DE102021132055B4 - New therapeutic concepts for the treatment of otitis - Google Patents

Abstract

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 otorrhea, 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 accompanying otorrhea.

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 area of otitis, such as otitis media (middle ear infection) or otitis externa (outer ear infection), preferably otitis media, and their treatment or therapy. In particular, the present invention relates to an active ingredient (here also referred to synonymously as active substance) as well as a medicament 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 ingredient and a medicament or a composition, each for use in the prophylactic and/or therapeutic treatment of inflammatory diseases of the ear or of otitis, such as otitis media or otitis externa, preferably otitis media.

In a corresponding manner, the present invention also relates to a use of an active ingredient for the prophylactic or therapeutic treatment of inflammatory diseases of the ear or of otitis, as well as to a related medicament or drug and to a related composition.

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

• 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 that records and processes sounds, such as tones, speech, sounds, noises, etc. The ear also functions as an organ of balance. The human ear can be divided into the outer ear, the middle ear, and the inner ear in terms of its anatomical structure, with each section having specific functions:

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

The middle ear includes the eardrum itself, 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 that is able to pass the sound energy absorbed by the eardrum to the inner ear via the oval window. The round window connects the tympanic scala of the inner ear with the middle ear. The middle ear is used in particular for the mechanical processing or (impedance) conversion of sound in order to enable the transmission of sound information from the outer ear to the inner ear. The intratympanic part of the facial nerve with the exit of the chorda tympani (facial nerve) is also located in the middle ear.

The inner ear includes the cochlea, the saccule, the utricle and the semicircular canals. In the inner ear, the signals transmitted from and received from the middle ear are converted into nerve impulses. The vestibular system is also part of the inner ear.

The path of the sound or its ultimate conversion into corresponding nerve signals starts from the auricle via the ear canal to the eardrum and then via the auditory ossicles, then via the cochlea and further via the auditory nerve, whereby the sound is transformed and processed on the way from the outer ear via the middle ear to the nerve cells of the inner ear.

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 sensory functions, so that the human ear has an important function as an underlying sensory organ, also with regard to the reception of speech as a means of communication and with regard to directional hearing (orientation in space) and also with regard to the function or guarantee of balance through the vestibular organ located in the ear.

The above statements show that the human ear is an organ or a functional unit with a complex interaction of the respective components. To ensure 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 inflammatory diseases of the ear. Such diseases can even lead to a permanent and lasting disruption of the functional properties of the ear. For this reason, there is a great need for appropriate therapies and prevention to treat or prevent inflammatory diseases of the ear in particular.

Against this background, diseases of the human ear are often problematic, as they can sometimes lead to a drastic restriction 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 an impairment of the balance function. In addition, diseases of the ear can also have an impact on the entire organism, for example in the case of bacterial infections or the like, which can also lead to systemic diseases or sepsis.

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

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

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

Inflammations of the ear or otitis can, as previously mentioned, be differentiated depending on where they occur and their further development or severity. Inflammatory diseases of the ear or otitis can also be accompanied by a discharge or outflow of body fluids or secretions from the (external) auditory canal, which is generally referred to as otorrhea and which occurs particularly in severe or chronic cases of the disease.

An inflammation of the outer ear, known as otitis externa, is an infection of the skin of the ear canal in particular, which is typically caused by pathogenic germs, particularly pathogenic bacteria. Symptoms in this case include pain, discharge (otorrhea) and hearing loss, particularly if the disease is accompanied by swelling in the ear canal. Inner ear inflammation or otitis interna, which can be acute (otitis interna acuta) or chronic (otitis interna chronica), is a mostly painful inflammation of the inner ear, with the bony labyrinth, cochlea and vestibular system, particularly affected or inflamed. Otitis interna can also have negative effects on hearing and the sense of balance.

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

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

Otitis media is generally referred to as a disease that is caused by a pathogenic are characterized by an inflammation of the middle ear caused by germs or, in particular, bacterial inflammation, whereby, depending on the course of the disease, a distinction can be made between acute otitis media or otitis media acuta and chronic otitis media or otitis media chronica. Middle ear inflammation is caused in particular by pathogenic germs, in particular pathogenic bacteria, whereby colonization of the middle ear can occur, for example, via the Eustachian tube from the nasal cavity or nasopharynx, but also via the bloodstream. If the eardrum is perforated, for example, pathogens or pathogenic germs can also enter the middle ear from outside, for example through bath water or the like. Middle ear inflammation can, for example, be accompanied by pulsating ear pain, fever, throbbing noises in the ears, hearing loss, nausea or the like. In severe cases, bodily fluids such as pus can leak out, the eardrum can be damaged, and hearing can be permanently impaired. 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, thus causing permanent hearing loss, particularly in the form of conductive hearing loss.

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

The so-called cholesteatoma or otitis media epitympanalis or otitis media chronica epitympanalis can be distinguished from chronic mucous membrane suppuration of the middle ear, which is also a severe form of middle ear infection or otitis media. Cholesteatoma or otitis media epitympanalis is generally understood to be an overgrowth of, in particular, multilayered keratinizing squamous epithelium in the middle ear with subsequent or associated, in particular chronic or in particular purulent inflammation of the middle ear. Cholesteatoma is generally a progressive, destructive inflammatory disease or lesion of the middle ear, whereby from a pathological point of view, the characteristics in particular are migration, increased cell proliferation, invasiveness, impaired cell differentiation, progression or a tendency to recurrence after surgical intervention. Cholesteatoma is therefore characterized by a proliferating-destructive course with possible complications, such as destruction of the bony structures, particularly with hearing loss, vestibular dysfunction, facial nerve paralysis and intracranial complications, so that in this respect it is an overall serious disease of the ear.

In industrialized nations, middle ear infection or otitis media is one of the diseases that most frequently leads to visits to the doctor, prescriptions of antibiotics and operations. Inflammation of the middle ear or otitis media, particularly in the chronic recurrent form, is often associated with a significant deterioration in the quality of life of the patients affected, who often suffer from runny ears (otorrhea), hearing loss, delayed speech development, total deafness and/or dizziness. In addition, the particularly aggressive form of middle ear infection, namely cholesteatoma or otitis media epitympanalis, behaves in a way like a malignant tumor, although the disease is often not amenable to antibiotic therapy and is characterized by progressive inflammatory-destructive processes in the middle ear, which can also affect or destroy the surrounding structures.

In general, infection of the middle ear or otitis media with pathogenic germs, such as bacterial or possibly viral pathogens or pathogenic fungi, primarily or initially leads to the clinical picture of acute otitis media, which is a common clinical picture in childhood. If the immune system is unable to contain the bacterial infection and the associated inflammatory processes, complete healing of the disease or restitutio ad integrum is not guaranteed, and the course of acute inflammation can be followed by recurrent episodes or an ongoing or chronic inflammation, which is referred to as chronic otitis media.

