed of a container body (10) and a container bottom (11), and a predetermined breaking point (12) that surrounds, at least in part, the bottom of the container, characterized by containing a collar (15) that surrounds the predetermined breaking point (12) by its outer part and extends the body of the container (10) on and beyond the bottom of the container (11).

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ΡΙ0805219 -0

DISPOSABLE AMPOULE FOR USE IN A GENERATING DEVICE

AEROSOL

The present invention relates to a disposable ampoule to be used in a device to be used to generate aerosol for topical application to the skin or body cavities such as, for example, the nose and lungs, in order to diagnose, prevent or to treat diseases in man and animals. The invention substantially describes a disposable ampoule, containing a liquid drug ', and the first opening in the device is performed so as to supply the liquid drug in the aerosol generator which can be designed so that it is generated and released in a continuous, synchronized or controlled by breathing, in order to diagnose, prevent or treat illnesses.

A disposable cartridge is described in DE 10 2005 083 619 A1. The disposable ampoule, described therein, comprises a medicine container, containing a medicine, being composed of a body of the container and a bottom of the container, as well as a predetermined breaking point surrounding the bottom of the container. By means of a needle, usually supplied in the aerosol generating device, the bottom of the container is pierced along the predetermined breaking point, in order to open the disposable ampoule in order to supply the liquid medication in the aerosol generator.

The object of the present invention is to develop an ampoule, based on the known disposable ampoule, of

2/27 so that it can be easily manipulated and inserted into the aerosol generating device without risk of damage, so that no amount of medication is wasted during the process of opening the ampoule when being inserted, and also when the aerosol is being generated, thus, the interface between the aerosol generating device and the ampoule must be sealed in order to prevent contamination or accidental leakage of the medication.

The present of an ampoule described. in the advantages of the claims invention solves these problems through disposable, according to the characteristics claim 1. Other features of the present invention are described in the dependents.

The underlying idea of ​​the present invention is to surround the bottom of the container, as well as the predetermined breaking point that at least partially surrounds the bottom of the container with a protective collar, so that an accidental opening or rupture of the ampoule outside the container can be prevented. aerosol generating device due to damage to the breaking point. In addition to this function, it has also been proven, advantageously, that the collar can be used for sealing during and, optionally, also after the opening process, as well as to guide the ampoule during this process.

In this sense, the disposable ampoule for use in an aerosol generating device, according to the present invention, comprises a medicine container that

3/27 contains a medicament, particularly a liquid medicament, being formed from a container body and a bottom of the container, as well as having a predetermined breaking point that surrounds, at least partially, the bottom of the container. The disposable ampoule, according to the invention, is characterized by a collar that surrounds the predetermined breaking point on its outside, extending the body of the container over and beyond the bottom of the container. The bottom of the container and the predetermined breaking point surrounding it are thus positioned at the rear at a distance from the front end of the ampoule. disposable and are therefore protected by the collar. In addition to protection, this displacement has the additional advantage that, during the process of opening the disposable ampoule in the aerosol generating device, for example, on a needle, an internal surface of the collar can be contacted with a sealing element, for example, an o-ring or a sealing edge, surrounding the needle, when the disposable ampoule is not yet open, such that the seal is also ensured during the opening process. In addition, due to its design, the collar 'also has a conductive function, thus facilitating the precise positioning of the ampoule during the opening process.

The internal surface of the collar advantageously extends in a conical manner, starting from the bottom of the container.

The entire necklace can be designed in the form of a truncated hollow cone for this purpose. This configuration

4/27 advantageously supports the conductive function of the collar and the actuation with a possible additional sealing element in the perforating component (needle) of the aerosol generating device.

