DE102021132055A1 - New therapy concepts for the treatment of otitis - Google Patents

Abstract

The present invention relates to the medical-pharmaceutical field of therapy for inflammatory diseases of the human ear, in particular, and in particular of otitis, such as otitis media; in particular, the present invention relates to an active ingredient and a drug or medicament containing this active ingredient for such a therapy.

Description

The present invention relates to the technical (i.e. medical-pharmaceutical) field of inflammatory diseases of the human ear in particular and in particular the field of otitis, such as otitis media (middle ear infection) or otitis externa (external ear infection), preferably otitis media, and their treatment or therapy . In particular, the present invention relates to an active substance (here also referred to synonymously as active substance) as well as a drug and a composition for use in the treatment or therapy of inflammatory diseases of the human ear or otitis.

The present invention relates in particular to an active substance and a pharmaceutical composition or a composition, each for use in the prophylactic and/or therapeutic treatment of inflammatory diseases of the ear or otitis, such as otitis media or otitis externa, preferably otitis media.

Correspondingly, the present invention also relates to the use of an active substance and a method for the prophylactic or therapeutic treatment of inflammatory diseases of the ear or otitis, as well as a drug or medicament relating thereto and a composition relating thereto and furthermore a pharmaceutical combination Basis of the present active substance.

In the context of the present invention, the active ingredient used is cineole, preferably 1,8-cineole, or a drug containing cineole, preferably 1,8-cineole, or a composition containing this active ingredient, as in the following description and in the Claims to the present invention further defined and described.

• Das Außenohr umfasst u. a. die Ohrmuschel sowie den äußeren Gehörgang (Ohrkanal) und die Außenseite des Trommelfells. Das Außenohr dient zur Aufnahme bzw. dem Einfangen von Schall, wobei auch eine bestimmte Einfallsrichtung des Schalls kodiert wird, und zwar unter Einbezug der zahlreichen Erhebungen und Vertiefungen der Ohrmuschel, welche akustische Resonatoren ausbilden und welche jeweils bei Schalleinfall aus einer bestimmten Richtung differenziert angeregt werden. Auch auf dieser Basis kann eine Schallortung bzw. räumliche Schallorientierung ermöglicht werden.

The human ear is a sensory organ with which sound, such as tones, speech, sounds, noises or the like, are recorded and processed, with the organ of balance also belonging to the ear in its organ function. With regard to its anatomical structure, the human ear can be divided into the outer ear, the middle ear and the inner ear, with each section having special functions:

• The outer ear includes the pinna, the external auditory canal (ear canal) and the outside of the eardrum. The outer ear is used to record or capture sound, whereby a specific direction of incidence of the sound is also encoded, taking into account the numerous elevations and depressions in the auricle, which form acoustic resonators and which are excited in a differentiated manner when sound arrives from a specific direction . Sound localization or spatial sound orientation can also be made possible on this basis.

The middle ear includes the eardrum as such, the auditory ossicles and the so-called oval window (entrance) and the round window (exit) to the inner ear. The auditory ossicles form a lever system which is able to transmit the sound energy picked up by the eardrum to the inner ear via the oval window. The round window connects the tympanic ladder of the inner ear to the middle ear. The middle ear is used in particular for the mechanical processing or (impedance) conversion of the sound in order to enable the sound information to be transmitted from the outer ear to the inner ear. In addition, the intratympanic part of the facial nerve with the origin of the chorda tympani (facial nerve) is located in the middle ear.

The inner ear includes the cochlea, the saccule, the utricle, and the semicircular canals. In the inner ear, the signal transmitted and received by the middle ear is converted into nerve impulses. The balance organ is also part of the inner ear.

The path of the sound and its transformation into corresponding nerve signals takes place starting from the auricle via the auditory canal to the eardrum and then via the auditory ossicles, then via the cochlea and further via the auditory nerve, with the sound on its way from the outer ear via the middle ear to the nerve cells of the inner ear and processed.

The human ear can perceive acoustic events within a certain frequency and sound pressure level range. Hearing in general, or auditory, aural or acoustic perception, is one of the most important senses, so that the human ear has an important function as the underlying sensory organ, also with regard to the reception of language as a means of communication and with regard to on directional hearing (orientation in space) and also with regard to the function or guarantee of balance by the vestibular organ located in the ear.

The above explanations show that the human ear is an organ or a functional unit with a complex interaction of the respective components. In order to guarantee the complete function, it is particularly necessary that the underlying structures are not impaired or damaged, as can be the case, for example, in the case of, in particular, inflammatory diseases of the ear. Such diseases can even lead to a sometimes permanent and lasting disruption of the functional properties of the ear. For this reason, too, there is a great need for appropriate therapies or prevention for the treatment or prevention of, in particular, inflammatory diseases of the ear.

Against this background, diseases of the human ear are often problematic, since they can also lead to a sometimes drastic limitation of the function as a sensory organ and even to a complete and irreversible loss of function, accompanied by a deterioration or even prevention of the perception of sound events and impairment the equilibrium function. In addition, diseases of the ear can also affect the entire organism, for example in the case of bacterial infections or the like, which namely can also lead to systemic diseases or sepsis.

The human ear can be affected by various forms of disease, which are also specific to the part of the ear affected.

Due to the relatively thin skin in the auditory canal and in the auricle, the outer ear is basically susceptible to infections with pathogenic germs, such as pathogenic bacteria or fungi, which can lead to an inflammation of the outer ear in the form of otitis externa. The middle ear is also particularly susceptible to inflammation caused by bacteria caused by pathogenic germs, in particular in the form of a middle ear infection or otitis media. The inflammation can also attack or even destroy the auditory ossicles, which can be accompanied by a lasting and irreversible reduction or even loss of hearing function. The middle ear infection can also be the starting point for further diseases such as mastoiditis or labyrinthitis. The inner ear can also be attacked by pathogenic germs or by bacterial and viral infections, specifically in the form of inner ear inflammation or otitis interna.

Inflammatory diseases of the ear can also be accompanied by a temporary or reversible or even permanent or irreversible reduction in hearing ability, up to and including hearing loss, tinnitus and dizziness.

Inflammation of the ear or otitis can, as also mentioned above, be differentiated in particular depending on where it occurs and its further development or severity. In particular, inflammatory diseases of the ear or otitis can also be accompanied by leakage or discharge of body fluids or secretions from the (external) auditory canal, which is generally referred to as otorrhea and which occurs in particular in the case of a severe or chronic course of the disease.

Inflammation of the outer ear, which is referred to as otitis externa, represents an infection, in particular of the skin of the auditory canal, which is typically caused by pathogenic germs, in particular based on pathogenic bacteria. Symptoms in this regard are in particular pain, discharge (otorrhoea) or hearing loss, especially if the disease is accompanied by swelling in the ear canal. Inflammation of the inner ear or otitis interna, which can be acute (otitis interna acuta) or chronic (otitis interna chronica), is a mostly painful inflammation of the inner ear, particularly affecting the bony labyrinth with the associated cochlea and vestibular system affected or inflamed. Internal otitis can also have negative effects on hearing, but also on the sense of balance.

In the case of otitis interna, an inflammation in particular spreads from the middle ear via the round window or the oval window to the inner ear. This can in particular also be an inflammation of the middle ear with inner ear involvement (in particular otitis media with inner ear involvement or in particular otitis media with accompanying inner ear inflammation). Such a disease can lead to significant limitations up to and including loss of function of the inner ear and vestibular system. Possible consequences can be deafness or loss of balance. The facial nerve and the posterior and middle cranial fossa can also be affected, especially with meningitis or brain abscess.

As far as the inflammatory diseases of the outer ear or otitis externa are concerned, these are, for example, inflammatory diseases which particularly affect the external auditory canal or are localized in the area of the external auditory canal.

Inflammation of the middle ear or otitis media is generally used to describe clinical pictures which are characterized by an inflammation of the middle ear caused in particular by pathogenic germs or in particular bacterial inflammation, with the course of the disease fundamentally distinguishing between acute otitis media or otitis media acuta and chronic otitis media or otitis media chronica can be distinguished. Inflammation of the middle ear is caused in particular by pathogenic germs, in particular pathogenic bacteria, in which case the colonization of the middle ear can take place, for example, via the Eustachian tube from the nasal cavity or nasopharynx, but also via the bloodstream. For example, in the case of an existing perforation of the eardrum, pathogens or germs can also enter the middle ear from outside, for example through bath water or the like. A middle ear infection can, for example, be accompanied by throbbing ear pain, fever, throbbing in the ears, hearing loss, nausea or the like. Severe cases can also result in bodily fluids such as pus escaping, damage to the eardrum and permanent impairment of hearing. In severe cases, the inflammation can also spread to other areas of the ear. Middle ear infections can also lead to scarring of the eardrum and adhesions in the area of the auditory ossicles and thus result in permanent hearing impairment, particularly in the form of conductive hearing loss.

Chronic suppuration of the mucous membranes or otitis media mesotympanalis or otitis media chronica mesotympanalis is also counted among the special or severe middle ear infections. This is a chronic disease that particularly affects the mucous membrane of the middle ear. Otitis media mesotympanalis is associated in particular with long-lasting or chronic or recurring (recurrent) inflammation of the middle ear, with permanent perforation of the eardrum and, in particular, a purulent-mucous discharge from the auditory canal or otorrhea.

The so-called cholesteatoma or otitis media epitympanalis or otitis media chronica epitympanalis can be distinguished from the chronic suppuration of the mucous membrane of the middle ear, which also represents a severe form of middle ear inflammation or otitis media. Cholesteatoma or otitis media epitympanalis is generally understood to mean an overgrowth of, in particular, multi-layered keratinized squamous epithelium in the middle ear with subsequent or accompanying, in particular chronic or in particular purulent, inflammation of the middle ear. The cholesteatoma is generally a progressive, destructive-inflammatory disease or lesion of the middle ear, with migration, increased cell proliferation, invasiveness, disturbed cell differentiation, progression or tendency to recurrences after surgical intervention being the relevant characteristics from a pathological point of view. The cholesteatoma is therefore characterized overall by a proliferating-destructive course with possible complications such as destruction of the bony structures, in particular with hearing loss, vestibular dysfunction, paralysis of the facial nerve and intracranial complications, so that overall there is a serious disease of the ear in this regard.

In industrialized nations, middle ear infection or otitis media is one of the diseases that most frequently lead to doctor visits, antibiotic prescriptions and operations. Inflammation of the middle ear or otitis media, especially in the chronically recurring form, is often accompanied by a significant deterioration in the quality of life of the patients affected, who often suffer from running ears (otorrhea), hearing loss, delays in speech development up to complete deafness and/or dizziness Suffer. In addition, the particularly aggressive form of middle ear inflammation, namely cholesteatoma or otitis media epitympanalis, behaves to a certain extent like a malignant tumor, whereby the disease is often not amenable to antibiotic therapy and is characterized by progressive inflammatory-destructive processes of the middle ear, whereby the surrounding structures can be affected or destroyed.

In general, the infection of the middle ear or otitis media with pathogenic germs, in particular with bacterial or possibly also viral pathogens or pathogenic fungi, primarily or initially leads to the clinical picture of the particularly acute middle ear infection or the particularly acute otitis media, which Childhood frequently occurring clinical picture represents. If the immune system does not succeed in curbing the bacterial infection with the associated inflammatory processes, complete healing of the disease or restitutio ad integrum is not guaranteed, with recurrent episodes or an existing or chronic Inflammation can follow, which is referred to as chronic otitis media.

In 2004, according to a report by the World Health Organization (WHO), the incidence of acute otitis in Central Europe was chronic-purulent Otitis media in 36.4 per 1,000 population, while chronic or acute otitis media affected about a tenth of these patients, namely 3.69 per 1,000 population. The incidence of chronic otitis media in children up to the age of nine is three to five times higher than in adults from a global perspective. In regions with developing countries, such as B. in Central and West Africa, there are even higher incidences, namely for the occurrence of acute otitis at 433 per 1,000 inhabitants and for chronic otitis at about 7 per 1,000 inhabitants.

A particularly chronic otitis such as otitis media or otitis externa, in particular otitis media, but also otitis interna (e.g. in particular otitis media with inner ear involvement or in particular otitis media with accompanying inner ear inflammation), can lead to otorrhoea, especially in the case of a special or severe course , as mentioned above, and thus associated with the escape of bodily fluids or secretions from the external auditory canal.

Severe courses of otitis and especially otitis media, for example if this lasts for more than six weeks or is accompanied by otorrhea, can lead to increasing destruction of the bone tissue and the mucous membrane of the affected middle ear. Without intervention, irreversible damage with eardrum defects including conductive hearing loss can occur.

With regard to severe courses of otitis, central tympanic membrane defects can lead to the clinical picture of chronic otitis media mesotympanalis in particular, while peripheral tympanic membrane defects can be associated as chronic otitis media epitympanalis or cholesteatoma. Severe forms of the disease must be taken very seriously, as they can lead to tissue destruction or mastoiditis, labyrinthitis, facial paralysis, meningitis, a brain abscess or sinus vein thrombosis and even death if the inflammation spreads and is not treated. The patients affected by the disease also suffer from a hearing impairment, which makes everyday communication extremely difficult and progressively worsens if left untreated. In this context, surgical reconstruction of the eardrum, replacement of the ossicular chain or removal of the cholesteatoma are often unavoidable.

Inflammatory ear diseases and in particular inflammation of the middle ear, such as otitis media or otitis externa, but also otitis externa or otitis interna (e.g. in particular otitis media with inner ear involvement or in particular otitis media with accompanying inner ear inflammation), often require therapeutic treatment, especially in children and older people Treatment using antibiotics, especially if the inflammation of the middle ear caused by bacterial and possibly viral pathogens or pathogens is not within the self-limiting range, as is often the case in patients with lower immune competence. In the case of persistent or recurrent infection in particular, there is often a need for therapeutic action using appropriate antibiotics in the prior art. In children in particular, however, the use of antibiotics is strictly indicated and should always be done in consideration of the risks. The antibiotic therapy, in particular of middle ear infections using appropriate antibiotics, is also associated with disadvantages in that side effects can often occur, such as gastrointestinal complaints, e.g. B. diarrhea, abdominal pain and nausea, allergic reactions in particular of the skin, such as redness and / or itching, and the occurrence of fungal infections or the like. Similarly, systemic allergic reactions can also occur under antibiotic treatment, up to and including the development of anaphylactic shock. In addition, if antibiotics are not used properly, the underlying pathogens, especially pathogenic bacteria, can develop resistance, which can make treatment even more difficult. In particular, germs or bacteria that are already resistant can no longer be satisfactorily combated with some antibiotics, so that their use is also limited against this background.

Pseudomonas aeruginosa, Proteus mirabilis and Staphylococcus aureus as well as occasionally Enterobacterales and anaerobes should be mentioned as pathogenic germs in the form of bacterial pathogens of chronic otitis. A similar spectrum of pathogens can also be seen in advanced inflammation with mastoiditis, with Streptococcus pneumoniae and Haemophilus influenza in particular also being the underlying pathogens.

With regard to otitis, the chronification of the inflammation is of multifactorial origin. In particular, with regard to otitis, it can be the case that the colonization of the ear with pathogenic germs, such as Streptococcus pneumoniae, Haemophilus influenza and Staphylococcus aureus, is related to the extent of any hearing loss, as is the case, for example, with otitis media with otorrhoea case can be. In particular, the hearing loss can be more pronounced when pathogenic germs are present than when pathogenic germs are not present. In particular, with regard to the pathogenic germs with regard to otitis, it can also behave in such a way that they form a particularly pathogenic biofilm in the area of the affected ear, as can be the case for Pseudomonas aeruginosa, for example, which can also influence the effectiveness of antibiotics .

In the light of the above statements, there is a great need for suitable forms of therapy based on efficient active substances or related compositions and drugs, which can be used efficiently for treatment - in particular because of the sometimes major health effects of inflammation of the ear and the sometimes irreversible consequential damage of inflammatory diseases of the ear or of otitis, in particular otitis media or otitis externa, but also of otitis interna, with a high level of tolerability with simultaneous high and specific effectiveness of the active substances used should also be ensured.

The present invention is therefore based on the object of providing an efficient concept or relevant active ingredients and compositions or medicaments based thereon, which enable efficient treatment of inflammatory diseases of the ear or otitis, in particular otitis media and/or otitis externa, but also of otitis interna, and in particular the related sub-forms of the diseases, such as otitis media mesotympanalis and cholesteatoma. In addition to good effectiveness, excellent or improved tolerability and simple application of the underlying active ingredients, compositions and medicaments should also be ensured at the same time.

A still further object of the present invention is also to be seen in the provision of corresponding active ingredients and compositions and pharmaceuticals based thereon which prevent incorrect colonization or excessive colonization with pathogens or non-physiological colonization of the ear, in particular the middle and/or outer ear , preferably the middle ear, but also the inner ear, in order to alleviate or treat the underlying inflammatory disease on this basis.

In particular, yet another object of the present invention is also to be seen as providing corresponding active ingredients or compositions or pharmaceuticals based thereon, which in principle enable a reduction in the use of antibiotics in particular, so that the side effects and disadvantages associated with antibiotics are avoided or reduced. can be minimized.

Against this background, another object of the present invention is therefore to be seen as providing corresponding active substances or compositions and pharmaceuticals based thereon with regard to the treatment of inflammatory diseases of the ear or otitis, which at least have the disadvantages of the prior art described above largely avoided or at least mitigated.

In a completely surprising manner, the applicant has now found that cineole, in particular 1,8-cineole, unexpectedly and efficiently as an active ingredient for the prophylactic or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle or outer ear , preferably of the middle ear, but also of the inner ear, or for the prophylactic or therapeutic treatment of otitis, in particular otitis media or otitis externa, preferably otitis media, but also of otitis interna, also with regard to such forms or Illnesses associated with or accompanied by otorrhea.