In 2004, according to a report by the World Health Organization (WHO) on chronic purulent otitis media, the incidence of acute otitis media in Central Europe was 36.4 per 1,000 inhabitants, while chronicity or acute otitis media affected about one tenth of these patients, namely 3.69 per 1,000 inhabitants. The incidence of chronic otitis media in children up to the age of nine is three to five times higher than in adults globally. In regions with developing countries, such as Central and West Africa, the incidence is even higher, namely 433 cases of acute otitis per 1,000 inhabitants and around 7 cases of chronic otitis per 1,000 inhabitants.

Chronic otitis, such as otitis media or otitis externa, particularly otitis media, but also otitis interna (e.g. particularly otitis media with inner ear involvement or particularly otitis media with accompanying inner ear inflammation), can be associated with otorrhea, as mentioned above, and thus with the discharge of body fluids or secretions from the external auditory canal, particularly in the case of a specific or severe course. Severe courses of otitis and particularly otitis media, for example if it lasts for more than six weeks or is accompanied by otorrhea, can lead to increasing destruction of the bone tissue and mucous membrane of the affected middle ear. Without intervention, this can lead to irreversible damage with eardrum defects including conductive hearing loss.

In severe cases of otitis, central eardrum defects can lead to the clinical picture of chronic otitis media mesotympanalis, while peripheral eardrum defects can be associated with chronic otitis media epitympanalis or cholesteatoma. Severe forms of the disease must be taken very seriously, as if the inflammation spreads and is left untreated, it can lead to tissue destruction, mastoiditis, labyrinthitis, facial paralysis, meningitis, brain abscess, sinus vein thrombosis, and even death. Patients affected by the disease also suffer from hearing impairment, which makes everyday communication extremely difficult and, if left untreated, progressively worsens. In this context, surgical reconstruction of the eardrum, replacement of the ossicular chain, or removal of the cholesteatoma is often unavoidable.

Inflammatory ear diseases and in particular middle ear infections, 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 using antibiotics, particularly in children and the elderly, particularly if the inflammation of the middle ear caused by bacterial and possibly viral pathogens or pathogenic germs is not self-limiting, as is often the case in patients with lower immune competence. In the case of persistent or recurrent infections in particular, the state of the art often requires therapeutic action using appropriate antibiotics. However, especially in children, the use of antibiotics must be strictly indicated and the risks should always be weighed up. Antibiotic therapy, particularly for 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, particularly of the skin, such as redness and/or itching, as well as the occurrence of fungal infections or the like. Likewise, systemic allergic reactions can also occur under antibiotics, even leading to the development of anaphylactic shock. In addition, if antibiotics are used incorrectly, resistance can also develop in the underlying pathogenic germs, particularly pathogenic bacteria, which can make treatment even more difficult. In particular, already resistant germs or bacteria can no longer be combated satisfactorily with some antibiotics, so that their use is limited in this context too.

Pathogenic germs in the form of bacterial pathogens that cause chronic otitis include Pseudomonas aeruginosa, Proteus mirabilis and Staphylococcus aureus, as well as Enterobacterales and anaerobes. A similar spectrum of pathogens is also seen in advanced inflammation with mastoiditis, whereby Streptococcus pneumoniae and Haemophilus influenza in particular can be present as underlying pathogens.

The chronicity of the inflammation in otitis is of multifactorial origin. In particular, in relation to otitis, the colonisation of the ear with pathogenic germs such as Streptococcus pneumoniae, Haemophilus influenza and Staphylococcus aureus can be related to the extent of any hearing loss, as can be the case with otitis media with otorrhoea. In particular, if pathogenic germs are present, the hearing loss can be more severe than if pathogenic germs are not present. In particular, in relation to the pathogenic germs in relation to otitis, the A particularly pathogenic biofilm can form in the area of the affected ear, as can be the case with Pseudomonas aeruginosa, for example, which can also affect the effectiveness of antibiotics.

The US 2019/0255024 A1 relates to a pharmaceutical composition based on amoxicillin, cineole and a pharmaceutically acceptable oil, which composition can be used for the treatment of bacterial infections, wherein cineole is used as an adjuvant for the amoxicillin.

Furthermore, the US 2020/0138710 A1 a pharmaceutical composition based on a therapeutic active ingredient, an enhancer and a matrix substance, where the enhancer can be, for example, cineole.

The document Martins Anita Oliveira Brito Pereira Bezerra et al.: “Anti-edematogenic and anti-inflammatory activity of the essential oil from Croton rhamnifolioides leaves and its major constituent 1,8-cineole (eucalyptol),” Biomedicine & Pharmacotherapy, Vol. 96, December 1, 2017, pages 384-395 concerns studies on the anti-edematogenous and anti-inflammatory effects of the essential oil of the leaves of Croton rhamnifolioides and its component 1,8-cineole (eucalyptol).

The document Chandrakanthan Madhuvanthi et al.: “Topical Anti-Inflammatory Activity of Essential Oils of Alpinia calcarata Rosc., Its Main Constituents, and Possible Mechanism of Action,” Evidence-Based Complementary and Alternative Medicine, Vol. 2020, April 28, 2020, pages 1-19 (D3) concerns investigations into the topical anti-inflammatory effect of the essential oils of Alpinia calcarata Rosc., their main constituents and details of possible mechanisms of action.

In light of the above statements, there is therefore - particularly due to the sometimes serious health effects of inflammation of the ear and the sometimes irreversible consequential damage - a great need for suitable forms of therapy based on efficient active substances or related compositions and medicinal products which are suitable in an efficient manner for the treatment of inflammatory diseases of the ear or otitis, in particular otitis media or otitis externa, but also otitis interna, whereby a high level of tolerability and at the same time a high and specific effectiveness of the active substances used should be ensured.

The present invention is therefore based on the object of providing an efficient concept or related active ingredients and compositions or drugs based thereon, which enable efficient treatment of inflammatory diseases of the ear or otitis, in particular otitis media and/or otitis externa, but also otitis interna, and in particular also the related subtypes 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 drugs should also be guaranteed.

Yet another object of the present invention is to provide corresponding active ingredients as well as compositions and medicaments based thereon, which counteract incorrect colonization or excessive colonization with pathogenic germs or non-physiological colonization of the ear, in particular of 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, a further object of the present invention is to provide corresponding active ingredients or compositions or medicaments based thereon, which fundamentally enable a reduction in the use of antibiotics in particular, so that the side effects and disadvantages associated with antibiotics can also be avoided or minimized.