In addition, it is preferred to divide the container body into two functional areas, so that the ampoule has a modular construction. It has proved to be particularly advantageous here that the first functional area comprising the bottom of the container, is geometrically designed with respect to the no-load behavior of the ampoule and so that it is preserved identical at least in the case of all ampoules, provided for the same aerosol generating device, regardless of the size and amount of filling, whereas the second functional area, on the other hand, it is configured in a substantially cylindrical manner and, with the aim of adapting to different amounts of filler, which is designed correspondingly with different lengths. This, in particular, makes it possible to use the same aerosol generator device, basically with the same ampoules that differ only in terms of their length, which is advantageous both for reasons of production technology and also from the point of view of ease. of use. The first functional area of ​​the ampoule, which faces the aerosol generating device and thus comprises the bottom of the container, is therefore designed in such a way that the drug can be supplied to the aerosol generator with reproducible dosing accuracy , when inter alia

5/27 different angles of retention of the aerosol generating device should be taken into account. Thus, it proved to be advantageous if, at least inside the ampoule, this first functional area extends in a conical way, that is, in a tapered shape, towards the bottom of the container, with the angle between the bottom of the container and the tapered side wall, preferably in the range of approximately 105 ° to 125 ° and, preferably, 110 °. In addition, the ampoule and particularly this first functional area, can be designed in different ways also in the case of ampoules that are provided for different aerosol generating devices, that is, so that in each case, only the ampoule provided for the respective device aerosol generator can be inserted into such a device and / or the aerosol generating device is only capable of functioning with a predetermined ampoule. This type of identification or coding can be done, for example, by means of one or more coding elements. These may consist, for example, of one or more projections extending from the body of the ampoule. These projections, which fit into corresponding grooves in the aerosol generating device for these intended, allow insertion of the ampoule or prevent insertion if the combination is not correct. Said one or more projections can also be used to activate an electrical switch in order to close a circuit¹· In the aerosol generating device. Only when the circuit is closed, could the power, for example, be supplied to the aerosol generator or aerosol producer.

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Alternatively, the coding elements can be so designed that they prevent the operation of the aerosol generating device unless they are correctly recognized by the aerosol generating device. For example, the container body may comprise a readable pattern, such as, for example, a bar code, a magnetic pattern or the like, which must be interpreted and confirmed by the aerosol generating device before the operation is permitted. .

In order for the ampoule to be firmly inserted into the aerosol generating device and for the empty ampoule to be easily removed again, a retaining groove is provided centrally or closer to the bottom of the container. preferably, it surrounds the ampoule. Its position in the center of the ampoule or closer to the bottom of the container thus has the advantage that the forces necessary to open the ampoule, which rises at the point break and predetermined break through the piercing component (needle), can be absorbed as close as possible to the region where the force is being introduced. If the ampoule, as described above, is divided into two functional areas, it proved to be advantageous if the retaining groove divides the ampoule into two functional areas.

In order to further reinforce the ampoule and to react to deformation during the opening process, at least one reinforcement rib is provided in the container body. Preferably, two force ribs

7/27 diametrically opposed are provided for. It will be preferable for these ribs to extend from the front end of the ampoule, that is, at least over a partial area of ​​the collar, above and beyond the bottom of the container and over a partial area of ​​the container body. If the ampoule is divided into two functional areas, it is therefore particularly preferred that the reinforcement ribs are provided only in the first functional area or if a retaining groove is provided, on the side of the retaining groove, comprising the bottom of the container.

In addition, it is also necessary to clearly label the ampoule so that the name of the drug, batch number and expiration date are apparent. This is solved according to the invention, in opposition to the bottom of the container an ear is provided in the container body, which preferably moves away from the container body in the opposite direction to the collar. This ear comprises two planes on opposite sides, in which the necessary information can be indicated. This ear can be used, additionally, to facilitate the removal of the ampoule, that is, it can form a kind of stamp that the user can hold to push or pull the ampoule out of the aerosol generating device. This is particularly useful in the case of short ampoules for small filling volumes (see modular construction).

For this purpose, the aerosol generating device will preferably be designed in such a way that the ear to remove the ampoule is exposed. Therefore, it is also

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I 'is particularly preferred so that the ear protrudes from the aerosol generating device when the ampoule is being inserted into the aerosol generating device, so that the information mentioned above remains visible also in this case.

Depending on a configuration of the present invention, the ampoule is formed in one piece, preferably a blow-fill-seal type ampoule, which means that the ampoule is produced according to the so-called blow-fill-seal process. This technique is known, for example, from DE 38 33 036, DE 38 23 428 and US 4, 671, 763,

9,319,374 and 4,995,511 and, therefore, the specialist in the subject should consult these documents regarding the technique. Preferably, the ampoule is made of polyethylene, polypropylene or a thermoplastic copolymer.