To solve the problem described above, the present invention proposes - according to a first aspect of the present invention - cineole, preferably 1,8-cineole, for use in the prophylactic and / or therapeutic treatment of inflammatory diseases of the ear or for use in the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhoea, according to claim 1. Advantageous developments and refinements of this aspect of the invention are the subject matter of the relevant secondary or subclaims. According to this aspect, the present invention also proposes cineole, preferably 1,8-cineole, for use in reducing the (germ) load or number of pathogens located or localized in the ear or for use in reducing the Proportion of the relevant pathogens in the prophylactic or therapeutic treatment of inflammatory diseases of the ear or otitis according to the relevant independent claim. Each advantageous further developments and refinements of this aspect of the invention are the subject of the relevant dependent claims.

Another subject of the present invention - according to a second aspect of the present invention - is the use according to the invention of cineole, preferably 1,8-cineole, (for the production of a drug or medicament) for the prophylactic or therapeutic treatment of inflammatory diseases of the ear or ear. of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhoea, according to the relevant independent claims. Advantageous developments and refinements of this aspect of the invention are the subject matter of the relevant dependent claims.

Yet another object of the present invention - according to a third aspect of the present invention - is the use of cineole, preferably 1,8-cineole, as an ear treatment agent or for the production of an ear treatment agent for the prophylactic or therapeutic treatment of inflammatory diseases of the ear or for the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhoea. Advantageous developments and refinements of this aspect of the invention are the subject matter of the relevant dependent claims.

Another subject of the present invention - according to a fourth aspect of the present invention - is also a method for the prophylactic or therapeutic treatment of inflammatory diseases of the ear or otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with concomitant (accompanying) otorrhea, according to the related independent claim. Advantageous developments and refinements of this aspect of the invention are the subject matter of the relevant dependent claims.

Also subject of the present invention - according to a fifth aspect of the present invention - is also a drug or medicament for (use in) prophylactic or therapeutic treatment of inflammatory diseases of the ear or otitis, in particular otitis media and / or otitis externa, preferably otitis media, preferably with concomitant (accompanying) otorrhoea, according to the relevant independent claim. Advantageous developments and refinements of this aspect of the invention are the subject matter of the relevant dependent claims.

Likewise, the subject of the present invention - according to a sixth aspect of the present invention - is a composition for (use in) the prophylactic or therapeutic treatment of inflammatory diseases of the ear or otitis, in particular otitis media and/or otitis externa, preferably otitis media , preferably with accompanying (accompanying) otorrhea, according to the relevant independent claim. Advantageous developments and refinements of this aspect of the invention are the subject matter of the relevant dependent claims.

Finally, the subject of the present invention - according to a seventh aspect of the present invention - is a pharmaceutical combination for (use in) the prophylactic or therapeutic treatment of inflammatory diseases of the ear or otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with concomitant (accompanying) otorrhea, according to the relevant independent claim. Advantageous developments and refinements of this aspect of the invention are the subject matter of the relevant dependent claims.

It goes without saying that configurations, embodiments, advantages and the like, which are listed below for the purpose of avoiding repetitions of one aspect of the invention, of course also apply correspondingly to the other aspects of the invention without requiring a separate mention.

In addition, with regard to the following description of the present invention, it is also the case that the features of the present invention specified in connection with the specific configurations, embodiments, advantages, examples or the like are also deemed to be disclosed in their combination. Thus, in the present case, superordinate combinations of individual or multiple features, which are specified for respective configurations, embodiments, application examples or the like, also apply as disclosed.

Furthermore, it goes without saying that in the following statements of values, numbers and ranges, the relevant statements of values, numbers and ranges are not to be understood as limiting; it goes without saying for the person skilled in the art that it is possible to deviate from the specified range or specifications in individual cases or in relation to the application, without departing from the scope of the present invention.

In addition, all values or parameters specified below or the like can be determined or determined using standardized or explicitly specified determination methods or using determination methods familiar per se to a person skilled in the art in this field.

Furthermore, with all relative or percentage, in particular weight-related quantity data mentioned below, it should be noted that these data are to be selected or combined within the scope of the composition according to the invention by the person skilled in the art in such a way that in total - possibly including other components or ingredients or Additives or components, in particular as defined below - always result in 100% or 100% by weight. This goes without saying for the expert.

The subject of the present invention - according to a first aspect of the present invention - is thus cineole, preferably 1,8-cineole, for use in the prophylactic and/or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and/or outer ear , preferably of the middle ear, preferably with accompanying (accompanying) otorrhea. This aspect also relates to cineole, preferably 1,8-cineole, for use in the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with concomitant (accompanying) otorrhoea.

In this regard, the present invention relates in particular to inflammatory diseases of the human ear. In other words, the present invention relates in particular to cineole, preferably 1,8-cineole, for use in the prophylactic and/or therapeutic treatment of inflammatory diseases of the human ear, in particular inflammatory diseases of the human middle and/or outer ear, preferably of the human middle ear.

In principle, the present invention also relates to the relevant use with regard to the human inner ear in particular.

The specific and novel application or medical indication for cineole, in particular 1,8-cineole, surprisingly found by the applicant in the context of the present invention has not been described in the prior art and has not been recognized either, although it is Cineole, in particular 1,8-cineole, is a sufficiently well-known active ingredient.

The active ingredient cineol, in particular 1,8-cineole, used according to the invention is what is known as a terpene, in particular a monoterpene. Terpenes are generally natural substances that can be isolated as part of the so-called essential oils in the form of liquids from plants or their components. They are often fragrances and flavorings which are used in the food industry or the cosmetics industry. In addition, however, the use of terpenes for medical purposes is also gaining in importance, since pharmacological effects can be demonstrated for a large number of terpenes. Formally, terpenes represent polymerization products of isoprene, with monoterpenes (C ₁₀ units), sesquiterpenes (C ₁₅ units), diterpenoids (C ₂₀ units), sesterterpenes (C ₂₅ units), triterpenes (C ₃₀ units), tetraterpenes (C ₄₀ units) and polyterpenes (cf. RÖMPP-Chemielexikon, 10th edition, Georg Thieme Verlag, Stuttgart/New York, 1999, pages 4449 and 4450, keyword “Terpen(oid)e "). In addition, terpenes can also be used as pharmacologically active substances, starting materials for the production of pharmaceuticals or vitamin preparations, and also in agriculture because of their often bactericidal or pesticidal effects. Especially for a number of monoterpenes, pharmacological effects in the fight against diseases in the case of systemic treatments have been proven, with menthol and cineole, in particular 1,8-cineole, being mentioned in particular.

Specifically, the active ingredient cineole used according to the invention, in particular 1,8-cineole, belongs to the bicyclic epoxy monoterpenes, more precisely to the limonene oxides. Synonymous names for 1,8-cineol with the chemical molecular formula C ₁₀ H ₁₈ O are eucalyptol, limonene-1,8-oxide, 1,8-epoxy-p-menthane or 1,3,3-trimethyl-2-oxabicyclo[ 2.2.2]octane. It is a colorless liquid with a spicy, camphor-like odor with a melting point of +1.5 °C and a boiling point of 176-177 °C, which is insoluble in water but miscible with most organic solvents.

Of course, 1,8-cineole is the main component of eucalyptus oil (eucalyptus oil contains up to 85% by weight of 1,8-cineole), but it is also found in other plants, e.g. B. in mint, medicinal sage, thyme, basil and in the tea tree. In addition, 1,8-cineole is also found, for example, in Niaouli, Junipe rus, piper, cannabis, cajeput, sage, myrtle and other essential oils.

Technically or pharmaceutically purified 1,8-cineole, which can generally be present with a purity of 99.6% to 99.8%, is generally obtained by fractional distillation of eucalyptus oil.

In the prior art, 1,8-cineole is used in particular as an expectorant in bronchial catarrh and other respiratory diseases, but also as a flavoring in the perfume industry. In addition, 1,8-cineole is used in dentistry in the revision of root fillings. Physiologically, 1,8-cineol has an expectorant effect in the upper and lower respiratory tract, particularly in the lungs and sinuses. According to the prior art, 1,8-cineole is used both topically (e.g. inhalatively) and systemically (e.g. in the form of capsules), mostly as a mixed oil together with a large number of other terpenes.

For further details on the active ingredient 1,8-cineole, reference can be made to RÖMPP Chemielexikon, Georg Thieme Verlag, Stuttgart/New York, 10th edition, volume 1, 1996, page 752, keyword: “cineol”, as well as the referenced there Literature.

Completely surprising and unexpected, however, is the potential of cineole, preferably 1,8-cineole, found by the applicant in the context of the present invention with regard to the treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle or outer ear, preferably of the Middle ear, preferably with accompanying otorrhoea, or with regard to the treatment of otitis, in particular otitis media or otitis externa, preferably otitis media, preferably with accompanying otorrhoea.

In this context, cineol, in particular 1,8-cineol, surprisingly also has an antibiotic effect in particular against pathogenic germs (synonymously also referred to as pathogens, pathogenic microorganisms or infectious agents), specifically in the form of pathogenic bacteria (but also against fungi). or viruses). These are, in particular, those pathogenic germs which are associated with or cause inflammatory diseases of the ear.

In this context, the applicant was surprisingly also able to show that the active ingredient cineole, preferably 1,8-cineole, leads to an efficient reduction or decrease in the number of germs or the germ load of pathogenic bacteria in an ear affected by otitis, namely in particular with regard to those pathogenic germs which are associated with otitis or which are capable of triggering otitis. Without wishing to be bound or restricted to this theory, the active substance cineole, preferably 1,8-cineole, has an antimicrobial or antibacterial or antiviral effect in particular with regard to pathogenic germs. In this context, inflammatory processes associated with otitis are also reduced, so that the active ingredient cineole, preferably 1,8-cineole, also has an anti-inflammatory or anti-inflammatory effect.

In this way, within the scope of the present invention, effective alleviation of otitis is made possible, and this with simultaneous high tolerability and the occurrence of at most few side effects when the active substance is used. In this context, within the scope of the present invention, in addition to good effectiveness, excellent or improved tolerability and simple application of the active ingredient in the form of cineole, preferably 1,8-cineole, is also ensured.

In particular, the use of the active substance in the form of cineole, preferably 1,8-cineole, in the context of the clinical picture of otitis leads to a reduction in incorrect colonization or colonization of the inflamed ear with non-physiological germs, with an improvement in the colonization of the ear in this regard physiological germs is supported or caused, so that an improvement in the germ ratio in the sense of a shift towards increased physiological ear colonization (i.e. colonization of the ear with physiological or non-pathogenic germs) through the use of cineole, preferably 1,8-cineole , is effected, which in turn leads to a weakening or healing of the underlying disease in the form of the otitis in question.

Consequently, within the scope of the present invention, the clinical clinical picture with regard to the underlying otitis or inflammatory diseases of the ear is significantly improved within the scope of the application of the active substance cineole, preferably 1,8-cineole. This is also accompanied by a significant improvement in the quality of life of the patients affected by the disease, and this also with regard to the pain symptoms associated with the disease and the associated level of suffering of the patients.

In this context, in relation to the treatment of otitis, in particular otitis media and / or otitis externa, preferably otitis media, but also of otitis interna (e.g. in particular otitis media with inner ear involvement or in particular otitis media with accompanying inner ear inflammation), as a result of the excellent Efficacy of cineole, preferably 1,8-cineole, also an escalation of the disease state can be prevented.

As far as the use of cineole, preferably 1,8-cineole, is concerned with regard to inflammatory diseases of the ear or the related otitis, otorrhea associated with the otitis can also be treated within the scope of the present invention, accompanied by an improvement in the associated symptoms, namely in particular as regards a reduction in the discharge of body fluids or secretions from the ear or the external auditory canal caused by cineol, preferably 1,8-cineol. Consequently, a “wet ear” associated with the inflammation is counteracted.

As a result of the high therapeutic effectiveness of cineole, preferably 1,8-cineole, found by the applicant in a completely surprising manner, various sub-forms or special forms of otitis can also be treated effectively, such as a therapy-refractory or therapy-resistant, such as antibiotic-resistant, form of Illness. For this reason, too, the active substance cineole, preferably 1,8-cineole, has a large spectrum of action with regard to a large number of correspondingly developed otitis. For example, special forms of otitis or particularly severe otitis, such as otitis media mesotympanalis or otitis media epitympanalis or cholesteatoma, can also be treated. With regard to the cholesteatoma, within the scope of the present invention, the underlying cholesteatoma masses are sometimes not or not significantly dissolved (which is less relevant to therapy), but the inflammatory character and aggressiveness of the inflammation is sustainably inhibited or treated is, so that here too there is overall a very high effectiveness when using cineol, preferably 1,8-cineol, with an improvement in the disease state.

As a result of the overall positive influence of cineole, preferably 1,8-cineole, on the inflammatory process in the ear and the high effectiveness with regard to the treatment of otitis, in particular otitis media and / or otitis externa, preferably otitis media, in the context of the present Invention also allows necessary therapeutic operations on the ear, for example as far as the implantation of a cochlear implant or a tympanoplasty or Vibrant Soundbridge implantation is concerned. Because as a result of the high effectiveness of cineol, preferably 1,8-cineol, the inflammatory processes in the ear are significantly reduced and the colonization of the ear with pathogens is significantly reduced, so that on this basis a prerequisite for carrying out surgical interventions is created. Cineole or 1,8-cineole can thus be used as part of a preoperative application and thus in preparation for corresponding ear operations, with the underlying disease being weakened or healed in preparation for the operation, which makes the subsequent surgical intervention easier or possible in the first place. In addition, cineole, preferably 1,8-cineole, can also be administered perioperatively or postoperatively, for example with a view to avoiding the occurrence of recurrences or the like. By administering cineole, preferably 1,8-cineole, and the associated reduction in the number of pathogenic germs in the ear affected by an inflammatory disease or otitis, a systemic infection during the operation or following an operation can also be avoided or the probability of this can be significantly reduced.

As a result of the surprisingly found effectiveness of cineole, preferably 1,8-cineole, the administration of antibiotics can sometimes be avoided in the present case or their use can be reduced. Consequently, within the scope of the present invention, the disadvantages associated with the administration of antibiotics, such as specific side effects and the development of resistances, can be overcome or avoided.

In particular, a new therapeutic approach is also provided according to the invention with regard to regulation or influencing inflammatory reactions or processes that are particularly chronic and associated with inflammatory diseases of the ear, and this without provoking antibiotic-induced resistance of the pathogenic germs or pathogenic microorganisms . In particular, vulnerable groups such as (small) children can also be treated with the concept according to the invention.

Due to the antimicrobial effectiveness against pathogenic germs, the administration of cineole, preferably 1,8-cineol, mentioned within the scope of the present invention, can also combat or break down or “break up” germs formed by pathogenic germs or caused pathogenic biofilms in the ear, so that the colonization of the ear with pathogenic germs is also reduced on this basis and the accessibility of any other active substances, such as antibiotics or the like, in relation to the site of action on or in the ear is improved ( so that their effect can be increased or their quantity can be reduced). The cineole, in particular 1,8-cineole, can infiltrate or penetrate the biofilms in question—without wanting to be limited or invoked to this theory—so that its effect can unfold there.

The demonstrated effectiveness of cineole, in particular 1,8-cineole, is all the more surprising since the underlying inflammatory processes and their chronification with regard to otitis are of multifactorial genesis, as mentioned above.

Overall, the present invention thus provides an effective concept with regard to the treatment of inflammatory diseases of the ear or otitis, such as otitis media and/or otitis externa, preferably otitis media, using cineole or 1,8-cineole provided as the underlying active substance.

As previously stated, the present invention focuses on the treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media. In this regard, it can also be an otitis with accompanying or accompanying otorrhoea.

According to the invention, inflammatory diseases of the inner ear or otitis interna (e.g. in particular otitis media with inner ear involvement or in particular otitis media with accompanying inflammation of the inner ear) can in principle also be treated, as mentioned above.

In particular, it is in the context of the present invention such that the active ingredient cineole, preferably 1,8-cineole, for use in the prophylactic or therapeutic treatment of otitis, in particular otitis media and / or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhea is used.

According to a preferred embodiment according to the invention, it is also the case that the active ingredient cineole, preferably 1,8-cineole, is used for use in the prophylactic and/or therapeutic treatment of otitis media with accompanying (accompanying) otorrhoea.

According to the present aspect, the present invention thus also relates in particular to the use of cineole, preferably 1,8-cineole, in particular as defined above, for use in the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with concomitant (accompanying) otorrhea.

Furthermore, according to the present aspect, the present invention also relates in particular to cineole, preferably 1,8-cineole, in particular as defined above, for use in the prophylactic and/or therapeutic treatment of otitis media with accompanying (accompanying) otorrhoea.

As mentioned above, the active ingredient cineole, preferably 1,8-cineole, also has an effect on pathogens in the ear: Against this background, the present invention also relates to cineole, preferably 1,8-cineole, in particular as above defined, for use in reducing the load (germ load) and/or the number (germ number) of pathogenic germs, in particular pathogenic bacteria, located and/or localized in the ear, in particular in the middle and/or outer ear, preferably in the middle ear, and / or for use in reducing the proportion (germ proportion) of pathogenic germs, in particular pathogenic bacteria, located and/or localized in the ear, in particular in the middle and/or outer ear, preferably in the middle ear, in the prophylactic and/or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and/or outer ear, preferably the middle ear, preferably with accompanying (accompanying) otorrhea, and/or in the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa , preferably otitis media, preferably with concomitant (accompanying) otorrhea.

With regard to the preceding and following statements, the situation is such that the proportion or germ proportion of pathogenic germs is related to the total number of germs (total number of germs) in the ear, in particular in the middle and/or outer ear (in particular the outer auditory canal of the outer ear), preferably in the middle ear (in particular so that the total number of germs represents the reference value to be used). In a corresponding manner, it is also in particular such that the presently listed proportion of pathogenic bacteria to the total number of bacteria in the ear, in particular in the middle and / or outer ear, preferably in the middle telohr, is related. The corresponding proportions are therefore relative values with reference to the total number of bacteria or germs given above.