Against this background, a further object of the present invention is to provide corresponding active substances or compositions and medicaments based thereon with regard to the treatment of inflammatory diseases of the ear or otitis, which at least largely avoid or at least mitigate the previously described disadvantages of the prior art.

In a completely surprising manner, the applicant has now discovered that cineole, in particular 1,8-cineole, can be used 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 the middle ear, but also the inner ear, or for the prophylactic or therapeutic treatment of otitis, in particular otitis media or otitis externa, preferably otitis media, but also otitis interna, and also with regard to those courses or diseases which are associated with or accompanied by otorrhea.

To solve the problem described above, the present invention - according to a first aspect of the present invention - proposes 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) otorrhea, according to claim 1. Advantageous further developments and embodiments of this aspect of the invention are the subject 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 pathogenic germs located or localized in the ear or for use in reducing the proportion of the relevant pathogenic germs in the prophylactic or therapeutic treatment of inflammatory diseases of the ear or of otitis according to the relevant independent claim. Advantageous further developments and embodiments of this aspect of the invention are the subject of the relevant subclaims.

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

Yet another subject matter 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 producing 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) otorrhea. Advantageous further developments and embodiments of this aspect of the invention are the subject matter of the relevant subclaims.

The present invention also relates - according to a fourth aspect of the present invention - to a medicament or drug for (use in the) prophylactic or therapeutic treatment of inflammatory diseases of the ear or of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhea, according to the relevant independent claim. Advantageous further developments and refinements of this aspect of the invention are the subject of the relevant subclaims.

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

It goes without saying that embodiments, embodiments, advantages and the like which are listed below for the purpose of avoiding repetition of one aspect of the invention naturally also apply to the other aspects of the invention, without this requiring separate mention.

Furthermore, with regard to the following description of the present invention, the features of the present invention cited in connection with the specific configurations, embodiments, advantages, examples or the like are also deemed to be disclosed in their combination. Thus, higher-level combinations of individual or multiple features which are cited for respective configurations, embodiments, application examples or the like are also deemed to be disclosed.

Furthermore, it goes without saying that the following information on values, numbers and ranges is not to be understood as limiting. It is self-evident to the person skilled in the art that, depending on the individual case or application, deviations from the specified range or information may occur without departing from the scope of the present invention.

In addition, all values or parameter specifications or the like mentioned below can in principle be determined using standardized or explicitly specified determination procedures or using determination methods that are familiar to the person skilled in the art.

Furthermore, it should be noted that for all relative or percentage, in particular weight-related, quantity information given below, these details must be selected or combined by the person skilled in the art within the framework of the composition according to the invention in such a way that the total - if necessary including other components or ingredients or additives or constituents, in particular as defined below - always results in 100% or 100% by weight. However, this is self-evident for the person skilled in the art.

The subject matter 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 the middle ear, preferably with accompanying (accompanying) otorrhea. The subject matter according to this aspect is also 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) otorrhea.

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 the human middle ear.

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

The special, new and inventive application or medical indication for cineole, in particular 1,8-cineole, surprisingly discovered by the applicant within the scope of the present invention has not been described or recognized in the prior art to date, even though cineole, in particular 1,8-cineole, is in itself a sufficiently known active ingredient.

The active ingredient used according to the invention, cineole, in particular 1,8-cineole, is a so-called terpene, in particular a monoterpene. Terpenes are generally natural substances which can be isolated as a component of 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 or cosmetics industries. In addition, the use of terpenes for medical purposes is also becoming increasingly important, as pharmacological effects can be demonstrated for a large number of terpenes. Terpenes are formally polymerization products of isoprene, whereby a distinction is made between 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 according to the number of isoprene residues (cf. RÖMPP-Chemielexikon, 10th edition, Georg Thieme Verlag, Stuttgart/New York, 1999, pages 4449 and 4450 , keyword "terpene(oid)s"). In addition, terpenes can also be used as pharmacologically active substances, starting materials for the production of medicines or vitamin preparations, and in agriculture due to their often bactericidal or pesticidal effects. Pharmacological effects in the fight against diseases in systemic treatments have been proven for a number of monoterpenes in particular, with menthol and cineole, especially 1,8-cineole, being particularly noteworthy.

The active ingredient used according to the invention, cineole, in particular 1,8-cineole, belongs to the bicyclic epoxy monoterpenes, more precisely to the limonene oxides. Synonymous names for 1,8-cineole with the chemical 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 to 177 °C, which is found in Insoluble in water but miscible with most organic solvents.

Naturally, 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, such as mint, medicinal sage, thyme, basil and tea tree. In addition, 1,8-cineole is also found in niaouli, juniper, piper, cannabis, cajeput, sage, myrtle oil 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 current state of the art, 1,8-cineole is used in particular as an expectorant for bronchial catarrh and other respiratory diseases, but also as a flavoring in the perfume industry. In addition, 1,8-cineole is used in dentistry for the revision of root fillings. From a physiological point of view, 1,8-cineole has an expectorant effect in the upper and lower respiratory tract, particularly in the lungs and sinuses. According to the current state of the art, 1,8-cineole is used both topically (e.g. inhalation) and systemically (e.g. in the form of capsules), usually as a mixed oil together with a variety of other terpenes.

For further details on the active ingredient 1,8-cineole, please refer to RÖMPP Chemistry Encyclopedia, Georg Thieme Verlag, Stuttgart/New York, 10th edition, Volume 1, 1996, page 752, keyword: "Cineol" , as well as the literature cited therein.

However, what is completely surprising and unexpected is the potential effect of cineole, preferably 1,8-cineole, discovered by the applicant within the scope 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 the middle ear, preferably with accompanying otorrhea, or with regard to the treatment of otitis, in particular otitis media or otitis externa, preferably otitis media, preferably with accompanying otorrhea.

In this context, cineole, particularly 1,8-cineole, surprisingly also has an antibiotic effect against pathogenic germs (also known synonymously as pathogens, pathogenic microorganisms or infectious agents), particularly in the form of pathogenic bacteria (but also against fungi or viruses). These are particularly pathogenic germs that are associated with or cause inflammatory diseases of the ear.

In this context, the applicant was also able to show, surprisingly, 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, in particular with regard to those pathogenic germs which are associated with otitis or which are capable of causing otitis. Without wishing to commit or limit oneself to this theory, the active ingredient cineole, preferably 1,8-cineole, therefore has an antimicrobial, antibacterial or antiviral effect with regard to the 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.

This enables the present invention to provide effective relief from otitis, while at the same time ensuring high tolerability and the occurrence of only minimal side effects when using the active substance. In this context, in addition to good efficacy, the present invention also ensures excellent or improved tolerability and simple application of the active substance in the form of cineole, preferably 1,8-cineole.