Finally, the single ampoule or multiple components may or may not be provided with an additional element, which is a separate sealing element, inserted in the collar, in order to produce a seal between the internal surface of the collar and the perforating component (for example, a needle) when inserting the ampoule into the aerosol generating device and, particularly, during the opening process.

In order to avoid the formation of air bubbles during the flow of the medicine, it is also preferred that the opening diameter of the ampoule, which consists of the diameter of the bottom of the container and the diameter, and at least one

9/27 part of the predetermined breaking point is greater than approximately 8 mm, preferably in the range between approximately 8 mm and approximately 15 mm. According to a particular preferred configuration, the opening diameter is approximately 10 mm. Therefore, it is preferred that the piercing component of the aerosol generating device, for example, a needle, has a minimum internal diameter of approximately 8 mm.

The medicine container of the above described ampoule 10 preferably contains up to 10 ml, more preferably between 0.25 and 5 ml of medicine. Within this volume range, it is possible, through sizing and the particular design of the second functional area, as explained above, to precisely dose volumes with an accuracy of +

25% ã + 5% of the target volume.

According to a preferred configuration, the medicament contained in the ampoule comprises at least one active agent and, preferably, at least one supporting agent in dissolved or suspended form. Preferably, the medication will be of the type for diagnosis, prophylaxis or treatment of diseases in man and animals, in nebulized form, being possible, in combination with a perforated oscillating diaphragm, to nebulize the medication in the form of droplets, having an average diameter of &lt; 6 pm or do the nebulization as a pulsating aerosol, having an average mass diameter. With regard to drugs and adjuvants including auxiliary agents that can possibly be used, reference is made to the following description.

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In this sense, the present invention also refers to the use of an ampoule, according to the invention, in an aerosol generator, where the drug is nebulized by an aerosol generator and being used for local, nasal or pulmonary application.

Other advantages and aspects of the present invention become clearer according to the description of a preferred configuration, which is carried out according to the accompanying drawings.

Fig. 1 - shows a perspective view of a disposable ampoule, according to the invention;

Figs. 2a and 2b - each of the figures shows a cross section of the ampoule according to the invention, Fig. 2a shows a cross-section through parallel and through the reinforcement ribs as well as through the ear, and Fig. 2b shows a cross section perpendicular to the cross section of Fig. 2a;

Fig. 3 - shows a perspective view of part of an aerosol generating device with an ampoule inserted;

<td>Fig.</td><td> 4</td><td>- shows</td><td>a cross section through</td><td>disposition</td>

<td>shown</td><td>at</td><td>Fig. 3;</td><td></td><td></td>

<td>Fig.</td><td> 5</td><td>- shows</td><td colspan="2">an enlarged view of the interface between the</td>

<td>ampoule and</td><td>The</td><td>needle of</td><td>Fig. 4; and</td><td></td>

<td>Fig.</td><td> 6</td><td>- shows'</td><td>the interface of Fig. 5 with</td><td>the bottom of</td>

open container, that is, with the ampoule inserted.

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Fig. 1 shows a disposable ampoule according to the invention, which comprises a medicine container, containing a liquid medicine (not shown) and consists of a container body 10 and a container bottom 11 (see Fig. 2 ). The body of the container 10 is substantially constructed in the form of a hollow cylinder and the bottom of the container has a basically circular shape with a diameter (including a predetermined breaking point 12) greater than approximately 8 mm in order to prevent the formation of air that may prevent the subsequent flow of the drug. Preferably, the diameter will be approximately 10 mm. The predetermined breaking point 12 is formed between the bottom of the container 11 and the body of the container 10. The predetermined breaking point surrounds, at least partially, the bottom 11 of the container, however, preferably and as shown, completely surrounds the bottom. of the container and has an annular shape. The predetermined breaking point 12 is formed, for example, by a weak point in the material, that is, the strength of the material of the predetermined breaking point 12 is reduced, in comparison with the resistance of the material of the bottom 11 of the container.

As shown in figures 1 and 2, the ampoule according to the invention also comprises a collar 15 which is also designed with an annular cross section and which extends the body of the container 10 over and beyond the bottom of the container 12. The bottom of the container is therefore at a distance from the front end 19 and the breaking point

12/27 predetermined 12 that surrounds it and is also protected by the collar 15 against damage and possible opening before use.