According to the present aspect, the present invention also relates to cineole, preferably 1,8-cineole, in particular as defined above, for use in the reduction and/or degradation and/or destruction of a pathogenic biofilm in the ear, in particular in the middle and /or outer ear (in particular in the outer auditory canal of the outer ear), preferably in the middle ear, in particular where the biofilm is formed by pathogenic germs, in particular pathogenic bacteria, in the prophylactic and/or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the agent - and/or outer ear, preferably the middle ear, preferably with accompanying (accompanying) otorrhoea, and/or in the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying ) otorrhea.

Consequently, with regard to the active ingredient cineole, preferably 1,8-cineole, the present invention is also aimed in particular at reducing or degrading or destroying pathogenic biofilms in the ear. In the context of the present invention, it is particularly the case that the pathogenic biofilms in connection with inflammatory diseases of the ear, in particular as defined above, and/or in connection with otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhoea, or which cause related inflammations or diseases, in particular on the basis of underlying pathogenic germs or bacteria. In particular, the pathogenic biofilms are formed by those pathogenic germs, in particular pathogenic bacteria, which are associated with the inflammations in the ear or in connection with the otitis or cause them.

The invention provides in particular that the cineole, preferably 1,8-cineole, for use according to any one of the preceding claims, to reduce the load (germ load) and / or the number (germ count) of in the ear, especially in the middle and / or Outer ear, preferably in the middle ear, located and / or localized pathogenic germs, in particular pathogenic bacteria, is employed or used.

In addition, within the scope of the present invention, the cineole, preferably 1,8-cineole, to reduce the proportion (germ proportion) of pathogenic germs located and/or localized in the ear, in particular in the middle and/or outer ear, preferably in the middle ear, in particular pathogenic bacteria, are employed or used.

• Insbesondere sind die pathogenen Keime ausgewählt aus der Gruppe von die entzündlichen Erkrankungen des Ohres, insbesondere entzündlichen Erkrankungen des Mittel- und/oder Außenohres, vorzugsweise des Mittelohres, bevorzugt mit begleitender (einhergehender) Otorrhoe, und/oder die Otitis, insbesondere Otitis media und/oder Otitis externa, vorzugsweise Otitis media, bevorzugt mit begleitender (einhergehender) Otorrhoe, verursachenden und/oder verstärkenden und/oder hiermit im Zusammenhang stehenden Keimen.

As far as the pathogenic germs in question are concerned, it can behave as follows in the context of the present invention:

• In particular, the pathogens are selected from the group consisting of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and/or outer ear, preferably the middle ear, preferably with accompanying (accompanying) otorrhea, and/or otitis, in particular otitis media and/or or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhoea, causing and/or intensifying and/or associated germs.

According to the invention, the pathogenic germs are also selected in particular from the group of bacteria, in particular pathogenic bacteria, preferably inflammatory diseases of the ear, in particular inflammatory diseases of the middle and/or outer ear, preferably the middle ear, preferably with accompanying (accompanying) otorrhoea, and/or or the bacteria causing and/or aggravating and/or associated therewith otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with concomitant (accompanying) otorrhoea.

Furthermore, within the scope of the present invention, it is particularly the case that the pathogenic germs are selected from the group of bacteria of the genus Pseudomonas, Proteus, Staphylococcus, Haemophilus, Streptococcus, Stenotrophomonas, Enterococcus and Moraxella and combinations thereof, in particular from the group of bacteria of the genus Pseudomonas, Proteus and Staphylococcus and combinations thereof, preferably from the group of bacteria of the genus Pseudomonas and Proteus and combinations thereof.

In this context, it can be provided in particular that the pathogens are selected from the group of bacteria of the species Pseudomonas aeruginosa, Pseudomonas stutzeri, Proteus mirabilis, Staphylococcus aureus, Haemophilus influenza, Streptococcus pneumoniae, Streptococcus pyogenes, Stenotrophomonas maltophila, Enterococcus faecalis and Moraxella catarrhalis and combinations thereof, in particular from the group of bacteria Species Pseudomonas aeruginosa, Proteus mirabilis and Staphylococcus aureus and combinations thereof, preferably bacteria of the species Pseudomonas aeruginosa and Proteus mirabilis and combinations thereof.

Cineole and 1,8-cineole are particularly effective against the aforementioned genera and species of bacteria. On this basis, an effective treatment of the underlying inflammatory diseases of the ear or otitis can take place. In this context, there is a direct connection between the above-mentioned special pathogenic bacterial genera or species with regard to the development or presence of inflammatory diseases of the ear or otitis, such as in particular Otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhoea, in particular insofar as the disease is caused by the pathogens in question (i.e. the germs are the cause of the disease) or that the in The germs in question are associated with the disease or maintain it or worsen it further.

As far as the pathogenic germs are concerned, it can also be the case within the scope of the present invention that the pathogenic germs are selected from the group of fungi, such as molds, and yeasts, in particular from the group of the genus Aspergillus and Candida, and their combinations. For example, the pathogens can be Aspergillus spp. or Candida parapilosis act. In principle, the pathogens can also be selected according to the invention from the group of viruses, in particular viruses associated with the aforementioned inflammatory diseases of the ear or the aforementioned otitis or causing the underlying inflammatory diseases.

Within the scope of the present invention, the use of cineole, preferably 1,8-cineole, also makes it possible in particular to improve or support the natural or physiological (germ) flora in the ear, which equally counteracts the underlying inflammatory diseases or otitis. Within the scope of the present invention, the use of cineole, in particular 1,8-cineole, can also behave in such a way that the physiological (germ) flora in the ear, in particular in the middle ear and/or in the outer ear (in particular in the outer auditory canal ), preferably in the middle ear, is improved or supported (i.e. in particular the number of physiological germs or their proportion of the total flora or of the total number of germs is increased).

Thus, according to the invention, it can behave in such a way that the cineole, preferably 1,8-cineole, for use, in particular as defined above, furthermore and/or additionally and/or equally to increase, increase or support in the ear, in particular in the Middle and / or outer ear, preferably in the middle ear, located and / or localized physiological germs (non-pathogenic germs), in particular physiological bacteria (non-pathogenic bacteria), is used or employed.

Likewise, it can behave according to the invention in such a way that the cineole, preferably 1,8-cineole, furthermore and/or additionally and/or equally to increase the load (germ load) or the number (germ number) or the proportion (germ proportion) of im Ear, in particular in the middle and / or outer ear, preferably in the middle ear, located and / or localized physiological germs (non-pathogenic germs), in particular physiological bacteria (non-pathogenic bacteria), is used or used.

In addition, it can also be provided according to the invention that the cineole, preferably 1,8-cineole, furthermore and/or additionally and/or equally to increase the colonization of the ear, in particular the middle and/or outer ear, preferably the middle ear physiological germs (non-pathogenic germs), in particular physiological bacteria (non-pathogenic bacteria), is used or employed.

As indicated above, numerous forms or sub-forms of otitis can be treated within the scope of the present invention.

According to the present aspect, the present invention also relates in this context to cineole, preferably 1,8-cineole, in particular as defined above,
for use in the prophylactic and / or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and / or outer ear, preferably the middle ear, preferably with accompanying (accompanying) otorrhea, the disease being a therapy-refractory and / or therapy-resistant, especially medication - and/or drug-resistant, preferably antibiotic-resistant, disease; or for use in the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhea, the otitis being a therapy-refractory and/or therapy-resistant, in particular drug- and/or drug-resistant, preferably antibiotic-resistant, otitis.

Thus, according to the invention, the situation can be such that the disease is a therapy-refractory and/or therapy-resistant, in particular drug- and/or drug-resistant, preferably antibiotic-resistant, disease.

Correspondingly, it can also be the case according to the invention that the otitis is therapy-refractory and/or therapy-resistant, in particular drug- and/or drug-resistant, preferably antibiotic-resistant, otitis.

In particular, it can behave according to the invention in such a way that the pathogens, in particular those associated with or causing inflammatory diseases of the ear and/or otitis, are refractory to therapy and/or therapy-resistant, in particular drug- and/or drug-resistant antibiotic-resistant, pathogenic germs. The pathogenic germs can preferably be drug- and/or drug-resistant, in particular antibiotic-resistant, pathogenic bacteria. In this regard, too, the applicant was able to show that cineole, in particular 1,8-cineole, was highly effective. The pathogenic germs can also be so-called MRGN bacteria (multi-resistant gram-negative bacteria), for example 3MRGN bacteria (resistance to three classes of antibiotics) or 4MRGN bacteria (resistance to four classes of antibiotics).

Furthermore, the otitis can be an acute otitis or a chronic otitis, in particular a chronic otitis, preferably a chronic polypoid otitis or a chronic granular otitis. In addition, the otitis can also be a recurrent otitis or chronic-recurrent otitis, in particular a chronic otitis, preferably a chronic polypoid otitis or a chronic granular otitis. According to the invention, it can be provided in particular that the otitis is in particular a recurring otitis media, preferably with accompanying (accompanying) otorrhoea.

In general, according to the invention, with regard to the inflammatory diseases of the ear, it can be otitis with accompanying (accompanying) otorrhoea. In particular, it can be a case of foetid otorrhea.

In particular, it can be the case according to the invention that the otitis is in particular a chronic otitis media, preferably with accompanying (accompanying) otorrhoea.

Furthermore, it can be the case according to the invention that the otitis is an otitis media epitympanalis (cholesteatoma or otitis media epitympanalis with cholesteatoma) or an otitis media mesotympanalis, preferably an otitis media epitympanalis. In this regard, chronic forms may be involved (i.e. otitis media chronica epitympanalis or otitis media chronica mesotympanalis). The aforementioned otitis can also be accompanied by or associated with otorrhoea (i.e. otitis media (chronica) epitympanalis with accompanying otorrhoea or otitis media (chronica) mesotympanalis with accompanying otorrhoea).

Furthermore, it can behave according to the invention in such a way that the inflammatory diseases of the ear or otitis, in particular otitis media and / or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhea, preferably otitis media epitympanalis, with an inflammatory mediation, in particular an upregulation and/or an increased production or an increased release of in particular pro-inflammatory cytokines, preferably TNF-alpha (tumor necrosis factor-alpha) and/or interleukin-1 (IL-1), preferably TNF-alpha, is associated with or associated with this.

In this regard, it can be provided in particular that the cineole, preferably 1,8-cineole, further and / or additionally and / or equally to suppress or weaken in the context of inflammatory diseases of the ear and / or otitis, especially otitis media and / or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhoea, preferably otitis media epitympanalis, occurring inflammatory mediation is used or used.

In particular, it can behave in the context of the present invention in such a way that the cineole, preferably 1,8-cineole, has a suppressing or weakening effect on an inflammatory disease of the ear and / or otitis, in particular otitis media and / or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhea, preferably otitis media epitympanalis, occurring inflammatory mediation exerts. In this regard, it can behave according to the invention in particular such that the cineole, preferably 1,8-cineole, a down-regulation and / or a reduced production and / or a reduced Aus release of, in particular, proinflammatory cytokines, preferably TNF-alpha (tumor necrosis factor-alpha or TNF-α) and/or interleukin-1beta (IL-1β), preferably TNF-alpha, causes or causes.

In particular, the cineole, preferably 1,8-cineole, can thus be used to downregulate and/or reduce the production and/or reduce the release of, in particular, proinflammatory cytokines, preferably TNF-alpha (tumour necrosis factor alpha) and/or interleukin-1 beta (IL-1β), preferably TNF-alpha, are used or employed.

In this context, with regard to the underlying diseases, in particular in the form of the cholesteatoma, the situation is such that - without wanting to limit or refer to this theory - the aforementioned proinflammatory cytokines, preferably TNF-alpha, the inflammation and/or apoptosis regulate or influence and also play an important role with regard to the chronification of the disease. These processes can also be counteracted by the action of cineol, preferably 1,8-cineol.

Especially in this context, the active ingredient cineole, preferably 1,8-cineole, can also be said to have an anti-inflammatory effect with regard to the use according to the invention with the treatment of inflammatory diseases of the ear or otitis. Consequently, inflammatory processes associated with inflammatory diseases of the ear or otitis are also reduced or down-regulated on this basis, so that on this basis a positive effect or an active effect with regard to the treatment of the inflammatory Diseases of the ear or otitis are present.

In particular, it can behave according to the invention in such a way that the cineole, preferably 1,8-cineole, is used or employed further and/or additionally and/or equally as an anti-inflammatory active ingredient, in particular as a locally and/or systemically acting anti-inflammatory active ingredient.

In addition, it can also be provided according to the invention that the cineole, preferably 1,8-cineole, furthermore and/or additionally and/or equally for the prevention and/or prevention and/or for the prophylactic and/or therapeutic treatment of the inflammatory Diseases of the ear and/or otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhoea, related and/or caused thereby sequelae and/or concomitant diseases, in particular selected from the group mastoisitis, labyrinthitis, meningitis, sinus vein thrombosis, sepsis, facial nerve palsy and tinnitus, and combinations thereof. Within the scope of the present invention, serious secondary or concomitant diseases of otitis, in particular otitis media, can thus be prevented, in particular in the sense of prophylaxis, or can be treated or co-treated concomitantly with an underlying otitis.

In addition, the cineole, preferably 1,8-cineole, can also be employed or used with a view to performing ear operations, in particular operations on the middle and/or outer ear, preferably the middle ear, in particular as follows: cineole, preferably 1,8-cineole, preoperatively and/or for preoperative preparation and/or to enable surgical interventions (surgical operations), in particular therapeutic-surgical interventions, on the ear (ear operations), in particular on the middle and/or outer ear (Middle and/or outer ear operations), preferably on the middle ear (middle ear operations), such as tympanoplastic operations and/or implantation operations (implantation), are used or employed.

In addition, the cineole, preferably 1,8-cineole, within the scope of the present invention can be used postoperatively and/or for the postoperative follow-up treatment of surgical interventions (surgical operations), in particular therapeutic-surgical interventions, on the ear (ear operations), in particular on the middle and/or or outer ear (middle and/or outer ear operations), preferably on the middle ear (middle ear operations), such as tympanoplastic operations and/or implantation operations (implantation). Thus, according to the invention, furthermore and/or additionally and/or equally, a preoperative and/or postoperative, preferably preoperative, use of cineole, preferably 1,8-cineole, can take place.

Furthermore, the cineole, preferably 1,8-cineole, can, within the scope of the present invention, be used intraoperatively and/or during surgical interventions, in particular therapeutic-surgical interventions, on the ear (ear operations), in particular on the middle and/or outer ear, preferably on the middle ear ( Middle ear operations), such as tympanic operations and/or implantation operations (implantation), are used or employed. Thus, according to the invention furthermore and/or additionally and/or equally an intraoperative use of cineole, preferably 1,8-cineole.

Overall, according to the invention, a perioperative use of cineole, preferably 1,8-cineole, can also take place and/or in addition.

• Diesbezüglich betrifft die vorliegende Erfindung gemäß dem vorliegenden Aspekt somit auch Cineol, vorzugsweise 1,8-Cineol, insbesondere wie zuvor definiert, zur Verwendung bei der prophylaktischen und/oder therapeutischen Behandlung von entzündlichen Erkrankungen des Innenohres, bevorzugt mit begleitender (einhergehender) Otorrhoe, bzw. zur Verwendung bei der prophylaktischen und/oder therapeutischen Behandlung von Otitis interna und/oder Otitis media mit begleitender Innenohrentzündung, jeweils bevorzugt mit begleitender (einhergehender) Otorrhoe.

According to the invention, the active substance cineole, preferably 1,8-cineole, can also be used with regard to the treatment of otitis interna (e.g. in particular otitis media with inner ear involvement or in particular otitis media with accompanying inner ear inflammation):

• In this regard, the present invention according to the present aspect thus also relates to cineole, preferably 1,8-cineole, in particular as defined above, for use in the prophylactic and/or therapeutic treatment of inflammatory diseases of the inner ear, preferably with accompanying (accompanying) otorrhoea, or for use in the prophylactic and/or therapeutic treatment of otitis interna and/or otitis media with accompanying inflammation of the inner ear, in each case preferably with accompanying (accompanying) otorrhoea.

Consequently, according to the invention, the situation can be such that the otitis is an otitis interna and/or an otitis media with accompanying inflammation of the inner ear, in each case preferably with accompanying (accompanying) otorrhoea.

As previously stated, the present invention focuses on inflammatory diseases of the ear. According to the invention, the situation can be such that the cineole is not intended for use in reducing pathogenic germs or pathogens in the human intestine, in particular in the human intestinal flora, or is excluded from this use.

In particular, it can behave according to the invention in such a way that cineole, preferably 1,8-cineole, is excluded for use in reducing the colonization of the human intestine, in particular the human intestinal flora, with pathogenic germs or pathogens. Consequently, it can be provided according to the invention in particular that the active ingredient cineole, preferably 1,8-cineole, is excluded from use in reducing the colonization of the human intestine, in particular the human intestinal flora, with pathogenic germs or pathogens. In particular, these can also be pathogenic germs or pathogens that are typical of incorrect colonization of the intestinal flora, i. H. in particular those pathogenic germs or pathogens which are particularly specifically associated with an incorrect colonization of the intestine, in particular the human intestine.

According to the invention, it can be the case in particular that cineole, preferably 1,8-cineole, is not used to reduce the colonization of the human intestine, in particular the human intestinal flora, with pathogenic germs or pathogens.