In particular, the application 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 the incorrect colonization or the colonization of the inflamed ear with non-physiological germs, whereby in this regard an improvement in the colonization of the ear with physiological germs is also supported or caused, so that an improvement in the germ ratio in the sense of a shift towards an increased physiological colonization of the ear (i.e. colonization of the ear with physiological or non-pathogenic germs) is also brought about by the application of cineole, preferably 1,8-cineole, which in turn leads to an attenuation or cure of the underlying disease in the form of the otitis in question.

Consequently, within the scope of the present invention, the clinical picture is examined with regard to the underlying otitis or inflammatory The use of the active substance cineole, preferably 1,8-cineole, has shown a significant improvement in the quality of life of patients affected by the disease, including in terms of the pain symptoms associated with the disease and the suffering caused to the patients.

In this context, with regard to the treatment of otitis, in particular otitis media and/or otitis externa, preferably 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), an escalation of the disease state can also be prevented due to the excellent efficacy of cineole, preferably 1,8-cineole.

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

As a result of the high therapeutic effectiveness of cineole, preferably 1,8-cineole, discovered by the applicant in a completely surprising manner, various subtypes or special forms of otitis can also be effectively treated, such as a form of the disease that is refractory or resistant to therapy, such as antibiotics. For this reason too, the active substance cineole, preferably 1,8-cineole, has a wide spectrum of activity with regard to a large number of corresponding 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 cholesteatoma, the situation within the scope of the present invention is particularly such that the underlying cholesteatoma masses are sometimes not or not significantly dissolved (which is less relevant for therapy), but the inflammatory character and the aggressiveness of the inflammation are sustainably inhibited or treated, so that here too there is an overall very high level of effectiveness when using cineole, preferably 1,8-cineole, with improvement in the condition of the disease.

Due to 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, the present invention also enables necessary therapeutic operations on the ear, for example with regard to the implantation of a cochlear implant or a tympanoplasty or Vibrant Soundbridge implantation. This is because due to the high effectiveness of cineole, preferably 1,8-cineole, the inflammatory processes in the ear are significantly reduced and the colonization of the ear with pathogenic germs is significantly reduced, so that on this basis a prerequisite for carrying out surgical interventions is created. Cineole or 1,8-cineole can therefore be used as part of a preoperative application and thus in preparation for corresponding ear operations, whereby the underlying disease is weakened or cured in preparation for the operation, which makes the subsequent surgical procedure easier or even possible. In addition, cineole, preferably 1,8-cineole, can also be administered perioperatively or postoperatively, for example with a view to preventing 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 likelihood of this can be significantly reduced.

As a result of the surprisingly discovered effectiveness of cineole, preferably 1,8-cineole, the administration of antibiotics can sometimes be avoided or their use 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 resistance, can be overcome or avoided.

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

Due to the antimicrobial effectiveness against pathogenic germs, the administration of cineole, preferably 1,8-cineole, as mentioned in the context of the present invention, can also lead to a fight against or a breakdown or a "breaking up" of pathogenic biofilms in the ear that are formed or caused by pathogenic germs, so that on this basis too the colonization of the ear with pathogenic germs is reduced and the accessibility of any other active ingredients, 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 amount reduced). The cineole, in particular 1,8-cineole, can infiltrate or penetrate the biofilms in question - without wishing to limit itself to this theory or to rely on it - so to speak, so that its effect can develop there.

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

Overall, the present invention provides an effective concept for 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 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 associated otorrhea.

According to the invention, in principle, treatment of 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 inner ear inflammation) can also be carried out, as previously mentioned.

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

According to a preferred embodiment of the invention, the active ingredient cineole, preferably 1,8-cineole, is used for the prophylactic and/or therapeutic treatment of otitis media with accompanying otorrhea.

According to the present aspect, the present invention therefore 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 accompanying (concomitant) 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 otorrhea.

As previously stated, the active ingredient cineole, preferably 1,8-cineole, also has an effect against pathogenic germs in the ear: Against this background, the present invention according to the present aspect also relates to cineole, preferably 1,8-cineole, in particular as previously 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 accompanying otorrhea.

With regard to the preceding and following statements, the proportion or germ content of the pathogenic germs is related to the total number of germs (total germ count) in the ear, in particular in the middle and/or outer ear (in particular the external 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, the proportion of pathogenic bacteria stated here is related to the total number of bacteria in the ear, in particular in the middle and/or outer ear, preferably in the middle ear. The corresponding proportions are therefore relative values with reference to the previously stated total number of bacteria or germs.

According to the present aspect, the present invention further 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 external 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 middle and/or outer ear, preferably of 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.

Consequently, the present invention, with regard to the active ingredient cineole, preferably 1,8-cineole, is particularly directed to a reduction or degradation or destruction of pathogenic biofilms in the ear. In the context of the present invention, the pathogenic biofilms are associated with inflammatory diseases of the ear, in particular as defined above, and/or with otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (associated) otorrhea, or cause the related inflammations or diseases, in particular on the basis of underlying pathogenic germs or bacteria. In particular, the pathogenic biofilms are formed by pathogenic germs, in particular pathogenic bacteria, which are associated with or cause inflammations in the ear or otitis.

According to the invention, it is particularly provided that the cineole, preferably 1,8-cineole, is employed or used for use according to one of the preceding claims, for reducing the load (germ load) and/or the number (germ number) of pathogenic germs, in particular pathogenic bacteria, present and/or localized in the ear, in particular in the middle and/or outer ear, preferably in the middle ear.

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

• 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, within the scope of the present invention, they may behave in particular as follows:

• In particular, the pathogenic germs are selected from the group of germs which cause and/or aggravate and/or are associated with inflammatory diseases of the ear, in particular inflammatory diseases of the middle and/or outer ear, preferably of the middle ear, preferably with accompanying (associated) otorrhea, and/or otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (associated) otorrhea.

According to the invention, the pathogenic germs are also selected in particular 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 of the middle ear, preferably with accompanying (associated) otorrhea, and/or the otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (associated) otorrhea, causing and/or aggravating and/or associated with bacteria.

Furthermore, within the scope of the present invention, 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 genera Pseudomonas and Proteus and their combinations.

In this context, it can be provided in particular that the pathogenic germs 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 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.

Compared to the aforementioned bacterial genera or species, cineole or 1,8-cineole is particularly effective. On this basis, effective treatment of the underlying inflammatory diseases of the ear or otitis can be carried out. In this context, there is in particular - without wishing to limit or rely on this theory - a direct connection between the previously mentioned specific 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 (associated) otorrhea, in particular insofar as the disease is caused by the pathogenic germs in question (i.e. the germs are the cause of the disease) or that the germs in question accompany the disease or maintain or further worsen it.