Starting from the bottom of the container, the collar 15 'was designed in such a way that the cross section of its internal contour becomes larger, that is, it was configured in a conical way, with its expansion starting from the bottom of the container 11 (the diameter of the annular cross section becomes larger from the bottom of the container 11).

As shown in Fig. 1, the container body 10 comprises an annular surrounding retaining groove 13 that is slightly closer to the bottom of the container 11 in a longitudinal direction, this groove serving to mount (retain or secure) the ampoule within a generating device aerosol spray (see below). The retaining groove divides the container body into first and second functional areas. In addition to the collar 15, the first functional area 21 comprises a section of the body of the container 10, whose geometric shape is designed in such a way that the medicine (not shown), contained in the ampoule, can be supplied to the aerosol generating device and , in particular, the aerosol generator with reproducible dosing accuracy. For this purpose, the first functional area 21 is projected conically towards the bottom of the container, that is, its internal contour is formed in a tapered shape towards the bottom of the container 11. The second functional area 20 is basically , designed with hollow cylinder. This design enables a modular construction of the ampoule, according to the invention. THE

13/27 functional area 21 will therefore preferably be the same in all ampoules, regardless of the filling volume, so that the interface between the ampoule and the aerosol generating device can remain unchanged, that is, different ampoules can be inserted into the aerosol generating device. In addition, ampoules can also be designed in such a way that they are only suitable for specific aerosol generating devices. Ampoules for an aerosol generating device can, for example, be designed in such a way that they do not fit within another aerosol generating device and vice versa. Encoding elements or identification elements, as they are usually called, can be provided for this purpose, which may include, for example, projections or bar codes or magnetic information. Projections can, for example, prevent the insertion of the ampoule into the aerosol generating device if it is not intended for the corresponding aerosol generating device. On the other hand, projections can also make contact with an electrical switch when the ampoule is inserted into the device

<td>generator</td><td>correct aerosol,</td><td>to</td><td>in</td><td>to secure</td><td>O</td>

<td>operation</td><td>of the device</td><td>generator</td><td>in</td><td>aerosol.</td><td>THE</td>

<td>interpretation</td><td>of information in</td><td>code</td><td>in</td><td>bars or</td><td>The</td>

Magnetic information allows the operation of the aerosol generating device in the case of the correct ampoule, also to work in a similar way. These elements are preferably also arranged in the first functional area. The second functional area 20, on the other hand, can vary in terms of its size in the longitudinal direction. In others

14/27 words, functional area 20 may be designed to be longer, that is, to have a larger volume, or smaller, that is, to have a smaller volume, depending on the filling volume of the respective ampoule. This is advantageous both for manufacturing reasons for the production of the different ampoules and also in terms of ease of use, since the user will always insert the ampoules into the device - aerosol generator in the same way, regardless of their size . Its operation also remains identical. Finally, this design makes it possible to use several types of ampoules, that is, with different filling volumes, in the same aerosol generating device.

The ampoule according to the invention also comprises two diametrically opposed reinforcement ribs in the first functional area 21. These provide dimensional stability to the ampoule, particularly during the opening process, in which the ampoule receives the impact of needle penetration (see below) in order to pierce the bottom 11 of the container along the predetermined breaking point 12. In the configuration shown in Fig. 1, the reinforcement ribs 14 pass over a part of the collar 15 and over a part of the body section of the container 10 which now has a tapered shape.

An ear 16 is also provided at the end of the container body 10, opposite the bottom 11 of the container.

This ear, which has a basically flat design with two opposite surface areas, makes it possible to connect an area

15/27 tagging 17 which may contain information about the introduced drug. Lot number 18 and expiration date can be affixed to the opposite surface.

As can be seen in Figs. 1 and 2, the ampoule according to the invention is formed in one piece. This is advantageously done in the blow-fill-seal process. With respect to this process, the specialist in the subject should consult the publications of the prior art, mentioned above. The ampoule can be made of polyethylene, polypropylene or a copolymer. The content has a variable, but previously definable, volume range of approximately 0.25 ml to 5 ml and is supplied 'to an aerosol generator, so that a medication can be nebulized and' used for topical application to the skin or cavities bodily effects, such as, for example, in the nose and lungs, in order to diagnose, prevent or treat illnesses in man and animals.