According to a particular embodiment of the present invention according to this aspect of the invention, it is provided that the cineole, preferably 1,8-cineole, is administered systemically, in particular perorally or parenterally, preferably perorally, and/or that the cineole, preferably 1,8-cineole , is prepared for systemic, in particular peroral or parenteral, preferably peroral application. In this way, high systemic effective doses or active substance levels (i.e. active substance levels or concentrations) are achieved, and this also at the site of action itself (i.e. in the area of the ear, in particular in the area of the middle or outer ear, preferably in the area of the middle ear), so that a particularly good effectiveness or efficiency can be realized.

In other words, it can behave according to the invention in such a way that the cineole, preferably 1,8-cineole, is administered in the form of a dosage form to be administered systemically, in particular perorally or parenterally, preferably perorally.

According to an advantageous embodiment according to this aspect of the invention, it is particularly provided that the cineole, preferably 1,8-cineole, is administered in the form of a dosage form to be administered orally or that the cineole, preferably 1,8-cineole, is administered in a dosage form to be administered orally Dosage form is prepared.

According to another particular embodiment of the present invention according to this aspect, it can be provided in particular that the cineole, preferably 1,8-cineole, is administered as a gastric juice-resistant but soluble in the small intestine systemic dosage form, preferably as a capsule, coated tablet, pill, tablet or the like and/or that the cineole, preferably 1,8-cineole, is prepared for administration as a systemic dosage form that is resistant to gastric juice but soluble in the small intestine, preferably a capsule, coated tablet, pill, tablet or the like.

For the systemic use of cineole, especially 1,8-cineole, various are commercially available dene preparations, in particular based on dosage forms or capsules that are generally resistant to gastric juice but soluble in the small intestine.

The advantage of such dosage forms is that on the one hand the active substance cineole, in particular 1,8-cineole, is stable over the long term and, on the other hand, particularly high systemic active substance concentrations or active substance levels can be achieved. In this way, particularly high-dose dosage forms can also be provided, so that precise and high dosage of the active substance is made possible.

Within the scope of the present invention, cineole, in particular 1,8-cineole, is usually used in an oral administration form, preferably in the form of capsules. According to the invention, it is particularly preferred to administer the cineole, in particular 1,8-cineole, in the form of an oral administration that is resistant to gastric juice but is soluble in the small intestine, in particular a capsule. Very particular preference is given to peroral administration forms which are resistant to gastric juice but soluble in the small intestine, in particular capsules which contain cineole, in particular 1,8-cineole, as the pure substance. Such products are commercially available or available (e.g. Soledum ^® capsules or Soledum ^® forte capsules, sold by Cassella-med GmbH & Co. KG or by Maria Clementine Martin Klosterfrau Vertriebsgesellschaft mbH, Cologne in each case , Germany).

In general, it is provided within the scope of the present invention that the peroral administration form, in particular capsule, is designed to be gastric juice-resistant but soluble in the small intestine. As a result, a particularly optimal release profile is achieved, since the active substance is only released in a targeted and purposeful manner in the intestine and, starting from there, is optimally absorbed by the body.

The definitions used in the context of this invention for the terms "gastric juice-resistant" or "soluble in the small intestine" and the relevant test methods are in European Pharmacopoeia 7.0, 04/2010: 1502, pages 707 to 709, keyword "Capsules", subchapter "Gastro-Resistant Capsules ' and European Pharmacopoeia 7.1, 04/2011: 20901, pages 3331 and 3332, keyword '2.9.1 Disintegration of Tablets and Capsules'.

In the context of the present invention, the term “enteric juice-resistant” means in particular that the capsules are kept for at least two hours in 0.1N hydrochloric acid, which is heated to temperatures of 35 to 39° C., with constant mixing, in particular stirring can be used without the capsules showing signs of deterioration, cracking or other damage.

In the context of the present invention, the term "soluble in the small intestine" is to be understood in particular as meaning that the capsules are dissolved in an aqueous phosphate buffer solution, which has been adjusted to a pH value of about 6.8, with stirring at temperatures in the range from 35 to 39 °C can be decomposed within one hour to such an extent that the active substance is released.

Within the scope of the present invention, however, it can also be provided that the cineole, preferably 1,8-cineole, is applied in the form of a dosage form to be administered topically, in particular auricularly and/or in the ear. In particular, the cineole, preferably 1,8-cineole, can be prepared in a dosage form to be administered topically, in particular auricularly and/or in the ear. Ear drops, for example, can be used in this regard. Due to the topical, in particular auricular, administration form, locally high amounts or concentrations of active substance can be specified. In particular, high amounts or concentrations of active ingredient can be achieved at the site of action itself at the local level.

According to the invention, it can also be provided in principle that the cineole is applied in the form of a dosage form to be administered nasally or topically-nasally or that the cineole, preferably 1,8-cineole, is prepared in a nasal dosage form.

Thus, the cineole, preferably 1,8-cineole, can also be administered in the form of ear drops or in the form of a nasal spray. As far as nasal application is concerned, the active substance can reach the site of action in particular through the Eustachian tube (tuba auditiva), in particular in addition to systemic absorption via the nasal mucosa.

In the context of the present invention, it is particularly provided that the cineole, preferably 1,8-cineole, is administered in pharmaceutically effective or therapeutically effective amounts and/or that the cineole, preferably 1,8-cineole, is administered in pharmaceutically effective amounts or therapeutically effective amounts is prepared.

In particular, it can be provided within the scope of the present invention according to this aspect of the invention according to a particular embodiment that the cineole, preferably 1,8-cineole, with a daily dose in the range from 1 mg/diem to 5,000 mg/diem, in particular in the range from 2 mg/diem to 3000 mg/diem, preferably in the range from 5 mg/diem to 2500 mg/diem, preferably in the range from 10 mg/diem to 2000 mg/diem, particularly preferably in the range from 50 mg/diem to 1,500 mg/diem, very particularly preferably in the range from 100 mg/diem to 1,200 mg/diem, more preferably in the range from 200 mg/diem to 1,000 mg/diem, and/ or that the cineole, preferably 1,8-cineole, for administration at a daily dose in the range of 1 mg/diem to 5,000 mg/diem, more preferably in the range of 2 mg/diem to 3,000 mg/diem, preferably in the range of 5 mg /diem to 2500 mg/diem, preferably in the range from 10 mg/diem to 2000 mg/diem, particularly preferably in the range from 50 mg/diem to 1500 mg/diem, very particularly preferably in the range from 100 mg/diem to 1200 mg /diem, more preferably in the range of 200 mg/diem to 1000 mg/diem.

According to a further particular embodiment of the present invention according to this aspect of the invention, provision can be made in particular for the cineole, preferably 1,8-cineole, to be present or administered as a pure substance. In particular, the cineole, preferably 1,8-cineole, with a purity of at least 95% by weight, in particular at least 96% by weight, preferably at least 97% by weight, particularly preferably at least 98% by weight, whole particularly preferably at least 99% by weight, even more preferably at least 99.5%, based on the cineole, preferably 1,8-cineole, is present or administered.

In this context, it is particularly preferred according to the invention if the cineole, preferably 1,8-cineole, is free from other terpenes or, in particular, where the cineole, preferably 1,8-cineole, contains no other terpenes.

As described above, it is preferred according to the invention that the monoterpene-based active substance (ie cineole, preferably 1,8-cineole) is in the form of a pure substance, ie. H. as the sole or technically isolated/purified active ingredient. In this way, it is possible, for example, to ensure that the dosage always remains the same or that the content of active substance is always the same in the dosage form provided according to the invention. In this way, high doses or amounts of active ingredient can also be realized at the site of action. In addition, this further focuses the spectrum of action and further reduces side effects.

Above all - as explained above - cineole, especially 1,8-cineole, in its pure form or as a pure substance has a particularly efficient steroid-like effect potential, since in its pure form or as a pure substance it has a particularly efficient inhibition of inflammatory mediators or the leukotriene and causes cytokine production. Essential mixed oils, which contain cineole as one of many active components (such as e.g. eucalyptus oil, etc.), on the other hand, stimulate prostaglandin production and only show a significantly reduced inhibition of leukotriene and cytokine production compared to pure cineole, since the mixed oils also contain substances that can stimulate cell activity and mediator production and therefore do not have an anti-inflammatory effect, but rather can cause intolerance reactions (i.e. such mixed essential oils or oil mixtures can therefore generally increase cell activity and even induce inflammatory mediator production). In contrast to this, however, isolated or pure cineole, in particular 1,8-cineole, exclusively causes a significant inhibition of the inflammatory mediator production.

According to yet another particular embodiment according to this aspect of the invention, it can be provided according to the invention that the cineole, preferably 1,8-cineole, is present and/or administered together with at least one physiologically acceptable carrier (excipient). In particular, it can be provided that the physiologically harmless carrier (excipient) is miscible with 1,8-cineol and/or soluble therein. Furthermore, it can be provided in particular that the physiologically harmless carrier (excipient) is present at 20° C. and at atmospheric pressure in the liquid or solid, preferably liquid, state of aggregation.

In turn, it can also be provided in this context that the physiologically acceptable carrier (excipient) can be selected from the group of fatty acid esters, preferably triglycerides of fatty acids, particularly preferably medium-chain triglycerides (medium chain triglycerides or MCT), very particularly preferably triglycerides of C ₆ -C ₁₂ fatty acids.

In this context, it can be provided according to the invention that the cineole, preferably 1,8-cineole, is present or administered as a pure substance or in the absence of other (additional) terpenes.

In this context, it can equally be provided that the cineole, preferably 1,8-cineole, is present or administered as a pure substance or in the absence of other (additional) terpenes, together with at least one physiologically harmless carrier (excipient).

According to a particular embodiment, the dosage form provided according to the invention thus contains--as described above--the monoterpene and the active substance cineol, in particular 1,8- Cineole, together with at least one physiologically acceptable carrier (excipient) which is miscible with the active substance and/or soluble therein, in particular liquid at 20° C. and atmospheric pressure. The carrier or excipient should not itself be pharmacologically active, but should form a preferably homogeneous mixture or solution with the active substance.

According to a preferred embodiment of the invention, as explained above, the carrier or excipient can be selected from the group of fatty acid esters, preferably triglycerides of fatty acids, particularly preferably medium-chain triglycerides (medium chain triglycerides or MCT), very particularly preferably triglycerides of C ₆ -C ₁₂ fatty acids.

Mixtures of fatty acid triglycerides which are liquid at room temperature (in particular 20° C.) and atmospheric pressure can be used with preference as carriers or excipients; in particular, this term denotes esters of the trihydric alcohol glycerol (propane-1,2-3-triol) with three, mostly different, predominantly even-numbered and unbranched aliphatic monocarboxylic acids, the so-called fatty acids. Compounds of this type are also called triglycerides (according to the IUPAC recommendation: triacylglycerols). Triglycerides, also synonymously referred to as glycerol triesters, are triple esters of the trihydric alcohol glycerol with three acid molecules, with the prefix "tri" referring to three acyl acid residues that are esterified with glycerol.

Especially medium-chain triglycerides, such as are preferably used according to the invention as a carrier or excipient for the monoterpene-containing active substance, are in particular semisynthetic neutral glycerol esters of saturated, generally unbranched monocarboxylic acids of medium chain length (ie C ₆ -C ₁₂ chains). In particular, the term medium-chain triglycerides denotes mixtures of triglycerides of saturated fatty acids, mainly caprylic acid (octanoic acid) and capric acid (decanoic acid). Medium chain triglycerides can generally be prepared from oil obtained from the solid and dried part of the endosperm of Cocos nucifera L. and/or from the dried endosperm of Elaeis guineenses Jacq. is extracted. For further details on the concept of medium-chain triglycerides, reference can be made, for example, to the monograph Ph. Eur., 6th edition, Grundwerk 2008, pages 4224 to 4226, and to the journal for nutritional science, volume 13, issue 1/2, 1973. Pages 6 ff., D. Sailer et al. "Medium-chain triglycerides - clinical physiology and application").

It is preferred according to the invention if the carrier or excipient is present in an active substance/carrier quantity ratio in the range from 1000:1 to 1:1000, in particular 100:1 to 1:100, preferably 50:1 to 1:50, particularly preferably 10 : 1 to 1:10, very particularly preferably 5:1 to 1:2, even more preferably 3:1 to 1:1. Mixing the active substance (ie cineol, in particular 1,8-cineol) with the excipient achieves significantly improved compatibility of the active substance with the other ingredients of the dosage form and improved stability, in particular storage stability.

According to an equally further special embodiment of the present invention, it can be provided that the cineole, preferably 1,8-cineole, in or in the form of a composition, in particular a pharmaceutical composition, in particular together with at least one pharmaceutically tolerable and/or physiologically acceptable excipient (carrier) is present and/or administered.

In this context, it can be provided in particular that the composition contains cineole, preferably 1,8-cineole, as the sole active ingredient, in particular as the sole pharmaceutical active ingredient, or as an individual active ingredient.

Furthermore, it can be provided in particular that the composition contains the cineole, preferably 1,8-cineole, as a pure substance, preferably with a purity of at least 95% by weight, in particular at least 96% by weight, preferably at least 97% by weight. -%, particularly preferably at least 98% by weight, very particularly preferably at least 99% by weight, even more preferably at least 99.5%, based on the cineole, preferably 1,8-cineole, and/or preferably free from others terpenes.

Equally, it can also be provided that the composition contains the cineole, preferably 1,8-cineole, free from other terpenes and/or that the composition contains no further terpene and/or that the composition is free from terpenes other than cineol, preferably 1,8-cineole.

Furthermore, it can be provided that the composition contains the cineole, preferably 1,8-cineole, in effective, in particular pharmaceutically and/or therapeutically effective, amounts.

It can also be provided in this context according to the invention that the composition relates to the cineole, preferably 1,8-cineole genes on the composition, in relative amounts ranging from 0.0001 to 80% by weight, in particular 0.001 to 75% by weight, preferably 0.005 to 70% by weight, preferably 0.01 to 60% by weight, particularly preferably 0.05 to 55% by weight, very particularly preferably 0.1 to 50% by weight.

Finally, it can also be provided according to the invention in this connection that the at least one pharmaceutically tolerable and/or physiologically harmless excipient (carrier) is miscible with 1,8-cineole and/or soluble therein. The at least one pharmaceutically tolerable and/or physiologically acceptable excipient (carrier) can preferably be in the liquid or solid, preferably liquid, state of aggregation at 20° C. and at atmospheric pressure. The at least one pharmaceutically acceptable and/or physiologically harmless excipient (carrier) can also preferably be selected from the group of fatty acid esters, preferably triglycerides of fatty acids, particularly preferably medium-chain triglycerides (medium chain triglycerides or MCT), very particularly preferably triglycerides of C ₆ -C ₁₂ fatty acids.

According to a particular embodiment of the present invention, the cineole, preferably 1,8-cineole, can be present and/or administered in liposome-enclosed and/or liposomally-packaged form. This also ensures a particularly good release profile.

According to a further particular embodiment of the present invention, the cineole, preferably 1,8-cineole, can be present and/or administered in micellar form or in the form of a micellar administration form. A particularly good release profile can also be ensured in this way.

According to a first embodiment of the invention, the cineole, preferably 1,8-cineole, can be present or administered as a single active ingredient or as a monopreparation or be prepared for administration. In this regard, the cineole, preferably 1,8-cineole, can be present or administered without or in the absence of other active substances different from cineole, preferably 1,8-cineole.

In particular, the cineole, preferably 1,8-cineole, can be present or administered or prepared for administration without and/or in the absence of other active substances different from cineole, preferably 1,8-cineole.

According to the invention, the cineole, preferably 1,8-cineole, can be present or present without and/or in the absence of and/or free of and/or not in combination with vitamin D receptor agonists (VDA), in particular compounds of the vitamin D group. be administered or prepared for administration.

According to a further embodiment according to the invention, however, it can be provided that the cineole, preferably 1,8-cineole, is present or administered with at least one other active ingredient or as a co-therapeutic agent. In this context, it can be provided in particular that the further active ingredient is selected from (i) anti-inflammatory active ingredients (antiphlogistics), in particular non-steroidal anti-inflammatory drugs (NSAIDs) or steroidal anti-inflammatory drugs; (ii) analgesics; (iii) antipyretics; (iv) antibiotics; as well as their combinations.

According to a further preferred embodiment, it can be provided in particular that the further active ingredient is used or administered separately, in particular spatially separated, from the cineole, preferably 1,8-cineole, but functionally related thereto, in particular in the form of a kit (kit -of part).

Through the targeted combination or joint administration of cineole or 1,8-cineole with at least one other active ingredient, it is particularly possible within the scope of the present invention to significantly increase the effect or efficiency of the other active ingredient, in particular in a synergistic manner, and to increase its use Significantly reduce the dose, combined with the associated advantages (e.g. avoidance or reduction of side effects or the like).

As stated above, it can be provided within the scope of the present invention that the cineole is used as a co-therapeutic agent or as a co-medication in the context of a basic otitis therapy or that the cineole, preferably 1,8-cineole, as or used in combination therapy with a basic otitis therapy. As mentioned above, the cineole used according to the invention, preferably 1,8-cineole, can lead to a significant, in particular synergistic, increase in the effect of the basic therapeutic agent or agents, as mentioned above.

• So betrifft die vorliegende Erfindung gemäß dem vorliegenden Aspekt insbesondere auch Cineol, vorzugsweise 1,8-Cineol, zur Verwendung bei der prophylaktischen und/oder therapeutischen Behandlung von Otitis, insbesondere Otitis media und/oder Otitis externa, vorzugsweise Otitis media, bevorzugt mit begleitender (einhergehender) Otorrhoe.

According to the present aspect, the present invention also relates in particular to the following objects:

• Thus, according to the present aspect, the present invention also relates in particular to cineole, preferably 1,8-cineole, for use in the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with concomitant (accompanying) otorrhea.

Furthermore, according to the present aspect, the present invention preferably also relates to cineole, preferably 1,8-cineole, for use in the prophylactic and/or therapeutic treatment of otitis media with accompanying (accompanying) otorrhoea.