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

Within the scope of the present invention, the use of cineole, preferably 1,8-cineole, in particular also enables an improvement or support of 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 thus in particular also be such that the physiological (germ) flora in the ear, in particular in the middle ear and/or in the outer ear (in particular in the external 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 the total number of germs is increased).

Thus, according to the invention, it can be in particular such that the cineole, preferably 1,8-cineole, is used or employed, in particular as defined above, further and/or additionally and/or equally for increasing, multiplying or supporting physiological germs (non-pathogenic germs), in particular physiological bacteria (non-pathogenic bacteria), located and/or localized in the ear, in particular in the middle and/or outer ear, preferably in the middle ear.

Likewise, according to the invention, the cineole, preferably 1,8-cineole, can be used or employed furthermore and/or additionally and/or equally to increase the load (germ load) or the number (germ number) or the proportion (germ proportion) of physiological germs (non-pathogenic germs), in particular physiological bacteria (non-pathogenic bacteria), located and/or localized in the ear, in particular in the middle and/or outer ear, preferably in the middle ear.

In addition, it can also be provided according to the invention that the cineole, preferably 1,8-cineole, is furthermore and/or additionally and/or equally used or employed 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).

As previously mentioned, numerous forms or subtypes of otitis can be treated within the scope of the present invention.

According to the present aspect, the present invention in this context also relates equally 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 of the middle ear, preferably with accompanying (associated) otorrhea, where the disease is a therapy-refractory and/or therapy-resistant, in particular drug- and/or medicinal product-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 (associated) otorrhea, where the otitis is a therapy-refractory and/or therapy-resistant, in particular drug- and/or medicinal product-resistant, preferably antibiotic-resistant, otitis.

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

In a corresponding manner, according to the invention, the otitis can also be a therapy-refractory and/or therapy-resistant, in particular drug- and/or medicinal product-resistant, preferably antibiotic-resistant, otitis.

In particular, according to the invention, the pathogenic germs, in particular the pathogenic germs associated with or causing inflammatory diseases of the ear and/or otitis, are therapy-refractory and/or therapy-resistant, in particular drug- and/or pharmaceutical-resistant, preferably antibiotic-resistant, pathogenic germs. The pathogenic germs can preferably be drug- and/or pharmaceutical-resistant, in particular antibiotic-resistant, pathogenic bacteria. The applicant has also been able to demonstrate the high effectiveness of cineole, in particular 1,8-cineole, in this regard. 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 chronic otitis, in particular a chronic otitis, preferably a chronic polypous 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 polypous otitis or a chronic granular otitis. According to the invention, it can be provided in particular that the otitis is a particularly recurrent otitis media, preferably with accompanying (concomitant) otorrhea.

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

In particular, it may be the case according to the invention that the otitis is a particularly chronic otitis media, preferably with accompanying (concomitant) otorrhea.

Furthermore, according to the invention, it can be the case 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 respect, it can be particularly chronic forms (i.e. otitis media chronica epitympanalis or otitis media chronica mesotympanalis). The aforementioned otitis can also be accompanied by or go hand in hand with otorrhea (i.e. otitis media (chronica) epitympanalis with accompanying otorrhea or otitis media (chronica) mesotympanalis with accompanying otorrhea).

Furthermore, according to the invention, it can be such that the inflammatory diseases of the ear or the otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (associated) otorrhea, preferably otitis media epitympanalis, are accompanied by or are related to 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.

In this regard, it can be provided in particular that the cineole, preferably 1,8-cineole, is used or employed furthermore and/or additionally and/or equally for the suppression or attenuation of an inflammatory mediation occurring in the context of inflammatory diseases 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.

In particular, within the scope of the present invention, it can behave in such a way that the cineole, preferably 1,8-cineole, exerts a suppressive or weakening effect on an inflammatory mediation occurring in the context of inflammatory diseases 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. In this regard, according to the invention, it can behave in such a way that the cineole, preferably 1,8-cineole, causes or induces a downregulation and/or a reduced production and/or a reduced 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.

In particular, cineole, preferably 1,8-cineole, can thus be used or employed for downregulation and/or for reducing the production and/or for reducing the release of, in particular, proinflammatory cytokines, preferably TNF-alpha (tumor necrosis factor-alpha) and/or interleukin-1beta (IL-1β), preferably TNF-alpha.

In this context, with regard to the underlying diseases, particularly in the form of cholesteatoma, it is particularly the case that - without wishing to limit or rely on this theory - the aforementioned proinflammatory cytokines, preferably TNF-alpha, regulate or influence the inflammation and/or apoptosis and also play an important role in the chronification of the disease. The effect of cineole, preferably 1,8-cineole, can therefore also counteract these processes.

In this context in particular, 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 in the treatment of inflammatory diseases of the ear or otitis. Consequently, inflammatory processes that are associated with inflammatory diseases of the ear or otitis are reduced or down-regulated on this basis, so that on this basis too there is a positive effect or an effective effect with regard to the treatment of the inflammatory diseases of the ear or otitis mentioned.

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

Furthermore, according to the invention, it can also be provided that the cineole, preferably 1,8-cineole, is used or employed furthermore and/or additionally and/or equally for the prevention and/or avoidance and/or for the prophylactic and/or therapeutic treatment of secondary and/or concomitant diseases associated with and/or caused by inflammatory diseases of the ear and/or otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (accompanying) otorrhea, in particular selected from the group of mastoisitis, labyrinthitis, meningitis, sinus vein thrombosis, sepsis, facial nerve paralysis and tinnitus, as well as 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 co-treated or co-treated in conjunction with an underlying otitis.

In addition, the cineole, preferably 1,8-cineole, can also be employed or used with regard to carrying out ear operations, in particular operations on the middle and/or outer ear, preferably the middle ear, in particular as follows: According to the invention, the cineole, preferably 1,8-cineole, can be employed or used 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).

In addition, the cineole, preferably 1,8-cineole, can be used or employed within the scope of the present invention postoperatively and/or for the postoperative aftercare 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). 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.

Furthermore, the cineole, preferably 1,8-cineole, can be used or employed within the scope of the present invention 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 tympanoplastic operations and/or implantation operations (implantation). Thus, according to the invention, an intraoperative use of cineole, preferably 1,8-cineole, can furthermore and/or additionally and/or equally take place.

Overall, according to the invention, further and/or additionally, a perioperative use of cineole, preferably 1,8-cineole, can equally be carried out.

• 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 ingredient cineole, preferably 1,8-cineole, can also be used for 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 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) otorrhea, or for use in the prophylactic and/or therapeutic treatment of otitis interna and/or otitis media with accompanying inner ear inflammation, in each case preferably with accompanying (accompanying) otorrhea.

Consequently, according to the invention, the otitis may be an otitis interna and/or an otitis media with accompanying inner ear inflammation, in each case preferably with accompanying (concomitant) otorrhea.