Fig. 3 shows the part of an aerosol generating device. It comprises at least one cover 30, designed to be removable from the body of the aerosol generating device, for example, so that it can be unscrewed. A transfixing orifice 31 is provided in this cap, in which the first element 32 of the opening mechanism is inserted. Projections, for example, are provided in the internal circumference of the .31 hole of the lid 30, which acts in threaded grooves in the element 32, or vice versa. Through a rotational movement of the lid 30 when the lid 30 is attached to the body (not shown) of the generating device

16/27 of aerosol, the actuation of the projections of the lid 30 with the threaded grooves of the element 32 causes a translational movement of the element 32. With reference to this drawing reference is made in particular to the document DE 10 2005 038 619 Al.

<td colspan="2">0 element</td><td>32 also</td><td colspan="2">comprises hooks 33, with</td><td>the</td>

<td>which</td><td>slot</td><td>retainer</td><td>13 da</td><td>ampoule according to</td><td>The</td>

<td>invention</td><td>may</td><td>cooperate,</td><td>to</td><td>to hold the ampoule</td><td>at the</td>

<td>element</td><td> 32.</td><td></td><td></td><td></td><td></td>

The aerosol generating device also comprises a needle 34, formed as a hollow cylinder and comprises a cutting edge 35 at one of its ends. The internal diameter of the needle 34 is greater than 8 mm, in order to react to the formation of air bubbles during the flow of the medication, which could prevent the subsequent flow of the medication. The aerosol generator, preferably a piezoelectric-acting diaphragm, is located at the opposite end of the needle 34. A transfixing orifice 37 is also preferably formed in the element 32, concentric with the orifice 31 of the lid 30, through which the ampoule protrudes out of the aerosol generating device when inserted.

Another sealing element, in the form of an o-ring 38, is additionally provided in the upper region of the needle 34. The use of an ampoule according to the invention is explained below, with references to Figs. 3 to 6.

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If an ampoule is to be inserted into the aerosol generating device, the cap 30 will be removed from the body of the aerosol generating device, for example, it is unscrewed. The element 32 thus moves upwards, translationally, through the orifice 31 of the cap 30. Once the cap is removed, the ampoule is inserted into the element 32 from the side opposite to the 37 of the element 32, the ear being 16 and part of the body of the container 10 conducted through the orifice 37 of the element

32. The retaining projections 33 of the element 32 thus act with the retaining groove 13 of the ampoule and retain it in its longitudinal direction. Then, the cap 30 is replaced on the body of the aerosol generating device. Due to the rotation of the lid 30 and the actuation of the projections of the lid 30 with the threaded grooves of the element 32, the element 32 will be moved translationally into the hole 31 of the lid 30. Since the bulb is connected to element 32, the bulb is also moved in a translational mode. An internal surface of the collar 15 thus acts first, as shown in Fig. 5; with the o-ring 38 'that completely surrounds the needle 34, creating a reliable seal between the inner surface of the collar 15 and the outer surface of the needle 34. As shown in FIG. 5, this occurs before the edge 35 of the needle 34 starts the opening process, that is, start to cut through the predetermined breaking point 12. The ampoule is also centered on the needle 34 by the conical internal contour of the collar 15. Due to this conformation reliably prevents leakage of the medication during the opening process. Besides that,

18/27 this seal is also maintained in the fully inserted state (Fig. 6), so it is possible to provide an optional seal also between the outer surface of the needle 34 and the inner surface of the container body, directly at or above the bottom 11 of the container. Reliable insertion of the ampoule will then also be ensured.

As a result of another rotation movement of the lid 30 and the other associated translational movement of the element 32 and, consequently, of the. ampoule, the bottom of the container, as shown in Figure 6, is pierced by a needle 34 and foldable to one side, so that the medicine contained in the ampoule can pass through needle 34 and reach the aerosol generator 36. The funnel-shaped internal contour of the first functional area 20 of the container body 10 thus provides the aerosol generator with a supply of the medicament with an exact reproducible dosage. Ά configuration of the retaining groove 13 in the center or closer to the bottom of the container 12 in the longitudinal direction of the ampoule, in addition, it gives the necessary forces to open the ampoule, which are transferred to element 32 and, consequently, the ampoule, due to the twisting of the cap, it is absorbed as close as possible to the region where the force is introduced up to the predetermined breaking point 12. In addition, the reinforcement ribs 14 support the ampoule in such a way that deformation is substantially prevented during the opening process.