According to the present aspect, the present invention also relates to cineole, preferably 1,8-cineole,
for use in reducing the load (germ load) and/or the number (germ number) of pathogenic germs located and/or localized in the ear, in particular in the middle and/or outer ear, preferably in the middle ear, and/or for use in the reduction the proportion (germ proportion) of pathogenic germs located and/or localized in the ear, in particular in the middle and/or outer ear, preferably in the middle ear
in the prophylactic and/or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and/or outer ear, preferably the middle ear, preferably with accompanying (accompanying) otorrhea, and/or in the prophylactic and/or therapeutic treatment of otitis , in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhea.

According to the present aspect, the present invention also relates to cineole, preferably 1,8-cineole, for use in the prophylactic and/or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and/or outer ear, preferably the middle ear with concomitant (accompanying) otorrhoea, and/or cineole, preferably 1,8-cineole, for use in the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with concomitant (accompanying ) otorrhea,
but excluding for use in reducing pathogenic germs in the human intestine, in particular in the human intestinal flora, and/or excluding for use in reducing the colonization of the human intestine, in particular the human intestinal flora, with pathogenic germs.

With regard to the aforementioned objects, reference can also be made to the above statements on the present aspect.

The present invention, both according to the first aspect of the present invention and according to all other aspects of the present invention, is therefore associated with a large number of advantages and special features which make the therapy concept according to the invention unique and special, in particular highly efficient.

For further details on the first aspect of the invention described above, reference can also be made to the statements on the other aspects of the invention, these statements equally applying to the present first aspect of the invention.

Another subject of the present invention - according to a second aspect of the present invention - is the inventive use of cineole, preferably 1,8-cineole, for the prophylactic and / or therapeutic treatment of inflammatory diseases of the ear, especially inflammatory diseases of the middle and / or Outer ear, preferably the middle ear, preferably with accompanying (accompanying) otorrhoea, and/or use of cineol, preferably 1,8-cineol, for the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media , preferably with concomitant (accompanying) otorrhea.

In this context, the present invention also relates to the use of cineole, preferably 1,8-cineole, for the production of a drug or medicament for the prophylactic and/or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and/or outer ear, preferably of the middle ear, preferably with accompanying (accompanying) otorrhoea, and/or use of cineole, preferably 1,8-cineole, for the manufacture of a pharmaceutical or medicament for the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa , preferably otitis media, preferably with concomitant (accompanying) otorrhea.

According to this aspect of the invention, the cineole, preferably 1,8-cineole, in particular the pharmaceutical or medicament or the composition can be administered in pharmaceutically effective amounts or therapeutically effective amounts. In this regard, the cineole, preferably 1,8-cineole, particularly the drug or medicament or composition may be adapted for administration in pharmaceutically effective or therapeutically effective amounts, respectively. In addition, the cineole, preferably 1,8- Cineol, in particular the drug or medicament or the composition, can be administered systemically or topically, in particular systemically, preferably orally. Furthermore, the cineole, preferably 1,8-cineole, in particular the medicinal product or medicament, can in principle be applied or administered topically, in particular auricularly or in the ear.

If necessary, according to yet another embodiment according to this aspect, the cineole, preferably 1,8-cineole, in particular the drug or medicament or the composition, can be used or administered together with at least one other active ingredient. In this regard, the further active ingredient can be selected from (i) anti-inflammatory active ingredients (antiphlogistics), in particular non-steroidal anti-inflammatory drugs (NSAIDs) or steroidal anti-inflammatory drugs; (ii) analgesics; (iii) antipyretics; (iv) antibiotics; as well as their combinations.

For further details on this aspect of the invention, reference can be made to the statements on the further aspects of the invention, these statements equally applying to the present aspect of the invention.

Equally the subject of the present invention is - according to a third aspect of the present invention - the inventive use of cineole, preferably 1,8-cineole, as an ear treatment agent or for the production of an ear treatment agent for the prophylactic and / or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and/or outer ear, preferably the middle ear, preferably with accompanying (accompanying) otorrhea, and/or use of cineole, preferably 1,8-cineole, as an ear treatment agent for the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with concomitant (accompanying) otorrhea.

In accordance with this aspect of the invention, the cineole, preferably 1,8-cineole, particularly the drug or medicament or composition or ear treatment agent may be administered in pharmaceutically effective amounts or therapeutically effective amounts, respectively. In this regard, the cineole, preferably 1,8-cineole, particularly the drug or medicament or composition may be adapted for administration in pharmaceutically effective or therapeutically effective amounts, respectively. In addition, the cineole, preferably 1,8-cineole, in particular the drug or medicament or the composition, can be administered systemically or topically, in particular systemically, preferably orally. Furthermore, the cineole, preferably 1,8-cineole, in particular the medicinal product or medicament, can in principle be applied or administered topically, in particular auricularly or in the ear.

If necessary, according to yet another embodiment according to this aspect, the cineole, preferably 1,8-cineole, in particular the drug or medicament or the composition or the ear treatment agent, can be used or applied together with at least one other active ingredient. In this regard, the further active ingredient can be selected from (i) anti-inflammatory active ingredients (antiphlogistics), in particular non-steroidal anti-inflammatory drugs (NSAIDs) or steroidal anti-inflammatory drugs; (ii) analgesics; (iii) antipyretics; (iv) antibiotics; as well as their combinations.

For further details on this aspect of the invention, reference can be made to the statements on the further aspects of the invention, these statements equally applying to the present aspect of the invention.

Another subject of the present invention - according to a further aspect of the present invention - is the method according to the invention for the prophylactic and / or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and / or outer ear, preferably the middle ear, preferably with concomitant (accompanying) otorrhoea, and/or methods for the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with concomitant (accompanying) otorrhoea,
wherein in the method a patient suffering from the inflammatory diseases of the ear and/or otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhea, receives a pharmaceutically effective or therapeutically effective amount of cineole , preferably 1,8-cineol, is administered.

In this regard, the cineole, preferably 1,8-cineole, may be administered in, or prepared for administration in, pharmaceutically effective or therapeutically effective amounts. In this respect, corresponding pharmaceuticals or medicaments or compositions or ear treatment agents for the administration of cineole, preferably 1,8-cineole, be used. Within the scope of this aspect of the invention, too, the cineole, preferably 1,8-cineole, or the drug or medicament or composition or ear treatment agent can be applied systemically or topically, in particular systemically, preferably orally. In principle, however, topical, in particular auricular administration or administration into the ear can also be provided.

If necessary, the cineole, preferably 1,8-cineole, in particular the drug or medicament or the composition, can be used or applied together with at least one other active ingredient, in particular where the other active ingredient is selected from (i) anti-inflammatory active ingredients (antiphlogistics), in particular nonsteroidal anti-inflammatory drugs (NSAIDs) or steroid anti-inflammatory drugs; (ii) analgesics; (iii) antipyretics; (iv) antibiotics; as well as their combinations.

For further details on this aspect of the invention, reference can also be made to the statements on the further aspects of the invention, as described here, with these statements equally applying to the present aspect of the invention.

Also subject matter of the present invention - according to a further aspect of the present invention - is the drug or medicament according to the invention, in particular ear treatment agents, for (use in) the prophylactic and/or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the central and/or or outer ear, preferably the middle ear, preferably with concomitant (accompanying) otorrhoea, and/or for (use in) the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with concomitant ( concomitant) otorrhoea, wherein the pharmaceutical or medicament, in particular antiviral agent, contains cineole, preferably 1,8-cineole, together with at least one pharmaceutically acceptable and/or physiologically acceptable excipient (carrier).

Also within the scope of this aspect of the invention, it can be provided in particular that the active ingredient or the cineole, preferably 1,8-cineole, or the drug or medicament, in particular ear treatment agents, is applied systemically or topically.

It is preferred according to the invention if the medicinal product or medicament contains cineole, preferably 1,8-cineole, as the sole active ingredient, in particular as the sole pharmaceutical active ingredient, or as an individual active ingredient.

According to a particular embodiment according to this aspect of the invention, the pharmaceutical or drug according to the invention can contain cineole, preferably 1,8-cineole, as a pure substance, preferably with a purity of at least 95% by weight, in particular at least 96% by weight, preferably at least 97 % by weight, particularly preferably at least 98% by weight, very particularly preferably at least 99% by weight, even more preferably at least 99.5%, based on the cineole, preferably 1,8-cineole, and/or preferably free from other terpenes.

According to a further particular embodiment according to this aspect of the invention, it can equally be provided that the drug or medicament contains cineol, preferably 1,8-cineol, free of other terpenes and/or wherein the drug or medicament contains no further terpene and/or wherein the drug or medicament is free of terpenes other than cineole, preferably 1,8-cineole.

According to yet another particular embodiment according to this aspect of the invention, it can be provided that the drug or medicament according to the invention contains cineole, preferably 1,8-cineole, in effective, in particular pharmaceutically and/or therapeutically effective, amounts.

In particular, it can be provided that the pharmaceutical or drug according to the invention contains the cineole, preferably 1,8-cineol, based on the drug or drug, in relative amounts in the range from 0.0001 to 80% by weight, in particular 0.001 to 75% by weight %, preferably 0.005 to 70% by weight, preferably 0.01 to 60% by weight, particularly preferably 0.05 to 55% by weight, very particularly preferably 0.1 to 50% by weight.

According to yet another particular embodiment according to this aspect of the invention, it can further be provided that the at least one pharmaceutically acceptable or physiologically acceptable excipient (carrier) is miscible with 1,8-cineol and/or soluble therein, preferably wherein the at least one pharmaceutically acceptable and/or physiologically acceptable excipient (carrier) at 20° C. and at atmospheric pressure in the liquid or solid, preferably liquid, aggregate state and/or preferably wherein the at least one pharmaceutically acceptable and/or physiologically acceptable excipient (carrier) is selected from the group of fatty acid esters, preferably triglycerides of fatty acids, particularly preferably mittelket term triglycerides (medium chain triglycerides or MCT), very particularly preferably triglycerides of C ₆ -C ₁₂ fatty acids.

According to the invention, it can be provided in particular that the drug or medicament does not contain any other active ingredients other than cineole, preferably 1,8-cineole, or that the drug or medicament is free of active ingredients other than cineole, preferably 1,8-cineol or that the medicinal product or medicament is not present and/or administered and/or prepared for administration in combination with other active ingredients other than cineol, preferably 1,8-cineol.

Furthermore, it can be provided within the scope of the present invention that the drug or drug does not contain any vitamin D receptor agonists (VDA), in particular no compounds of the vitamin D group, or that the drug or drug is free of vitamin D receptor agonists (VDA ), in particular free of compounds from the vitamin D group, or that the drug or medicament is not present and/or administered in combination with vitamin D receptor agonists (VDA), in particular not in combination with compounds from the vitamin D group and/or prepared for administration.

In contrast, it can also be provided within the scope of this aspect of the invention that the active ingredient or cineole, preferably 1,8-cineole, or the drug or medicament, in particular ear treatment agent, is used or applied together with at least one other active ingredient. The additional active ingredient can be selected in particular from (i) anti-inflammatory active ingredients (antiphlogistics), in particular non-steroidal anti-inflammatory drugs (NSAIDs) or steroidal anti-inflammatory drugs; (ii) analgesics; (iii) antipyretics; (iv) antibiotics; as well as their combinations.

According to this aspect of the invention, the cineole, preferably 1,8-cineole, in particular the drug or medicament, can be administered in pharmaceutically effective amounts or therapeutically effective amounts. In this regard, the cineole, preferably 1,8-cineole, particularly the drug or medicament or composition may be adapted for administration in pharmaceutically effective or therapeutically effective amounts, respectively. In addition, the cineole, preferably 1,8-cineole, in particular the drug or medicament or the composition, can be administered systemically or topically, in particular systemically, preferably orally. Furthermore, the cineole, preferably 1,8-cineole, in particular the medicinal product or medicament, can in principle be applied or administered topically, in particular auricularly or in the ear.

If necessary, according to yet another embodiment according to this aspect, the cineole, preferably 1,8-cineole, in particular the pharmaceutical or medicament, can be used or administered together with at least one other active ingredient. In this regard, the further active ingredient can be selected from (i) anti-inflammatory active ingredients (antiphlogistics), in particular non-steroidal anti-inflammatory drugs (NSAIDs) or steroidal anti-inflammatory drugs; (ii) analgesics; (iii) antipyretics; (iv) antibiotics; as well as their combinations.

For further details on this aspect of the invention, reference can also be made to the further explanations on the aspects of the invention described here, these explanations equally applying to the present aspect of the invention.

Another subject of the present invention - according to a further aspect of the present invention - is also the composition according to the invention, in particular pharmaceutical composition, for (use in) prophylactic and / or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and /or outer ear, preferably the middle ear, preferably with accompanying (accompanying) otorrhea, and/or for (use in) prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhea,
wherein the composition contains cineole, preferably 1,8-cineole, in particular together with at least one pharmaceutically acceptable and/or physiologically acceptable excipient (carrier).

Also within the scope of this aspect of the invention, it is provided in particular that the composition contains cineol as the sole active ingredient, in particular as the sole pharmaceutical active ingredient, or as an individual active ingredient.

In particular, it can be provided that the composition contains the cineole, preferably 1,8-cineole, as a pure substance, preferably with a purity of at least 95% by weight, in particular at least 96% by weight, preferably at least 97% by weight. , particularly preferably at least 98% by weight, very particularly preferably at least 99% by weight, even more preferably at least 99.5%, based on the cineole, preferably 1.8- cineole, and/or preferably free of other terpenes.

In particular, the composition may contain the cineole, preferably 1,8-cineole, free from other terpenes. In this regard, it may be the case that the composition contains no other terpene or that the composition is free of terpenes other than cineole, preferably 1,8-cineole. In particular, the composition can contain the cineole, preferably 1,8-cineole, in effective, in particular pharmaceutically and/or therapeutically effective, amounts.

In this regard, the composition may contain the cineole, preferably 1,8-cineole, in relative amounts ranging from 0.0001 to 80% by weight, more preferably from 0.001 to 75% by weight, preferably from 0.005 to 70% by weight of the composition. -%, preferably 0.01 to 60% by weight, particularly preferably 0.05 to 55% by weight, very particularly preferably 0.1 to 50% by weight.

According to the invention it can also be provided according to the present aspect that the at least one pharmaceutically acceptable and/or physiologically acceptable excipient (carrier) is miscible with 1,8-cineol and/or soluble therein, preferably wherein the at least one pharmaceutically acceptable and/or physiologically acceptable excipient (carrier) at 20 °C and at atmospheric pressure in the liquid or solid, preferably liquid, state of aggregation and/or preferably wherein the at least one pharmaceutically acceptable and/or physiologically acceptable excipient (carrier) is selected from the group of fatty acid esters, preferably triglycerides of fatty acids, particularly preferably medium-chain triglycerides (medium chain triglycerides or MCT), very particularly preferably triglycerides of C ₆ -C ₁₂ fatty acids.

According to this aspect of the invention, the cineole, preferably 1,8-cineole, in particular the pharmaceutical or medicament or the composition can be administered in pharmaceutically effective amounts or therapeutically effective amounts. In this regard, the cineole, preferably 1,8-cineole, particularly the drug or medicament or composition may be adapted for administration in pharmaceutically effective or therapeutically effective amounts, respectively. In addition, the cineole, preferably 1,8-cineole, in particular the drug or medicament or the composition, can be administered systemically or topically, in particular systemically, preferably orally. Furthermore, the cineole, preferably 1,8-cineole, in particular the medicinal product or medicament, can in principle be applied or administered topically, in particular auricularly or in the ear.

According to the invention, it can in particular be the case that the composition contains no other active ingredients other than cineole, preferably 1,8-cineole, or that the composition is free of active ingredients other than cineole, preferably 1,8-cineole, or that the The composition is not present and/or administered and/or prepared for administration in combination with other active ingredients other than cineole, preferably 1,8-cineole; and or

In particular, it can be provided that the composition contains no vitamin D receptor agonists (VDA), in particular no compounds from the vitamin D group, or that the composition is free from vitamin D receptor agonists (VDA), in particular free from compounds from vitamin D group, or that the composition is not present and/or administered and/or prepared for administration in combination with vitamin D receptor agonists (VDA), in particular not in combination with compounds of the vitamin D group.

On the other hand, if necessary, according to yet another embodiment according to this aspect, the cineole, preferably 1,8-cineole, in particular the drug or medicament or the composition, can be used or administered together with at least one other active ingredient. In this regard, the further active ingredient can be selected from (i) anti-inflammatory active ingredients (antiphlogistics), in particular non-steroidal anti-inflammatory drugs (NSAIDs) or steroidal anti-inflammatory drugs; (ii) analgesics; (iii) antipyretics; (iv) antibiotics; as well as their combinations.

For further details on this aspect of the invention, reference can be made to the further explanations on the aspects of the invention described here, these explanations equally applying to the aspect of the invention described here.

1. (A) Cineol, vorzugsweise 1 ,8-Cineol; sowie
2. (B) mindestens einen weiteren Wirkstoff, ausgewählt aus (i) entzündungshemmenden Wirkstoffen (Antiphlogistika), insbesondere nichtsteroidalen Entzündungshemmern (NSAIDs) oder steroidalen Entzündungshemmern; (ii) Analgetika; (iii) Antipyretika; (iv) Antibiotika; sowie deren Kombinationen.

Finally, the subject of the present invention - according to a further aspect of the present invention - is a pharmaceutical combination for (use in) the prophylactic and / or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and / or outer ear, preferably des middle ear, preferably with concomitant (accompanying) otorrhea, and/or for (use in) prophylactic and/or therapeutic Treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhea, the pharmaceutical combination comprising at least the following components (A) and (B):

1. (A) cineole, preferably 1,8-cineole; as well as
2. (B) at least one further active ingredient selected from (i) anti-inflammatory active ingredients (antiphlogistics), in particular non-steroidal anti-inflammatory drugs (NSAIDs) or steroidal anti-inflammatory drugs; (ii) analgesics; (iii) antipyretics; (iv) antibiotics; as well as their combinations.