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

In particular, according to the invention, it can be such that 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 pathogenic agents. Consequently, according to the invention, it can be provided in particular that in the present case 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 pathogenic agents. In particular, these can also be pathogenic germs or pathogenic agents that are typical of incorrect colonization of the intestinal flora, i.e. in particular those pathogenic germs or pathogenic agents that are specifically associated with incorrect colonization of the intestine, in particular the human intestine.

According to the invention, it can therefore be such that cineole, preferably 1,8-cineole, is not used for reducing the colonization of the human intestine, in particular the human intestinal flora, with pathogenic germs or pathogenic agents.

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 orally or parenterally, preferably orally, and/or that the cineole, preferably 1,8-cineole, is prepared for systemic, in particular orally or parenterally, preferably orally, administration. In this way, high systemic active doses or active ingredient levels (i.e. active ingredient 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 particularly good effectiveness or efficiency can be achieved.

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

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 prepared in a dosage form to be administered orally.

According to a further 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 small intestine-soluble systemic dosage form, preferably as a capsule, dragee, pill, tablet or the like, and/or that the cineole, preferably 1,8-cineole, is prepared for administration as a gastric juice-resistant but small intestine-soluble systemic dosage form, preferably capsule, dragee, pill, tablet or the like.

For the systemic use of cineole, in particular 1,8-cineole, various preparations are commercially available, in particular based on generally enteric-coated but intestinal-soluble dosage forms or capsules.

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

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

In general, within the scope of the present invention, it is intended that the oral dosage form, in particular capsule, is resistant to gastric juice but soluble in the small intestine. This achieves a particularly optimal release profile, since the active ingredient is only released in the intestine in a targeted and purposeful manner and is then optimally absorbed by the body.

The definitions of the terms “enteric” and “small intestine soluble” used in this invention as well as the corresponding test methods are given in European Pharmacopoeia 7.0, 04/2010: 1502, pages 707 to 709, keyword "Capsules", subchapter "Gastro-Resistant Capsules" as well as European Pharmacopoeia 7.1, 04/2011: 20901, pages 3331 and 3332, keyword “2.9.1 Disintegration of Tablets and Capsules “ is reproduced.

In the context of the present invention, the term “enteric acid resistant” is to be understood in particular to mean that the capsules can be stored, in particular stirred, for at least two hours in 0.1 N hydrochloric acid, which is heated to temperatures of 35 to 39 °C, with constant mixing, without the capsules showing signs of decomposition or cracks or other damage.

In the context of the present invention, however, the term “small intestine soluble” is to be understood in particular to mean that the capsules are decomposed in an aqueous phosphate buffer solution, which is adjusted to a pH value of about 6.8, with stirring at temperatures in the range of 35 to 39 °C 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 administered 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. In this regard, ear drops can be used, for example. The topical, in particular auricular, dosage form can provide locally limited high amounts or concentrations of active ingredient. In particular, high amounts or concentrations of active ingredient can be achieved at the site of action itself at a local level.

According to the invention, it can also be provided in principle that the cineole is administered 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.

Cineole, preferably 1,8-cineole, can therefore 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 ingredient can reach the site of action in particular through the Eustachian tube (tuba auditiva), in addition to systemic absorption via the nasal mucosa.

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

In particular, within the scope of the present invention, according to this aspect of the invention, according to a particular embodiment, it can be provided that the cineole, preferably 1,8-cineole, is administered with a daily dose in the range of 1 mg/diem to 5,000 mg/diem, in particular in the range of 2 mg/diem to 3,000 mg/diem, preferably in the range of 5 mg/diem to 2,500 mg/diem, preferably in the range of 10 mg/diem to 2,000 mg/diem, particularly preferably in the range of 50 mg/diem to 1,500 mg/diem, very particularly preferably in the range of 100 mg/diem to 1,200 mg/diem, further preferably in the range of 200 mg/diem to 1,000 mg/diem, and/or that the cineole, preferably 1,8-cineole, is administered with a daily dose in the range of 1 mg/diem to 5,000 mg/diem, in particular in the range of 2 mg/diem to 3,000 mg/diem, preferably in the range of 5 mg/diem to 2,500 mg/diem, more preferably in the range of 10 mg/diem to 2,000 mg/diem, particularly preferably in the range of 50 mg/diem to 1,500 mg/diem, most preferably in the range of 100 mg/diem to 1,200 mg/diem, more preferably in the range of 200 mg/diem to 1,000 mg/diem.

According to a further particular embodiment of the present invention according to this aspect of the invention, it can be provided in particular that the cineole, preferably 1,8-cineole, is present or administered as a pure substance. In particular, the cineole, preferably 1,8-cineole, can be present or administered 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.

In this context, it is particularly preferred according to the invention if the cineole, preferably 1,8-cineole, is free of other terpenes or in particular where the cineole, preferably 1,8-cineole, does not contain any other terpenes. As described above, it is preferred according to the invention that the monoterpene-based active substance (i.e. cineole, preferably 1,8-cineole) is used in the form of a pure substance, i.e. as the sole or technically isolated/purified active substance. In this way, for example, a constant dosage or a constant content of active substance can be ensured in the dosage form provided according to the invention. In this way, high doses or amounts of active substance can also be achieved at the site of action. In addition, this further focuses the spectrum of action and further reduces side effects.

Above all - as previously explained - 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 causes a particularly efficient inhibition of inflammatory mediators or leukotriene and cytokine production. Essential mixed oils that contain cineole as one of many active components (such as 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 can rather cause intolerance reactions (i.e. such essential mixed oils or oil mixtures can therefore generally increase cell activity and even induce inflammatory mediator production). In contrast, however, isolated or pure cineole, especially 1,8-cineole, only causes a significant inhibition of 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 acceptable carrier (excipient) is miscible with 1,8-cineole and/or soluble therein. Furthermore, it can be provided in particular that the physiologically acceptable carrier (excipient) is in the liquid or solid, preferably liquid, state of aggregation at 20 °C and at atmospheric pressure.

In this context, it can further be provided 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 (MCT), very particularly preferably triglycerides of C ₆ -C ₁₂ fatty acids.

In this context, it can be provided according to the invention in particular that the cineole, preferably 1,8-cineole, 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 preferably as a pure substance or in the absence of other (further) terpenes, together with at least one physiologically acceptable carrier (excipient).

According to a particular embodiment, the dosage form provided according to the invention contains - as previously described - the monoterpene and the active ingredient cineole, in particular 1,8-cineole, together with at least one carrier (excipient) that is miscible with the active substance and/or soluble therein, in particular liquid at 20 °C and atmospheric pressure, and is physiologically acceptable. 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 (MCT), very particularly preferably triglycerides of C ₆ -C ₁₂ fatty acids.