In the state of complete insertion, the holes 37 of the element 31, 32 of the lid 30 are distributed

19/27 substantially on a plan. However, ear 16 protrudes through hole 37 of element 32 and out of the aerosol generating device also in this position, such that the labeling area 17, as well as lot number 18 and expiration details not shown are still visible even when in the inserted state.

To remove the ampoule, the cap 30 is rotated in the opposite direction, causing the element 32 to be moved translationally in the opposite direction when the ampoule is opened, and the ampoule moves away from needle 34 again. The seal between the ampoule ( collar) and the needle (ring at 0) remains this way until the ampoule can actually be removed from needle 34 with the cap 30 and in this way it is possible to prevent contamination of the device by medicine residues. To remove the ampoule from the cap 30, the user can hold the ear 16 and push the ampoule out (down in the figures) from the engagement with the projections 33, so that it can be removed. The user should therefore not touch the area of ​​the ampoule that is most likely to be wetted by a medication, and which is additionally protected by a collar 15. Removing the ampoule outside can also be facilitated in the case of a second short functional area 20, due to at least the projected ear 16.

In summary, the present invention thus offers a plurality of advantages compared to the prior art ampoule. However, it is clear that the configuration described is only a possibility of carrying out the

20/27 present invention, and it is in fact defined by the claims attached to this report.

The classes of active ingredient and / or substances listed below may be contained in the ampoule, according to the invention, but this list is not conclusive:

The active compounds include, for example, substances selected from the group consisting of anti-inflammatory compounds, glucocorticoids, antiallergic drugs, antioxidants, vitamins, leukotrin antagonists, anti-infectious agents, antibiotics, antifungicides, antiviral agents, mucolytic agents, decongestants, antiseptics, cyto-static agents , immunomodulators, vaccines, wound healing agents, local anesthetics, oligonucleotides, peptides, proteins and plant extracts.

Examples of potentially useful anti-inflammatory compounds are glucocorticoids and non-steroidal anti-inflammatory agents such as, for example, betamethasone, beclomethasone, budesonide, ciclesonide, dexamethasone, deoxymethasone, fluocinolone acetonide, flunisolid, fluticasone, icometasone, triamcinolone, fluorohydrone, acetaminophenone, fluorohydride, 17-hydroxy-butylone. , flucinonide, rofleponide, hydrocortisone, prednicarbate, β-methylprednisolone aceponate, mometasone furoate, dehydroepiandrosterone sulfate (DHEAS), elastane, prostaglandin, leukotriene, bradykinin antagonist, non-steroidal anti-inflammatory drugs

21/27 (NSAIDs), such as ibuprofen, including any pharmaceutically acceptable salts, esters, isomers, stereoisomers, diastereomers, epimers, solvates or other hydrates, prodrugs, derivatives or any other chemical or physical forms of compounds which comprise the respective active waste.

Examples of anti-infectious agents whose classes or therapeutic category are included in this document, as they include compounds that are effective against bacterial, fungal and viral infections, such as, for example, the classes of microbicidal, antibiotic, fungicidal, antiseptic and antiviral agents are:

- penicillins, including benzylpenicillins (penicillin-Gsodium, penicillin clemizone, penicillin G benzathine), phenoxypenicillins (penicillin V, propicillin), aminobenzylpenicillin (ampylicin, amoxicillin, bacampicillin), acylaminacillin, and acylaminicillin; carbenicillin, ticarcillin, temocillin), isoxazolylpenicillins (oxacillin, cloxacillin, dicloxacillin, flucloxacillin), and amidine penicillins (mecilinam);

cephalosporins, including cefazolines (cefazolin, cefazedone); cefuroxime (cerufoxime, cefamandole, cefotiam); cefoxitins (cefoxitin, cefotetan, latamoxef, flomoxef) '; 'cefotaximes (cefotaxime, ceftriaxone, ceftizoxime, cefmenoxime); ceftazidimes (ceftadzidime,