Also according to this aspect of the present invention, it can be provided that the active ingredient of component (A) or the cineole, preferably 1,8-cineole, is administered systemically or topically, in particular systemically, preferably orally.

The further active substance (B) can also be used or applied systemically in particular in the same way.

According to a particular embodiment of this aspect of the invention, it can be provided in particular that components (A) and (B) are present and/or administered separately from one another, in particular spatially separate from one another, but functionally connected and/or functionally associated with one another.

Furthermore, according to another particular embodiment of this aspect of the invention, it can be provided in particular that the pharmaceutical combination is present in the form of a kit (kit-of-parts), in particular as a kit of components (A) and (B).

In particular, components (A) and (B) can be present or prepared or administered as a kit (kit-of-parts).

In the context of the present invention, a kit or kit-of-parts is understood in particular as a unit or arrangement or assembly or combination of the two components (A) and (B), in which the two components (A) and (B ) are present separately and/or separately, in particular spatially separate and/or spatially separated, but are provided or administered as functionally related components or as components that are functionally associated with one another.

For further details on this aspect of the invention, reference can be made to the statements on the further aspects of the invention, these statements equally applying to the present aspect of the invention.

• 1A/1B eine jeweilige grafische Darstellung in Form von Kreisdiagrammen zur bakteriellen Besiedlung des Gehörgangs von Patienten mit Otitis media (n = 9; ein Patient mit Untersuchung beider Ohren, d.h. insgesamt zehn untersuchte Ohren) vor Verabreichung (1A) und nach Verabreichung (1B) von dreimal täglich 200 mg 1,8 Cineol (Verabreichungszeitraum: 14 Tage, perorale Verabreichung); die Untersuchungen zeigen deutliche Verschiebungen hin zu einer vermehrt physiologischen Besiedlung des Ohres, einhergehend mit einer verminderten Besiedlung durch pathogene Keime, wobei auch für Pseudomonas aeroginosa ein besonders deutlicher Rückgang festzustellen ist;
• 2 eine graphische Darstellung in Form eines Balkendiagramms mit der exemplarischen Auswertung der bakteriellen Besiedlung bei einem Patienten (mit chronischer Otitis media mesotympanalis mit chronischer Otorrhoe, perorale Verabreichung) im zeitlichen Verlauf vor und nach Verabreichung von dreimal täglich 200 mg 1,8-Cineol (Verabreichungszeitraum: 14 Tage); Testung auf Erreger und Resistenzen in der Routinediagnostik und Darstellung einer Verschiebung der mikrobiellen Besiedlung anhand des Befundes mittels der Skala (dargestellt auf der y-Achse) 5 = massenhaft, 4 = reichlich, 3 = mäßig, 2 = vereinzelt, 1 = physiologische Keimflora, 0 = keine Keime nachgewiesen;
• 3 eine graphische Darstellung in Form eines Balkendiagramms mit der exemplarischen Darstellung des zeitlichen Verlaufs der Entwicklung bzw. des Zustands der Keimflora im Gehörgang eines Patienten (mit chronisch-granulierender Otitis media und Cholesteatom sowie foetider Otorrhoe unter Besiedelung durch Proteus mirabilis) vor und nach Behandlung mit 1,8-Cineol unter Auswertung mikrobieller Abstriche aus dem Gehörgang des Patienten vor und nach der Einnahme von dreimal täglich 200 mg 1,8-Cineol (Verabreichungszeitraum: 14 Tage, perorale Verabreichung); Testung auf Erreger und Resistenzen in der Routinediagnostik (Darstellung einer Verschiebung der mikrobiellen Besiedlung anhand des Befunds mittels der Skala (y-Achse) 5 = massenhaft, 4 = reichlich, 3 = mäßig, 2 = vereinzelt, 1 = physiologische Keimflora, 0 = keine Keime nachgewiesen);
• 4 eine schematische Darstellung in Form eines Balkendiagramms mit der Verdeutlichung der Verbesserung des klinischen Krankheitsbildes bei Patienten mit Otitis media im Hinblick auf das Vorliegen von Otorrhoe („feuchtes Ohr“) nach Behandlung mit dreimal täglich 200 mg 1,8-Cineol (Verabreichungszeitraum: 14 Tage, perorale Verabreichung); Auswertung auf Basis eines Patientenfragebogens an neun Patienten (bei einem Patienten wurden beide Ohren herangezogen und bei den weiteren Patienten jeweils ein Ohr); das Balkengram bezieht sich auf die Situation nach Behandlung mit 1,8-Cineol, wonach in sieben Fällen eine verbesserte Situation (linker Balken) und in drei Fällen eine stark verbesserte Situation (rechter Balken) in Bezug auf die Schwere der Otorrhoe angegeben wurde;
• 5 eine graphische Darstellung in Form eines Balkendiagramms zur Entwicklung der Besiedlung des Ohres mit Keimen auf Basis mikrobieller Abstriche aus dem Gehörgang von acht Patienten (ein Patient mit zwei untersuchen Ohren, vgl. Patient 3a bzw. 3b) mit chronischer Otitis media mesotympanalis bzw. Otitis media epitympanalis vor und nach Verabreichung von dreimal täglich 200 mg 1,8-Cineol (Verabreichungszeitraum: 14 Tage perorale Verabreichung); Testung auf Erreger und Resistenzen in der Routinediagnostik und Darstellung einer Verschiebung der mikrobiellen Besiedlung anhand des Befundes mittels der Skala (y-Achse) 5 = massenhaft, 4 = reichlich, 3 = mäßig, 2 = vereinzelt, 1 = physiologische Keimflora, 0 = keine Keime;
• 6 eine graphische Darstellung in Form eines Balkendiagramms mit einer exemplarischen Veranschaulichung der bakteriellen Besiedlung vor und nach Verabreichung von dreimal täglich 200 mg 1,8-Cineol unter Auswertung mikrobieller Abstriche aus dem Gehörgang bei drei Patienten vor und nach der oralen Verabreichung von dreimal täglich 200 mg 1,8-Cineol (Verabreichungszeitraum: 14 Tage, perorale Verabreichung); auch bei diesen Patienten konnte nach Verabreichung von 1 ,8-Cineol eine Reduktion der Entzündung mit Otorrhoe beobachtet werden und ein Implantat zur Verbesserung des Hörens und damit der Lebensqualität eingesetzt werden; Testung auf Erreger und Resistenzen in der Routinediagnostik und Darstellung an der Verschiebung der mikrobiellen Besiedelung anhand des ärztlichen Befundes mittels der Skala (y-Achse) 5 = massenhaft, 4 = reichlich, 3 = mäßig, 2 = vereinzelt, 1 = physiologische Keimflora, 0 = keine Keime.

Further advantageous properties, aspects and features of the present invention result from the following description of exemplary embodiments illustrated in the figures, as they are listed in detail below. It shows:

• 1A / 1B a respective graphical representation in the form of pie charts for the bacterial colonization of the ear canal of patients with otitis media (n = 9; one patient with examination of both ears, ie a total of ten ears examined) before administration ( 1A ) and after administration ( 1B ) of 200 mg 1.8 cineole three times a day (administration period: 14 days, peroral administration); the investigations show clear shifts towards an increased physiological colonization of the ear, accompanied by a reduced colonization by pathogenic germs, whereby a particularly clear decrease can also be determined for Pseudomonas aeroginosa;
• 2 a graphic representation in the form of a bar chart with the exemplary evaluation of the bacterial colonization in a patient (with chronic otitis media mesotympanalis with chronic otorrhoea, peroral administration) over time before and after administration of 200 mg 1,8-cineole three times a day (administration period: 14 days); Testing for pathogens and resistances in routine diagnostics and depiction of a shift in microbial colonization based on the findings using the scale (shown on the y-axis) 5 = massive, 4 = abundant, 3 = moderate, 2 = isolated, 1 = physiological germ flora, 0 = no germs detected;
• 3 a graphic representation in the form of a bar chart with an example of the development over time or the state of the germ flora in the auditory canal of a patient (with chronic granulating otitis media and cholesteatoma as well as foetid otorrhoea colonized by Proteus mirabilis) before and after treatment with 1 ,8-cineole evaluating microbial swabs from the patient's ear canal before and after ingestion of 1,8-cineole 200 mg three times a day (administration period: 14 days, peroral administration); Testing for pathogens and resistances in routine diagnostics (representation of a shift in microbial colonization based on the findings using the scale (y-axis) 5 = massive, 4 = abundant, 3 = moderate, 2 = isolated, 1 = physiological germ flora, 0 = none germs detected);
• 4 a schematic representation in the form of a bar graph showing the improvement in the clinical picture in patients with otitis media with regard to the presence of otorrhea ("wet ear") after treatment with 200 mg 1,8-cineole three times a day (administration period: 14 days , peroral administration); Evaluation based on a patient questionnaire on nine patients (both ears were used in one patient and one ear each in the other patients); the bargram refers to the situation after treatment with 1,8-cineole, according to which an improved situation (left bar) and in three cases a greatly improved situation (right bar) with regard to the severity of the otorrhea was reported in seven cases;
• 5 a graphic representation in the form of a bar chart of the development of the colonization of the ear with germs based on microbial swabs from the auditory canal of eight patients (one patient with two ears examined, cf. patient 3a and 3b) with chronic otitis media mesotympanalis or otitis media epitympanalis before and after administration of 200 mg three times a day of 1,8-cineole (administration period: 14 days peroral administration); Testing for pathogens and resistances in routine diagnostics and representation of a shift in microbial colonization based on the findings using the scale (y-axis) 5 = massive, 4 = abundant, 3 = moderate, 2 = isolated, 1 = physiological germ flora, 0 = none germs;
• 6 Figure 13 is a bar graph graph showing an exemplary illustration of bacterial colonization before and after administration of 200 mg 1,8-cineole three times a day evaluating microbial swabs from the ear canal in three patients before and after oral administration of 200 mg 1 three times a day ,8-cineole (administration period: 14 days, peroral administration); A reduction in inflammation with otorrhoea was also observed in these patients after administration of 1,8-cineole and an implant was used to improve hearing and thus the quality of life; Testing for pathogens and resistances in routine diagnostics and depiction of the shift in microbial colonization based on medical findings using the scale (y-axis) 5 = massive, 4 = abundant, 3 = moderate, 2 = isolated, 1 = physiological germ flora, 0 = no germs.

For further details on the embodiments and exemplary embodiments illustrated in the figure representations, to avoid unnecessary repetition, reference can also be made to the above explanations and to the following supplementary explanations on the exemplary embodiments, which apply correspondingly with regard to the figure representations.

Further configurations, modifications and variations as well as advantages of the present invention can be easily recognized and implemented by a person skilled in the art when reading the description, without departing from the scope of the present invention.

The following exemplary embodiments only serve to illustrate the present invention, but without restricting the present invention thereto.

EXEMPLARY EMBODIMENTS:

The following exemplary embodiments show the therapeutic benefit of cineole, in particular 1,8-cineole, in the treatment of otitis with the reduction of pathogenic germs in the ears of the patients affected by the diseases shown here.

In the treatment of patients described below, systemic 1,8-cineole comes in pure form (together with an excipient based on medium chain triglycerides (= medium chain triglycerides or MCT), ie triglycerides of C ₆ -C ₁₂ fatty acids) as enteric-coated small intestine soluble Capsules for use (namely the commercial preparation Soledum ^® capsules or Soledum ^® forte capsules, sold by Cassella-med GmbH & Co. KG or by Maria Clementine Martin Klosterfrau Vertriebsgesellschaft mbH, each in Cologne, Germany).

Example 1:

Bacterial colonization in otitis

The pathogen colonization of patients with otitis was examined as part of a pilot study. For this purpose, microbial swabs were taken from the auditory canal of 22 patients with chronic mesotympanic or epitympanic otitis media and tested for pathogens and resistances in routine diagnostics. For this purpose, a colonization with pathogenic germs could be determined in the patients affected by chronic otitis. In patients with chronic otitis media mesotympanalis, pathogenic germs in the form of Pseudomonas aeroginosa and supports as well as Proteus mirabilis and Staphylococcus aureus appeared in addition to the physiological germ flora (whereby in a single patient no germs could be found be provided). In patients with chronic otitis media epitympanalis in particular, pathogenic germs in the form of Staphylococcus aureus and Stenotrophomonas maltophila were found in addition to the physiological germ flora (whereby no proof of germs could be provided in only three patients). One patient had both Enterococcus faecalis and Staphylococcus aureus. Another patient had Aspergillus spp. and Candida parapsilosis. The above statements show that in patients with otitis media, pathogenic germs associated with the disease occur in a corresponding manner.

Example 2:

1,8-Cineole counteracts pathogenic germs in the middle ear

Investigations of bacterial colonization from the auditory canal of otitis media patients (cf. 1A as well as 1B ; n = 9; one patient with examination of both ears, ie a total of 10 ears examined, patients with in particular chronic otitis media mesotympanalis or epitympanalis) show significant shifts towards increased physiological ear colonization as a result of treatment with 1,8-cineol, accompanied by reduced colonization by pathogenic germs , whereby a particularly clear decrease can also be observed for Pseudomonas aeroginosa, whereby a clear increase can also be observed for the physiological germ flora. You can also do this 1A as well as 1B to get expelled.

Example 3:

Pathogenic germs in chronic otitis media before and after therapy with 1,8-cineole; Enabling therapeutic operations on the ear (case study I)

The surprisingly found according to the invention extremely positive influence of 1,8-cineol on the inflammatory process or the colonization of germs in the ear of patients with otitis, especially with regard to a significant reduction in otorrhea and a reduction in pathogenic germs in the ear, made possible in the context of the therapeutic Applications Therapeutic operations on a patient's ear ( 2 , cf. patient 3 according to 5 ), some of which were not considered possible or could not be carried out before the use of 1,8-cineole. This can be done 2 be referred to, which shows an example of the relevant course in the underlying patient (with chronic otitis media mesotympanalis and chronic otorrhea colonized by a multi-resistant Pseudomonas aeroginosa germ) before and after taking 1,8-cineole. At the in 2 In the patients shown as an example, a cochlear implant could be implanted with previously antibiotic and therapy-resistant pathogens after administration of 1,8-cineol with a dry ear and physiological germ flora. This is all the more remarkable as the patient before treatment was heavily colonized with a multi-resistant Pseudomonas aeroginosa germ (in 2 designated MRGN (multi-resistant gram-negative pathogen)) with resistance to three antibiotic groups (3MRGN) or even to four antibiotic groups (4MRGN).

Example 4:

Pathogenic germs in chronic otitis media before and after therapy with 1,8-cineole; Enabling therapeutic operations (case study II)

Furthermore shows 3 example of the course of another patient (with chronic granulating otitis media and cholesteatoma as well as foetid otorrhea colonized by Proteus mirabilis) ( 3 , cf. patient 5 according to 5 ). The patient presented with a medical history after multiple remedial ear operations (for more than ten years) with recurrent cholesteatoma. After administration of 1,8-cineole, a tympanoplasty (type III) with Vibrant Soundbridge implantation could be performed if the bacterial flora was physiological, with the operations being carried out under antibiotic protection.

Example 5:

Evaluation of patient questionnaires: 1,8-cineole improves the clinical picture and the quality of life

As part of the therapeutic treatment, patients were treated with 1,8-cineol in accordance with the 4 treated, whereby an evaluation was carried out on the basis of patient questionnaires, namely on the basis of nine patients (both ears were used in one patient and one ear each in the other patients). The patient questionnaire is based on scoring systems or scoring classifications, which the patients use to evaluate the underlying questions or aspects.

The patient collective consisted of patients aged between 27 and 75 years (30% female and 70% male). Before the treatment, there was chronic otitis media mesotympanalis in seven cases, a perforation of the eardrum in one case, a chronic tube ventilation disorder in another case and a chronic otitis in another case media mesotympanalis with mastoiditis, four cases affecting the right ear and six cases affecting the left ear. With regard to the underlying diseases, there was also a very severe hearing loss in one case and a severe hearing loss in six cases. In another case there was a moderate hearing impairment, and in two cases a slight hearing loss could be determined.

As in 4 In particular, a significant improvement with regard to otorrhea (“wet ear”) was found on the basis of the patient questionnaires (before therapy, in 20% of the cases, an occasional running of the ears and in 80% of the cases a constant (“always”) running of the ears was stated). In 70% of the cases it was stated that the running in the ears improved after the therapy had been carried out. In 30% of the cases, even a strong improvement after therapy was reported. A significant improvement could be determined, especially with regard to the severe impairment of the patients due to a "wet ear" or otorrhea.

Furthermore, positive effects of the therapy with 1,8-cineol in terms of improvement of ear pain and the pressure (feeling) in the ear could also be determined on the basis of the patient questionnaires. Furthermore, the evaluation of the questionnaires showed that before the therapy was carried out, all patients had limitations in everyday life (namely 60% of the patients had major and 40% of the patients had very great limitations), while after the therapy there was a high level of satisfaction among the patients with regard to the treatment. In particular, the limitations in everyday life decreased significantly after the therapy was carried out, according to which 90% of the patients reported minor limitations and only 10% of the patients continued to report very large limitations.

In addition, no side effects were reported in 80% of the cases, and no patient stopped taking 1,8-cineole prematurely.

The evaluation of the patient questionnaires thus also shows the successful therapeutic approach based on the use of 1,8-cineol with regard to the underlying diseases of the ear, as demonstrated according to the invention.