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

Specifically medium-chain triglycerides, as preferably used according to the invention as a carrier or excipient for the monoterpene-containing active substance, are in particular semi-synthetic 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 refers to mixtures of triglycerides of saturated fatty acids, mainly caprylic acid (octanoic acid) and capric acid (decanoic acid). Medium-chain triglycerides can generally be produced from oil which is extracted from the solid and dried part of the endosperm of Cocos nucifera L. and/or from the dried endosperm of Elaeis guineenses Jacq. For further details on the term medium-chain triglycerides, reference can be made, for example, to the Monograph Ph. Eur., 6th edition, basic work 2008, pages 4224 to 4226 , as well as the Journal of Nutritional Science, Volume 13, Issue 1/2, 1973, pages 6 ff., D. Sailer et al. “Medium-chain triglycerides - clinical physiology and application “).

According to the invention, it is preferred if the carrier or excipient is used in an active substance/carrier ratio in the range from 1,000:1 to 1:1,000, 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. By mixing the active substance (i.e. cineole, in particular 1,8-cineole) with the excipient, a significantly improved compatibility of the active substance with the other ingredients of the dosage form and improved stability, in particular storage stability, are achieved.

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

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 a single 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 other terpenes.

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

In this context, it can also be provided according to the invention that the composition contains the cineole, preferably 1,8-cineole, based on the composition, in relative amounts in the range of 0.0001 to 80 wt.%, in particular 0.001 to 75 wt.%, preferably 0.005 to 70 wt.%, preferably 0.01 to 60 wt.%, particularly preferably 0.05 to 55 wt.%, very particularly preferably 0.1 to 50 wt.%.

Finally, in this context, it can also be provided according to the invention that the at least one pharmaceutically acceptable and/or physiologically acceptable excipient (carrier) is miscible with 1,8-cineole and/or soluble therein. Preferably, the at least one pharmaceutically acceptable and/or physiologically acceptable excipient (carrier) can be in the liquid or solid, preferably liquid, state of aggregation at 20 °C and at atmospheric pressure. Likewise preferably, the at least one pharmaceutically acceptable and/or physiologically acceptable excipient (carrier) can be selected from the group of fatty acid esters, preferably triglycerides of fatty acids, particularly preferably medium-chain triglycerides (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 micellized form or in the form of a micellar dosage form. This can also ensure a particularly good release profile.

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

According to a further embodiment of 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 other active ingredient is selected from (i) anti-inflammatory agents (antiphlogistics), in particular non-steroidal anti-inflammatory drugs (NSAIDs) or steroidal anti-inflammatory drugs; (ii) analgesics; (iii) antipyretics; (iv) antibiotics; and combinations thereof.

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 possible within the scope of the present invention in particular to significantly increase the effect or efficiency of the other active ingredient, in particular in a synergistic manner, and to significantly reduce the dose amount used, combined with the associated advantages (e.g. avoidance or reduction of side effects or the like).

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

• 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 subjects:

• 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 accompanying (concomitant) 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 otorrhea.

The present invention also relates, according to the present aspect, 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 reducing 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 of the middle ear, preferably with accompanying (accompanying) otorrhea, 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 accompanying (accompanying) otorrhea,
however, excluding use in reducing pathogenic germs in the human intestine, in particular in the human intestinal flora, and/or however, excluding use in reducing the colonization of the human intestine, in particular the human intestinal flora, with pathogenic germs.

With regard to the above-mentioned items, reference can also be made to the above comments 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 thus associated with a multitude 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 further aspects of the invention, whereby these statements equally apply to the present first aspect of the invention.

A further subject matter 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, in particular inflammatory diseases of the middle and/or outer ear, preferably of 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) otorrhea.

In this context, the present invention also relates to the use of cineole, preferably 1,8-cineole, for producing a medicament or drug 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) otorrhea, and/or use of cineole, preferably 1,8-cineole, for producing a medicament or drug 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.

According to this aspect of the invention, the cineole, preferably 1,8-cineole, in particular the drug 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, in particular the drug or medicament or the composition, can be prepared for administration in pharmaceutically effective or therapeutically effective amounts. In addition, the cineole, preferably 1,8-cineole, in particular the drug or medicament or the composition, can be applied systemically or topically, in particular systemically, preferably orally. Furthermore, the cineole, preferably 1,8-cineole, in particular the drug or medicament, can generally 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 applied together with at least one further 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; and combinations thereof.

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

The present invention also relates - according to a third aspect of the present invention - to the inventive use of cineole, preferably 1,8-cineole, as an ear treatment agent or for producing 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 of 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) otorrhea.

According to this aspect of the invention, the cineole, preferably 1,8-cineole, in particular the drug or medicament or the composition or the ear treatment agent, can be administered in pharmaceutically effective amounts or therapeutically effective amounts. In this regard, the cineole, preferably 1,8-cineole, in particular the drug or medicament or the composition, can be prepared for administration in pharmaceutically effective or therapeutically effective amounts. In addition, the cineole, preferably 1,8-cineole, in particular the drug or medicament or the composition, can be applied systemically or topically, in particular systemically, preferably orally. Furthermore, the cineole, preferably 1,8-cineole, in particular the drug or medicament, can generally be applied or administered topically, in particular auricularly or into 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 further 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; and combinations thereof.

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

The present invention also describes a method 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 (associated) 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 accompanying (associated) otorrhoea,
wherein in the method a pharmaceutically effective or therapeutically effective amount of cineole, preferably 1,8-cineole, is administered to a patient suffering from inflammatory diseases of the ear and/or otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying (concomitant) otorrhea.

In this context, the cineole, preferably 1,8-cineole, can be administered in pharmaceutically effective amounts or can be prepared for administration in pharmaceutically effective or therapeutically effective amounts. In this regard, corresponding drugs or medicaments or compositions or ear treatment agents can equally be used for administering cineole, preferably 1,8-cineole. Also within the scope of this aspect of the invention, 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.

Optionally, 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 further active ingredient, in particular wherein 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 combinations thereof.

For further details of the method described here, reference can also be made to the statements on the aspects of the invention as described here, whereby these statements apply equally to the method described here.

The present invention also relates - according to a further aspect of the present invention - to the pharmaceutical or medicament according to the invention, in particular ear treatment agent, 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) 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 accompanying (accompanying) otorrhoea,
wherein the drug 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), and
wherein the medicinal product or medicament contains cineole, preferably 1,8-cineole, as the sole active ingredient and/or as a single active ingredient.

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

According to the invention, the medicinal product or drug contains cineole, preferably 1,8-cineole, as the sole active ingredient, in particular as the sole pharmaceutical active ingredient, or as a single active ingredient.