22/27 cefpirome, 'cefepime); cephalexins (cephalexin, cefaclor, cefadroxil, cefradine, loracarbef, cefprozil), and cefiximes (cefixime, cefpodoxime, proxetil, cefuroxime-axetil, cefetamet pivoxil, cefotiam hexetil, cefotiamine;

- synergists, including beta-lactamase inhibitors, such as clavulanic acid, sulbactam and tazobactam;

- carbapenems, including imipenem, cilastine, meropenem, doripenem, tebipenem, ertapenem, ritipenam and biapenem;

- monobactam, including aztreonam;

aminoglycosides, such as, apramicin, amicacin, isepamicin, arbekacin, tobramicin, spectinomicin, streptomicin, capreomicin, paromoicin and kanamycin;

gentamicin, netilmicin, neomicin,

- macrolides, including, erythromycin, clarithromycin, roxithromycin, azithromycin, dithromycin,. josamycin, spiramycin and telithromycin;

gyrase or fluroquinolone inhibitors, including: floxacin, gatifloxacin, norfloxacin, ofloxacin, levofloxacin, perfloxacin, lomefloxacin, garenoxacin, clinafloxacin, sitafloxacin, prulifloxacin, olamufloxacin, tramofloxacin, tramofloxacin, trilofloxacin, trilofloxacin, trulofloxacin, tramofloxacin, trulofloxacin, trulofloxacin, trulofloxacin, trulofloxacin, trulofloxacin, trulofloxacin;

- tetracyclines, including: tetracicline, oxitetracicline, rolitetracicline, minocicline, doxicicline, tigecicline and aminocicline;

<img file="BRPI0805219A2_D0003.tif" />

23/27 glycopeptides, including: vancomycin, teicoplanin, ristocetin, avoparcin, oritavancin, ramosplanin and peptide 4;

polypeptides, including: daptomycin, oritavancin, telavancin, bacitracin, plectasin, ramosplanin, tirotricin, dalbavancin, dalbavancin, neomycin, kanamycin, colistin;

mupirocin, paromomycin, polymyxin B and

- sulfonamides, including: sulfadiazine, sulfamethoxazole, sulfalene, cotrimoxazole, cotrimetrol, cotrimoxazine, cotetraxazine;

- azoles, including: clotrimazole, exiconazole, miconazole, ketoconazole, itraconazole, fluconazole, metronidazole, tinidazole, bifonazole, ravuconazole, posaconazole, voriconazole and ornidazole, and other antifungals, including: flofitosoxine, tonofoxin, terise, grise, grise echinocandin, such as, micafungin, caspofungin, anidulafungin;

nitrofuranes, including: nitrofurantoin and nitrofuranzone;

polyenes, including: amphotericin B, natamycin, nystatin, flucocytosine;

- other antibiotics, including: titromycin, lincomycin, clindamycin, oxazolidinones (linezolid), ranbezolid, streptogramin A + B, pristinamycin aA + B, viginiamycin

A + B, dalfopristin / quinopristin (sinercid), chloramphenicol,

24/27 ethambutol, pyrazinamide, terizidone, dapsone, protionamide, fosfomycin, fucidine acid, rifampicin, isoniazid, cicloserine, terizidone, ansamycin, lysostafine, iclaprime, mirocin B17, clerocidine, filgrastime and pentamidine;

, anciclovir, didanosine, zalcitabine, trifluridine,, amantadine, inhibitors of antiviral agents, including: aziclovir brivudine, valacyclovir, zidovudine, tiacitidine, estavudine, lamivudine, ribavirine, nevirapirine, delaviroxine, trinavirinine, trinavirinine, trinavirinine, trinavirine and proteinase;

- antiseptics, including: derivatives of acridine, iodine providon, benzoates, rivanol, clohexidine, quaternary ammonia compounds, cetrimides, biphenylol, chlorophen and octenidine;

- plant extracts or components, such as chamomile plant extracts, hamamelis, echinacea, marigold, thymus, papain, pelargonium ,. pine, essential oils, mirtol, pinene, limonene, cineole, thymol, menthol, camphor, tannin, alpha-hederin, bisabolol, lycopodine, vitaferol;