Example 6:

Pathogenic germs before and after therapy with 1,8-cineol (patient overview)

The effectiveness of 1,8-cineol with regard to the reduction of pathogenic germs or pathogenic bacteria in patients with chronic otitis media is also based on 5 clarifies which shows an overview of the patients examined in this regard. In particular, as a result of the treatment with 1,8-cineol, a reduction in pathogenic germs or pathogenic bacteria can be observed, even with regard to multi-resistant pathogen germs or bacteria.

Example 7:

Pathogenic germs before and after therapy with 1,8-cineole - further examples enabling necessary ear operations

Both 6 three patients listed as an example (cf. also related patients according to 5 ) treatment with 1,8-cineol was able to achieve a significant reduction in inflammation or infestation with pathogens, which made it possible to surgically insert a cochlear implant or a Vibrant Soundbridge implant. This in turn leads to a significant improvement in the hearing ability and thus the quality of life of the affected patients.

Example 8:

Synopsis of exemplary clinical disease and therapy courses

Below is a synopsis of exemplary clinical course of the disease and therapy and the successful influence of 1,8-cineol in relation to two patients.

The relevant areas of application are chronic otitis media mesotympanalis (COM) and chronic otitis media epitympanalis (cholesteatoma).

With regard to the patient with chronic mesotympanic otitis media, a reduction in otorrhea was observed after two weeks of oral administration (preoperatively) of 200 mg 3 times a day of 1,8-cineol in previously therapy-refractory otorrhea (local and systemic antibiotics), so that an operation on the ear is possible has been. In the condition after tympanoplasty, renewed otorrhea with recurrent perforation was observed. After further administration of 200 mg 1,8-cineole three times a day over a period of four weeks, a decrease in this otorrhea and spontaneous tympanic membrane occlusion was observed.

With regard to the patient with chronic otitis media epitympanalis or cholesteatoma, after preoperative administration of three times a day After 200 mg of 1,8-cineole (duration of administration: 2 weeks, peroral administration) in previously refractory otorrhea (local and systemic antibiotics), a reduction in the accompanying otorrhea was observed, so that an operation on the ear was made possible. In particular, there was a positive effect on the inflamed mucosa of the middle ear and with regard to a mastoid (although the cholesteatoma masses were not significantly reduced, but - and this is therapy-relevant - the inflammatory character and the aggressiveness of the inflammation of the cholesteatoma were inhibited or treated could become). In the condition after tympanoplasty, there was renewed otorrhea with recurrent perforation. After administration of 200 mg 1,8-cineol three times a day (administration period: 4 weeks, peroral administration), there was a reduction in otorrhea and spontaneous tympanic membrane closure in this case as well.

Example 9:

Further comments on patient data and examinations

In industrialized nations, otitis media is one of the diseases that most often lead to doctor visits, antibiotic prescriptions and surgery. Chronic recurrent middle ear (COM) infections result in significant impacts on patients' quality of life, e.g. B. by running ears, hearing loss, speech development delays etc. up to complete deafness and dizziness. The particularly aggressive form, the cholesteatoma (cf. chronic otitis media epitympanalis) behaves like a malignant tumor because it evades antibiotic therapy due to progressive inflammatory destructive processes in the middle ear and destroys the surrounding structures.

The patient group recruited from this group was treated preoperatively and in individual cases postoperatively with ^Soledum® forte capsules within the scope of the present invention. The permanent purulent otorrhoea could not be controlled with conventional means such as local ear drops, systemic antibiotic therapy or various rinses. However, operating on a wet ear calls into question the overall success of the operation.

Surprisingly, otitis, especially inflammation of the middle ear, with a chronically runny ear was successfully treated with Soledum ^® forte capsules. Patients with very stubborn otorrhoea based on chronic mesotympanic or epitympanic otitis media were successfully treated with Soledum ^® forte capsules (1 capsule 200 mg 1,8-cineole three times a day) over a period of 14 days. In all preoperative cases, there was a significant reduction in otorrhea, so that a timely operation became possible and was then successful in each case. In some cases, patients were also successfully treated postoperatively with Soledum ^® forte capsules.

Surprisingly, treatment with Soledum ^® forte capsules was also successful in patients with often longstanding chronic mesotympanic otitis media with accompanying otorrhea and complete resistance to pathogens in the antibiogram carried out by microbiology before therapy.

Overall, cineole, especially 1,8-cineole, is therefore suitable based on the applicant's surprising findings in an efficient manner for use in the prophylactic or therapeutic treatment of inflammatory diseases of the ear, especially inflammatory diseases of the middle or outer ear, preferably of the middle ear, in particular with accompanying or associated otorrhoea, or for use in the prophylactic or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, in particular with accompanying otorrhoea.

Claims (52)