Compounds for treating wounds, including: dexapanthenol, allantoin, vitamins, hyaluronic acid, alpha-antitrypsin, inorganic and organic zinc salts / compounds, bismuth salts and selenium salts;

interferons (alpha, beta, gamma), tumor necrosis factors, cytokines, interleukins;

25/27 immunomodulators, including: methotrexate, azathioprine, ciclosporine, tacrolism, sirolism, rapamycin, mofetil, mofetil-microfenolate;

- cytostatic agents and metastasis inhibitors;

alkalizing agents, such as nimustine, melphalan, carmustine, lomustine, cyclophosphamide, ifosfamide, trophosphamide, chlorambucil, busulfan, treosulfan, prednimustine, thiotepa;

- anti-metabolites, for example: cytarabine, fluorouracil, methotrexate, mercaptopurine, thioguanine;

<td>alkaloids, vindesine;</td><td>such</td><td>as,</td><td>vinblastine,</td><td>vincristine,</td>

<td>antibiotics,</td><td>such</td><td>as,</td><td>for example:</td><td>alcarubicin,</td>

bleomycin, dactinomycin, daunorubicin, doxorubicin, spirubicin, idarubicin, mitomycin, plicamycin;

- complexes of transition elements (for example, Ti, Zr, V, Nb, Ta, Mo, W, Pt), such as, carboplatinim, cisplatin and metallocene compounds, such as, for example: titanocene dichloride;

amsacrine, dacarbazine, estramustine, etoposide, beraprost, hydroxycarbamide, mitoxantrone, procarbazine, temiposide;

- paclitaxel, iressa, zactime, enzyme inhibitors (PRAP) poly-ADP-ribose polymerase, banoxantrone, gemcitabine, pemetrexed, bevacizumab, ranibizumab.

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Examples of potentially useful mucolytic agents are DNase, P2Y2 angonists (denufosol), drugs that affect the penetration of chlorine and sodium, such as, for example, N- (3,5-diamino-6-chloropyrazine-2-carbonyl) - N '- {4 [4- (2,3-dihydroxypropoxy) -phenyl] butyl] guanidine-methane sulfonate. (PARION 552-02) heparinoids, guaifenesine, acetylcysteine, carbocysteine, ambroxol, bromhexine, tiloxapol, lecithin, mirtol and recombinant surfactant proteins.

Examples of potentially useful vasoconstrictors and decongestants that can be used to reduce swelling of the mucous membrane are feniíeprine, nafazoline, tramazoline, tetrizoline, oxymetazoline, phenoxazoline, xylometazoline, epinefrine, isoprenaline, hexoprenaline and efidrine.

Examples of potentially useful local anesthetics are benzocaine, tetracaine, procaine, lidocaine and bupivacaine.

Examples of potentially useful antiallergic agents are the aforementioned glucocorticoids, sodium chromoline, nedocromil, cetrizine, loratidine, montelukast, roflumilast, ziluton, omalizumab, heparinoids and other antihistamines, including azelastine, cetirizine, levine, dehydrate, dehydrate, dehydrate.

The antisense oligonucleotides are sequences of

DNA (or analogues) that are complementary or opposite to

27/27 target sequence (DNA, RNA) and that are designed in such a way that they stop a biological process such as, for example, transcription, translation or combination. The inhibition of gene expression thus caused makes oligonucleotides useful for the treatment of many diseases, depending on their composition, and numerous compounds are currently being tested clinically, such as, for example, ALN-RSV01 for the treatment of syncytial viruses respiratory, AVE-7279 for the treatment of asthma and allergies, the TPI_ASM8 for the treatment of allergic asthma and the 1018-ISS for the treatment of cancer.

Examples of potentially useful peptides and proteins are amino acids, such as, for example, L-arginine, L-lysine, antibodies to toxins produced by microorganisms, antimicrobial peptides such as cecropins, .defensins, thionines and catelicidines.

For each and other examples mentioned explicitly, there are drug substances that. -they are potentially useful for carrying out the invention, the names of compounds specified in this document must be interpreted also including any pharmaceutically acceptable salts, solvates or other hydrates, prodrugs, isomers or any chemical or physical forms of the relevant compounds containing the residues corresponding assets.

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