Cineole, preferably 1,8-cineole, for use in the prophylactic and/or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and/or outer ear, preferably the middle ear, preferably with accompanying (accompanying) otorrhoea, and/or or cineole, preferably 1,8-cineole, for use in the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with concomitant (accompanying) otorrhoea. Cineole, preferably 1,8-cineole, for use after claim 1 , in the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhoea. Cineole, preferably 1,8-cineole, for use after claim 1 or 2 , in the prophylactic and/or therapeutic treatment of otitis media with concomitant (accompanying) otorrhea. Cineole, preferably 1,8-cineole, in particular according to one of the preceding claims, for use in the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhoea. Cineole, preferably 1,8-cineole, in particular according to one of the preceding claims, for use in the prophylactic and/or therapeutic treatment of otitis media with accompanying (accompanying) otorrhoea. Cineole, preferably 1,8-cineole, in particular according to one of the preceding claims, for use in reducing the load (germ load) and/or the number (germ number) of pathogenic germs, in particular pathogenic bacteria, located and/or localized in the ear, in particular in the middle and/or outer ear, preferably in the middle ear, and/or for use in reducing the proportion (germ proportion) of pathogenic germs, in particular pathogenic bacteria, located and/or localized in the ear, in particular in the middle and/or outer ear, preferably in the middle ear, in the prophylactic and/or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and/or outer ear, preferably the middle ear, preferably with accompanying (accompanying) otorrhea, and/or in the prophylactic and/or therapeutic treatment of otitis , in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhea. Cineole, preferably 1,8-cineole, for use according to any one of the preceding claims, the cineole, preferably 1,8-cineole, for reducing the load (germ load) and/or the number (germ number) of pathogenic germs located and/or localized in the ear, in particular in the middle and/or outer ear, preferably in the middle ear , in particular pathogenic bacteria, is employed or used; and/or wherein the cineole, preferably 1,8-cineole, is used to reduce the proportion (germ proportion) of pathogenic germs, in particular pathogenic bacteria, located and/or localized in the ear, in particular in the middle and/or outer ear, preferably in the middle ear, deployed or used; and or wherein the pathogens are selected from the group consisting of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and/or outer ear, preferably the middle ear, preferably with accompanying (accompanying) otorrhea, and/or otitis, in particular otitis media and/or or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhoea, causing and/or intensifying and/or associated germs; and or wherein the pathogenic germs are selected from the group of bacteria, in particular pathogenic bacteria, preferably the inflammatory diseases of the ear, in particular inflammatory diseases of the middle and/or outer ear, preferably the middle ear, preferably with accompanying (accompanying) otorrhea, and/or the Otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with concomitant (accompanying) otorrhoea, causing and/or aggravating and/or associated bacteria; and or wherein the pathogens are selected from the group of bacteria of the genus Pseudomonas, Proteus, Staphylococcus, Haemophilus, Streptococcus, Stenotrophomonas, Enterococcus and Moraxella and combinations thereof, in particular from the group of bacteria of the genus Pseudomonas, Proteus and Staphylococcus and combinations thereof, preferably from the group of bacteria of the genus Pseudomonas and Proteus and combinations thereof; and or wherein the pathogens are selected from the group of bacteria of the species Pseudomonas aeruginosa, Pseudomonas stutzeri, Proteus mirabilis, Staphylococcus aureus, Haemophilus influenza, Streptococcus pneumoniae, Streptococcus pyogenes, Stenotrophomonas maltophila, Enterococcus faecalis and Moraxella catarrhalis and combinations thereof, in particular from the group from bacteria of the species Pseudomonas aeruginosa, Proteus mirabilis and Staphylococcus aureus and combinations thereof, preferably from bacteria of the species Pseudomonas aeruginosa and Proteus mirabilis and combinations thereof. Cineole, preferably 1,8-cineole, for use according to any one of the preceding claims, wherein the cineole, preferably 1,8-cineole, further and/or additionally and/or equally to increase the number, increase or support in the ear, is used or employed in particular in the middle and/or outer ear, preferably in the middle ear, located and/or localized physiological germs (non-pathogenic germs), in particular physiological bacteria (non-pathogenic bacteria); and/or wherein the cineole, preferably 1,8-cineole, furthermore and/or additionally and/or equally to increase the load (germ load) or the number (germ number) or the proportion (germ proportion) of in the ear, in particular on average - and/or outer ear, preferably in the middle ear, located and/or localized physiological germs (non-pathogenic germs), in particular physiological bacteria (non-pathogenic bacteria), is used or employed; wherein the cineole, preferably 1,8-cineole, furthermore and/or additionally and/or equally to increase the colonization of the ear, in particular the middle and/or outer ear, preferably the middle ear, with physiological germs (non-pathogenic germs), in particular physiological bacteria (non-pathogenic bacteria), is used or employed. Cineole, preferably 1,8-cineole, in particular according to one of the preceding claims, for use in the prophylactic and / or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and / or outer ear, preferably the middle ear, preferably with accompanying (accompanying) otorrhea, the disease being a therapy-refractory and / or therapy-resistant, especially medication - and/or drug-resistant, preferably antibiotic-resistant, disease; and or for use in the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhea, the otitis being a therapy-refractory and/or therapy-resistant, in particular drug and/or drug-resistant, preferably antibiotic-resistant, otitis. Cineole, preferably 1,8-cineole, for use according to any one of the preceding claims, wherein the disease is a therapy-refractory and/or therapy-resistant, in particular drug- and/or drug-resistant, preferably antibiotic-resistant, disease; and or wherein the otitis is therapy-refractory and/or therapy-resistant, in particular drug- and/or drug-resistant, preferably antibiotic-resistant, otitis. Cineole, preferably 1,8-cineole, for use according to any one of the preceding claims, wherein the otitis is an acute otitis or a chronic otitis, in particular a chronic otitis, preferably a chronic polypoid otitis or a chronic granular otitis; and or wherein the otitis is recurrent otitis or chronic-recurrent otitis, in particular chronic otitis, preferably chronic polypoid otitis or chronic granular otitis; Cineole, preferably 1,8-cineole, for use according to any one of the preceding claims, wherein the otitis is otitis media epitympanalis (cholesteatoma or otitis media epitympanalis with cholesteatoma) or otitis media mesotympanalis, preferably otitis media epitympanalis. Cineole, preferably 1,8-cineole, for use according to any one of the preceding claims, wherein the inflammatory diseases of the ear and / or otitis, in particular otitis media and / or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhoea, preferably otitis media epitympanalis, with an inflammatory mediation, in particular an upregulation and/or an increased production or an increased release of in particular proinflammatory cytokines, preferably TNF-alpha (tumor necrosis factor-alpha) and/or interleukin-1 (IL-1), preferably TNF -alpha, accompanies or is related hereto. Cineole, preferably 1,8-cineole, for use according to any one of the preceding claims, wherein the cineole, preferably 1,8-cineole, furthermore and/or additionally and/or equally for the suppression or alleviation of an inflammatory disease of the ear and/or otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhoea, preferably otitis media epitympanalis, occurring inflammatory mediation is used or employed; and or wherein the cineole, preferably 1,8-cineole, has a suppressing or weakening effect on an inflammatory disease of the ear and/or otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) Otorrhoea, preferably otitis media epitympanalis, occurring inflammatory mediation, in particular wherein the cineole, preferably 1,8-cineole, down-regulates and/or reduces production and/or reduced secretion of, in particular, proinflammatory cytokines, preferably TNF-alpha (tumor necrosis factor-alpha ) and/or interleukin-1 beta (IL-1β), preferably TNF-alpha causes and/or induces; and or wherein the cineole, preferably 1,8-cineole, for down-regulating and/or reducing the production and/or reducing the release of, in particular, proinflammatory cytokines, preferably TNF-alpha (tumor necrosis factor alpha) and/or interleukin-1beta (IL- 1β), preferably TNF-alpha, is used or employed. Cineole, preferably 1,8-cineole, for use according to any one of the preceding claims che, wherein the cineole, preferably 1,8-cineole, is used or employed further and/or additionally and/or equally as an anti-inflammatory active ingredient, in particular as a locally and/or systemically acting anti-inflammatory active ingredient. Cineole, preferably 1,8-cineole, for use according to any one of the preceding claims, wherein the cineole, preferably 1,8-cineole, further and/or additionally and/or equally for prevention and/or prevention and/or for prophylactic and /or therapeutic treatment of the inflammatory diseases of the ear and/or otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhoea, related to and/or caused by consequential and/or or concomitant diseases, in particular selected from the group consisting of mastoisitis, labyrinthitis, meningitis, sinus vein thrombosis, sepsis, paralysis of the facial nerve and tinnitus, and combinations thereof. Cineole, preferably 1,8-cineole, for use according to any one of the preceding claims, wherein the cineole, preferably 1,8-cineole, preoperatively and/or for preoperative preparation and/or to enable surgical interventions (surgical operations), in particular therapeutic-surgical interventions, on the ear (ear operations), in particular on the middle and/or outer ear (middle and/or outer ear operations), preferably on the middle ear (middle ear operations), such as tympanoplastic operations and/or implantation operations (implantation); and or wherein the cineole, preferably 1,8-cineole, is used postoperatively and/or for the postoperative follow-up treatment of surgical interventions (surgical operations), in particular therapeutic-surgical interventions, on the ear (ear operations), in particular on the middle and/or outer ear (middle and /or outer ear operations), preferably on the middle ear (middle ear operations), such as tympanoplastic operations and/or implantation operations (implantation), is used or employed. Cineole, preferably 1,8-cineole, in particular according to one of the preceding claims, for use in the prophylactic and/or therapeutic treatment of inflammatory diseases of the inner ear, preferably with accompanying (accompanying) otorrhoea, and/or for use in the prophylactic and/or or therapeutic treatment of otitis interna and/or otitis media with accompanying inflammation of the inner ear, in each case preferably with accompanying (accompanying) otorrhea. Cineole, preferably 1,8-cineole, for use according to any one of the preceding claims, wherein the otitis is an otitis interna and/or an otitis media with accompanying inflammation of the inner ear, in each case preferably with accompanying (accompanying) otorrhoea. Cineole, preferably 1,8-cineole, for use according to one of the preceding claims, but except for use in reducing pathogenic germs or pathogens in the human intestine, in particular in the human intestinal flora, and/or except for use in reduction the colonization of the human intestine, in particular the human intestinal flora, with pathogenic germs or pathogens. Cineole, preferably 1,8-cineole, for use according to any one of the preceding claims, wherein the cineole, preferably 1,8-cineole, is administered systemically, in particular perorally or parenterally, preferably perorally, and/or wherein the cineole, preferably 1, 8-cineol, for systemic, in particular peroral or parenteral, preferably peroral, application. Cineole, preferably 1,8-cineole, for use according to any one of the preceding claims, wherein the cineole, preferably 1,8-cineole, is administered in the form of a dosage form to be administered perorally and/or wherein the cineole, preferably 1,8-cineole , is prepared in a dosage form to be administered perorally. Cineole, preferably 1,8-cineole, for use according to any one of the preceding claims, wherein the cineole, preferably 1,8-cineole, is administered as a systemic administration form that is resistant to gastric juice but soluble in the small intestine, preferably as a capsule, coated tablet, pill, tablet or the like and/or wherein the cineole, preferably 1,8-cineole, is prepared for administration as a systemic dosage form that is resistant to gastric juice but soluble in the small intestine, preferably a capsule, coated tablet, pill, tablet or the like. Cineole, preferably 1,8-cineole, for use according to any one of Claims 1 until 20 , Wherein the cineole, preferably 1,8-cineole, is administered in the form of a dosage form to be administered topically, in particular auricularly and/or in the ear, and/or where the cineole, preferably 1,8-cineole, is administered topically in a , especially auricular and/or in the ear to be administered, dosage form is prepared. Cineole, preferably 1,8-cineole, for use according to any one of the preceding claims, wherein the cineole, preferably 1,8-cineole, is administered in pharmaceutically effective or therapeutically effective amounts and/or wherein the cineole, preferably 1,8- cineole, for administration in pharmaceutically effective or therapeutically effective amounts. Cineole, preferably 1,8-cineole, for use according to any one of the preceding claims, wherein the cineole, preferably 1,8-cineole, is administered at a daily dose in the range from 1 mg/diem to 5,000 mg/diem, in particular in the range of 2 mg /diem to 3000 mg/diem, preferably in the range from 5 mg/diem to 2500 mg/diem, preferably in the range from 10 mg/diem to 2000 mg/diem, particularly preferably in the range from 50 mg/diem to 1500 mg/diem , most preferably in the range from 100 mg/diem to 1200 mg/diem, more preferably in the range from 200 mg/diem to 1000 mg/diem, and/or wherein the cineole, preferably 1,8-cineole, is administered for administration with a daily dose in the range from 1 mg/diem to 5000 mg/diem, in particular in the range from 2 mg/diem to 3000 mg/diem, preferably in the range from 5 mg/diem to 2500 mg/diem, preferably in the range of 10 mg /diem to 2,000 mg/diem, more preferably in the range from 50 mg/diem to 1,500 mg/diem, most preferably in the range from 100 mg/diem to 1,200 mg/diem, more preferably in the range from 200 mg/diem to 1,000 mg/diem. Cineole, preferably 1,8-cineole, for use according to any one of the preceding claims, wherein the cineole, preferably 1,8-cineole, is present and/or administered as a pure substance; in particular wherein the cineole, preferably 1,8-cineole, has a purity of at least 95% by weight, in particular at least 96% by weight, preferably at least 97% by weight, particularly preferably at least 98% by weight, very particularly preferably at least 99% by weight, more preferably at least 99.5%, based on the cineole, preferably 1,8-cineole, is present and/or administered; and or in particular wherein the cineole, preferably 1,8-cineole, is free from other terpenes and/or in particular wherein the cineole, preferably 1,8-cineole, contains no other terpenes. Cineole, preferably 1,8-cineole, for use according to any one of the preceding claims, wherein the cineole, preferably 1,8-cineole, is present and/or administered together with at least one physiologically acceptable carrier (excipient); in particular where the physiologically acceptable carrier (excipient) is miscible with 1,8-cineol and/or soluble therein; and/or in particular where the physiologically acceptable carrier (excipient) is in the liquid or solid, preferably liquid, state of aggregation at 20° C. and at atmospheric pressure; and/or in particular where the physiologically acceptable carrier (excipient) is selected from the group of fatty acid esters, preferably triglycerides of fatty acids, particularly preferably medium-chain triglycerides (medium chain triglycerides or MCT), very particularly preferably triglycerides of C ₆ -C ₁₂ fatty acids ; and/or in particular where the cineole, preferably 1,8-cineole, is present and/or administered as a pure substance and/or in the absence of other (additional) terpenes; and/or wherein the cineole, preferably 1,8-cineole, is present and/or administered as a pure substance and/or in the absence of other (additional) terpenes, together with at least one physiologically acceptable carrier (excipient). Cineole, preferably 1,8-cineole, for use according to any one of the preceding claims, wherein the cineole, preferably 1,8-cineole, in or in the form of a composition, in particular pharmaceutical composition, in particular together with at least one pharmaceutically acceptable and/or physiologically acceptable excipients (carrier), is present and/or administered; In particular, the composition containing cineole, preferably 1,8-cineole, as the sole active ingredient, in particular as the sole pharmaceutical active ingredient, or as an individual active ingredient; and/or in particular where the composition contains cineole, preferably 1,8-cineole, as a pure substance, preferably with a purity of at least 95% by weight, in particular at least 96% by weight, preferably at least 97% by weight, in particular preferably at least 98% by weight, very particularly preferably at least 99% by weight, even more preferably at least 99.5%, based on the cineole, preferably 1,8-cineole, and/or preferably free from other terpenes; and/or in particular wherein the composition contains the cineol, preferably 1,8-cineole, free from other terpenes and/or in particular wherein the composition contains no further terpene and/or in particular wherein the composition is free from terpenes other than cineol, preferably 1, 8-cineole; is; and/or in particular wherein the composition contains the cineole, preferably 1,8-cineole, in effective, ins contains particular pharmaceutically and/or therapeutically effective amounts; and/or in particular wherein the composition contains the cineole, preferably 1,8-cineole, in relative amounts of the composition in the range 0.0001 to 80% by weight, more preferably 0.001 to 75% by weight, preferably 0.005 to 70% by weight, preferably 0.01 to 60% by weight, particularly preferably 0.05 to 55% by weight, very particularly preferably 0.1 to 50% by weight; and/or in particular wherein the at least one pharmaceutically acceptable and/or physiologically acceptable excipient (carrier) is miscible with and/or soluble in 1,8-cineole, preferably wherein the at least one pharmaceutically acceptable and/or physiologically acceptable excipient (carrier) contributes 20 °C and at atmospheric pressure in the liquid or solid, preferably liquid, state of aggregation and/or preferably wherein the at least one pharmaceutically acceptable and/or physiologically harmless excipient (carrier) is selected from the group of fatty acid esters, preferably triglycerides of fatty acids, particularly preferably medium-chain triglycerides (Medium Chain Triglycerides or MCT), very particularly preferably triglycerides of C ₆ -C ₁₂ fatty acids. Cineole, preferably 1,8-cineole, for use according to any one of the preceding claims, wherein the cineole, preferably 1,8-cineole, is present and/or administered in liposome-enclosed and/or liposomally-packaged form; and or wherein the cineole, preferably 1,8-cineole, is present and/or administered in micellated form and/or in a micellar administration form. Cineole, preferably 1, 8-cineole, for use according to one of Claims 1 until 30 wherein the cineole, preferably 1,8-cineole, is present and/or administered and/or prepared for administration as a single agent and/or as a monopreparation; and/or wherein the cineole, preferably 1,8-cineole, is present and/or administered and/or prepared for administration without and/or in the absence of other active ingredients different from cineole, preferably 1,8-cineole; and/or wherein the cineole, preferably 1,8-cineole, is present without and/or in the absence of and/or free of and/or not in combination with vitamin D receptor agonists (VDA), in particular compounds of the vitamin D group and/or administered and/or prepared for administration. Cineole, preferably 1, 8-cineole, for use according to one of Claims 1 until 30 , wherein the cineole, preferably 1,8-cineole, is present and/or administered together with at least one other active substance and/or as a co-therapeutic agent; in particular where the further active ingredient is selected from (i) anti-inflammatory active ingredients (antiphlogistics), in particular non-steroidal anti-inflammatory drugs (NSAIDs) or steroidal anti-inflammatory drugs; (ii) analgesics; (iii) antipyretics; (iv) antibiotics; and their combinations; and/or in particular wherein the further active substance is used and/or administered separately, in particular spatially separated, from the cineole, preferably 1,8-cineole, but functionally connected thereto, in particular in the form of a kit (kit-of-part). Cineole, preferably 1,8-cineole, for use in the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with concomitant (accompanying) otorrhoea. Cineole, preferably 1,8-cineole, for use in the prophylactic and/or therapeutic treatment of otitis media with concomitant (accompanying) otorrhoea. cineole, preferably 1,8-cineole, for use in reducing the load (germ load) and/or the number (germ number) of pathogenic germs located and/or localized in the ear, in particular in the middle and/or outer ear, preferably in the middle ear, and/or for use in the reduction the proportion (germ proportion) of pathogenic germs located and/or localized in the ear, in particular in the middle and/or outer ear, preferably in the middle ear in the prophylactic and/or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and/or outer ear, preferably the middle ear, preferably with accompanying (accompanying) otorrhea, and/or in the prophylactic and/or therapeutic treatment of otitis , in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhea. Cineole, preferably 1,8-cineole, for use in the prophylactic and/or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and/or outer ear, preferably the middle ear, preferably with accompanying (accompanying) otorrhoea, and/or or cineole, preferably 1,8-cineole, for use in the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhoea, but except for use in reducing pathogenic germs in the human intestine, in particular in the human intestinal flora, and/or except for use in reducing the colonization of the human intestine, in particular the human intestinal flora, with pathogens Germinate. Cineole, preferably 1,8-cineole, for use according to any one of Claims 33 until 36 , each characterized by one or more of the features of Claims 1 until 32 . Use of cineole, preferably 1,8-cineole, for the prophylactic and/or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and/or outer ear, preferably the middle ear, preferably with accompanying (accompanying) otorrhea, and/or Use of cineole, preferably 1,8-cineole, for the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhoea. Use of cineole, preferably 1,8-cineole, for the manufacture of a pharmaceutical or medicament for the prophylactic and/or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and/or outer ear, preferably the middle ear, preferably with accompanying (accompanying ) Otorrhoea, and/or use of cineole, preferably 1,8-cineole, for the manufacture of a drug or medicament for the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying ( associated) otorrhea. Use of cineole, preferably 1,8-cineole, as an ear treatment agent for the prophylactic and/or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and/or outer ear, preferably the middle ear, preferably with accompanying (accompanying) otorrhea, and /or Use of cineole, preferably 1,8-cineole, as an ear treatment agent for the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhoea. Use of cineole, preferably 1,8-cineole, for the production of an ear treatment agent for the prophylactic and/or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and/or outer ear, preferably the middle ear, preferably with accompanying (accompanying) otorrhoea , And / or use of cineole, preferably 1,8-cineole, for the manufacture of an ear treatment agent for the prophylactic and / or therapeutic treatment of otitis, in particular otitis media and / or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhea. Methods for the prophylactic and/or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and/or outer ear, preferably the middle ear, preferably with accompanying (accompanying) otorrhea, and/or methods for the prophylactic and/or therapeutic treatment of otitis , in particular otitis media and/or otitis externa, preferably otitis media, preferably with concomitant (accompanying) otorrhea, wherein the method involves one of the inflammatory diseases of the ear and/or otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhoea, a pharmaceutically effective or therapeutically effective amount of cineole, preferably 1,8-cineole, is administered to sick patients. Medicament or medicament, in particular ear treatment agents, for (use in) the prophylactic and/or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and/or outer ear, preferably the middle ear, preferably with accompanying (accompanying) otorrhoea, and/ or for (use in) the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with concomitant (accompanying) otorrhoea, wherein the pharmaceutical or medicament, in particular antiviral agent, cineole, preferably 1 ,8-cineole, together with at least one pharmaceutically acceptable and/or physiologically acceptable excipient (carrier). Medicines or medicines, in particular ear treatment products, after Claim 43 or drug or medicament, in particular antiviral agent, for use after Claim 43 , wherein the drug or medicament contains cineole, preferably 1,8-cineole, as the sole active ingredient, in particular as the sole pharmaceutical active ingredient, and/or as an individual active ingredient; and/or where the medicinal product or medicament contains cineole, preferably 1,8-cineole, as a pure substance, preferably with a purity of at least 95% by weight, in particular at least 96% by weight, preferably at least 97% by weight, particularly preferably at least 98% by weight, very particularly preferably at least 99% by weight, even more preferably at least 99.5%, based on the cineole, preferably 1,8-cineole, and/or preferably free from other terpenes; and/or wherein the drug or drug contains cineole, preferably 1,8-cineol, free from other terpenes and/or wherein the drug or drug contains no other terpene and/or wherein the drug or drug is free from terpenes other than cineole, preferably 1,8-cineole; and/or wherein the medicinal product or medicament contains the cineole, preferably 1,8-cineole, in effective, in particular pharmaceutically and/or therapeutically effective, amounts; and/or wherein the drug or medicament contains the cineole, preferably 1,8-cineole, based on the drug or medicament, in relative amounts ranging from 0.0001 to 80% by weight, in particular 0.001 to 75% by weight, preferably 0.005 to 70% by weight, preferably 0.01 to 60% by weight, particularly preferably 0.05 to 55% by weight, very particularly preferably 0.1 to 50% by weight; and/or wherein the at least one pharmaceutically acceptable and/or physiologically acceptable excipient (carrier) is miscible with and/or soluble in 1,8-cineole, preferably wherein the at least one pharmaceutically acceptable and/or physiologically acceptable excipient (carrier) is 20 °C and at atmospheric pressure in the liquid or solid, preferably liquid, state of aggregation and/or preferably wherein the at least one pharmaceutically acceptable and/or physiologically acceptable excipient (carrier) is selected from the group of fatty acid esters, preferably triglycerides of fatty acids, particularly preferably medium-chain ones Triglycerides (medium chain triglycerides or MCT), very particularly preferably triglycerides of C ₆ -C ₁₂ fatty acids. Medicines or medicines, in particular ear treatment products, after Claim 43 or 44 or drug or medicament, in particular antiviral agent, for use after Claim 43 or 44 , wherein the drug or drug contains no other active ingredients other than cineole, preferably 1,8-cineole, and/or wherein the drug or drug is free from active ingredients other than cineole, preferably 1,8-cineole, and/or wherein the Medicament or medicament is not present and/or administered and/or prepared for administration in combination with other active ingredients other than cineol, preferably 1,8-cineol; and/or wherein the drug or drug contains no vitamin D receptor agonists (VDA), in particular no compounds from the vitamin D group, and/or wherein the drug or drug is free from vitamin D receptor agonists (VDA), in particular free from compounds of vitamin D group, and/or wherein the drug or medicament is not present and/or administered and/or prepared for administration in combination with vitamin D receptor agonists (VDA), in particular not in combination with compounds of the vitamin D group is. Composition, in particular pharmaceutical composition, for (use in) the prophylactic and/or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and/or outer ear, preferably the middle ear, preferably with accompanying (accompanying) otorrhea, and/or for (use in) the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with concomitant (accompanying) otorrhea, the composition comprising cineol, preferably 1,8-cineol, in particular together with at least one pharmaceutically acceptable and/or physiologically acceptable excipient (carrier). Composition, in particular pharmaceutical composition, after Claim 46 or composition, in particular pharmaceutical composition, for use Claim 46 , wherein the composition contains the cineole, preferably 1,8-cineole, as the sole active ingredient, in particular as the sole pharmaceutical active ingredient, and/or as a single active ingredient; and/or wherein the composition contains the cineole, preferably 1,8-cineole, as a pure substance, preferably with a purity of at least 95% by weight, in particular at least 96% by weight, preferably at least 97% by weight, particularly preferably at least 98% by weight, very particularly preferably at least 99% by weight, even more preferably at least 99.5%, based on the cineole, preferably 1,8-cineole, and/or preferably free from other terpenes; and/or wherein the composition contains the cineole, preferably 1,8-cineole, free from other terpenes and/or wherein the composition contains no further terpene and/or wherein the composition is free from terpenes other than cineole, preferably 1,8-cineole , is; and/or wherein the composition contains the cineole, preferably 1,8-cineole, in effective, in particular pharmaceutical and/or therapeutically effective amounts; and/or wherein the composition contains the cineole, preferably 1,8-cineole, based on the composition, in relative amounts ranging from 0.0001 to 80% by weight, more preferably from 0.001 to 75% by weight, preferably from 0.005 to 70% % by weight, preferably 0.01 to 60% by weight, particularly preferably 0.05 to 55% by weight, very particularly preferably 0.1 to 50% by weight; and/or wherein the at least one pharmaceutically acceptable and/or physiologically acceptable excipient (carrier) is miscible with and/or soluble in 1,8-cineole, preferably wherein the at least one pharmaceutically acceptable and/or physiologically acceptable excipient (carrier) is 20 °C and at atmospheric pressure in the liquid or solid, preferably liquid, state of aggregation and/or preferably wherein the at least one pharmaceutically acceptable and/or physiologically acceptable excipient (carrier) is selected from the group of fatty acid esters, preferably triglycerides of fatty acids, particularly preferably medium-chain ones Triglycerides (medium chain triglycerides or MCT), very particularly preferably triglycerides of C ₆ -C ₁₂ fatty acids. Composition, in particular pharmaceutical composition, after Claim 46 or 47 or composition, in particular pharmaceutical composition, for use Claim 46 or 47 , wherein the composition contains no other active ingredients other than cineole, preferably 1,8-cineole, and/or wherein the composition is free of active ingredients other than cineole, preferably 1,8-cineole, and/or wherein the composition is not in combination is present and/or administered and/or is prepared for administration with other active substances different from cineol, preferably 1,8-cineol; and/or wherein the composition contains no vitamin D receptor agonists (VDA), in particular no compounds from the vitamin D group, and/or wherein the composition is free from vitamin D receptor agonists (VDA), in particular free from compounds from the vitamin D group , and/or wherein the composition is not in combination with vitamin D receptor agonists (VDA), in particular not in combination with compounds of the vitamin D group, and/or is administered and/or is prepared for administration. Cineole, preferably 1,8-cineole, for use according to any one of Claims 1 until 37 , use after one of Claims 38 until 41 , procedure after Claim 42 , drug or medicament according to any of the Claims 43 until 45 and composition according to one of Claims 46 until 48 , wherein the cineole, preferably 1,8-cineole, in particular the drug or medicament or the composition, is administered in pharmaceutically effective or therapeutically effective amounts and/or wherein the cineole, preferably 1,8-cineole, in particular the drug or medicament or the composition is adapted for administration in pharmaceutically effective or therapeutically effective amounts, respectively; and/or wherein the cineole, preferably 1,8-cineole, in particular the drug or medicament or the composition, is applied systemically or topically, in particular systemically, preferably orally; and/or wherein the cineole, preferably 1,8-cineole, in particular the drug or medicament or the composition, is used or administered together with at least one other active ingredient, in particular the other active ingredient is selected from (i) anti-inflammatory active ingredients (antiphlogistics) , especially nonsteroidal anti-inflammatory drugs (NSAIDs) or steroidal anti-inflammatory drugs; (ii) analgesics; (iii) antipyretics; (iv) antibiotics; as well as their combinations. Pharmaceutical combination for (use in) the prophylactic and/or therapeutic treatment of inflammatory diseases of the ear, in particular inflammatory diseases of the middle and/or outer ear, preferably the middle ear, preferably with concomitant (accompanying) otorrhea, and/or for (use in der) prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhoea, wherein the pharmaceutical combination comprises at least the following components (A) and (B): (A) cineole, preferably 1,8-cineole; as well as (B) at least one further active ingredient selected from (i) anti-inflammatory active ingredients (antiphlogistics), in particular non-steroidal anti-inflammatory drugs (NSAIDs) or steroidal anti-inflammatory drugs; (ii) analgesics; (iii) antipyretics; (iv) antibiotics; as well as their combinations. Pharmaceutical combination after Claim 50 or pharmaceutical combination for use according to Claim 50 , wherein the components (A) and (B) are present and/or administered separately from one another, in particular spatially separated from one another, but functionally connected and/or functionally associated with one another; and/or wherein the pharmaceutical combination is in the form a kit (kit-of-parts), in particular as a kit of components (A) and (B), and/or where components (A) and (B) are present as a kit (kit-of-parts) and/or are prepared and/or administered. Use after one of Claims 38 until 41 or after Claim 49 procedure after Claim 42 or after Claim 49 , drug or medicament according to any of the Claims 43 until 45 or after Claim 49 , Composition according to one of Claims 46 until 49 , as well as pharmaceutical combination after Claim 50 or 51 , each characterized by one or more of the features of Claims 1 until 37 .

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