According to a particular embodiment according to this aspect of the invention, the pharmaceutical or medicament according to the invention can contain 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.

According to a further particular embodiment according to this aspect of the invention, it can equally be provided that the drug or medicament contains the cineole, preferably 1,8-cineole, free from other terpenes and/or wherein the drug or medicament contains no further terpene and/or wherein the drug or medicament is free from 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 pharmaceutical 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 medicament according to the invention contains the cineole, preferably 1,8-cineole, based on the pharmaceutical or medicament, 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-cineole and/or soluble therein, preferably wherein the at least one pharmaceutically acceptable and/or physiologically acceptable excipient (carrier) is in the liquid or solid, preferably liquid, state of aggregation at 20 °C and at atmospheric pressure 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 (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-cineole, or that the drug or medicament is not present and/or administered and/or prepared for administration in combination with other active ingredients other than cineole, preferably 1,8-cineole.

Furthermore, within the scope of the present invention, it can be provided that the drug or medicament does not contain any vitamin D receptor agonists (VDA), in particular any compounds of the vitamin D group, or that the drug or medicament is free of vitamin D receptor agonists (VDA), in particular free of compounds of the vitamin D group, or that 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.

In contrast, within the scope of this aspect of the invention, it can also be provided, if necessary, 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 further active ingredient. The further active ingredient can in particular 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; and combinations thereof.

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, in particular the drug or medicament or the composition, can be prepared for administration in pharmaceutically effective or therapeutically effective amounts. In addition, the cineole, preferably 1,8-cineole, in particular the drug or medicament or the composition, can be applied systemically or topically, in particular systemically, preferably orally. Furthermore, the cineole, preferably 1,8-cineole, in particular the drug or medicament, can generally 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, can be used or applied together with at least one further 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; and combinations thereof.

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

Yet another subject matter 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 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 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,
wherein the composition contains cineole, preferably 1,8-cineole, in particular together with at least one pharmaceutically acceptable and/or physiologically acceptable excipient (carrier), and
wherein the composition contains cineole, preferably 1,8-cineole, as the sole active ingredient and/or as a single active ingredient.

Within the scope of this aspect of the invention, it is therefore also provided that the composition contains cineole as the sole active ingredient, in particular as the sole pharmaceutical active ingredient, or as a single 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 from other terpenes.

In particular, the composition can contain cineole, preferably 1,8-cineole, free from other terpenes. In this regard, it can be the case that the composition contains no other terpene or that the composition is free from terpenes other than cineole, preferably 1,8-cineole. In particular, the composition can contain 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, based on the composition, in relative amounts in the range of 0.0001 to 80 wt.%, in particular 0.001 to 75 wt.%, preferably 0.005 to 70 wt.%, preferably 0.01 to 60 wt.%, particularly preferably 0.05 to 55 wt.%, most preferably 0.1 to 50 wt.%.

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-cineole and/or soluble therein, preferably wherein the at least one pharmaceutically acceptable and/or physiologically acceptable excipient (carrier) is in the liquid or solid, preferably liquid, state of aggregation at 20 °C and at atmospheric pressure 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 (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 drug 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, in particular the drug or medicament or the composition, can be prepared for administration in pharmaceutically effective or therapeutically effective amounts. In addition, the cineole, preferably 1,8-cineole, in particular the drug or medicament or the composition, can be applied systemically or topically, in particular systemically, preferably orally. Furthermore, the cineole, preferably 1,8-cineole, in particular the drug or medicament, can generally be applied or administered topically, in particular auricularly or in the ear.

According to the invention, it can be the case in particular that the composition does not contain any other active ingredients other than cineole, preferably 1,8-cineole, or that the composition is free from active ingredients other than cineole, preferably 1,8-cineole, or that 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 does not contain any vitamin D receptor agonists (VDA), in particular no compounds of the vitamin D group, or that the composition is free of vitamin D receptor agonists (VDA), in particular free of compounds of the vitamin D group, or that the composition is not present and/or administered in combination with vitamin D receptor agonists (VDA), in particular not in combination with compounds of the vitamin D group, and/or is not prepared for administration.

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 applied together with at least one further 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; and combinations thereof.

For further details on this aspect of the invention, reference can be made to the further explanations of the aspects of the invention described here, which Statements apply equally to the invention aspect 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 present invention describes 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 of the middle ear, preferably with accompanying (associated) 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 accompanying (associated) otorrhoea,
wherein the pharmaceutical combination comprises at least the following components (A) and (B):

1. (A) Cineole, preferably 1,8-cineole; and
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; and combinations thereof.

Also according to the pharmaceutical combination described here, 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 other active ingredient (B) can also be used or applied systemically.

According to a particular embodiment, it can be provided in particular that 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.

Furthermore, according to a further particular embodiment, it can be provided in particular that the pharmaceutical combination is 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 presented or prepared or administered as a kit (kit of parts).

In the present case, a kit or kit-of-parts is understood to mean in particular a unit or arrangement or compilation or combination of the two components (A) and (B), in which the two components (A) and (B) are separate and/or apart, in particular spatially separated and/or spatially separated, but are intended or administered as components that functionally belong together or are functionally assigned to one another.

For further details on the pharmaceutical combination described here, reference can be made to the statements on the aspects of the invention, which statements equally apply to the pharmaceutical combination described here.

• 1A/B 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 emerge from the following description of embodiments shown in the figures, as they are set out in more detail below. It shows:

• 1A /B a respective graphical representation in the form of pie charts of the bacterial colonisation 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 daily (administration period: 14 days, oral administration); the studies show clear shifts towards an increased physiological colonization of the ear, accompanied by a reduced colonization by pathogenic germs, with a particularly significant decrease also being observed 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 otorrhea, oral 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 representation 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 bacterial flora, 0 = no germs detected;
• 3 a graphical representation in the form of a bar chart with an exemplary representation of the temporal course of the development or the state of the germ flora in the ear canal of a patient (with chronic granulating otitis media and cholesteatoma as well as foetid otorrhea colonized by Proteus mirabilis) before and after treatment with 1,8-cineole, evaluating microbial swabs from the patient's ear canal before and after taking 200 mg 1,8-cineole three times a day (administration period: 14 days, oral 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 bacterial flora, 0 = no germs detected);
• 4 a schematic representation in the form of a bar chart illustrating 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, oral administration); evaluation based on a patient questionnaire of nine patients (in one patient both ears were examined and in the other patients one ear each); the bar chart refers to the situation after treatment with 1,8-cineole, according to which an improved situation (left bar) and a greatly improved situation (right bar) in relation to the severity of otorrhea were reported in seven cases;
• 5 a graphic representation in the form of a bar chart showing the development of colonization of the ear with germs based on microbial swabs from the ear canal of eight patients (one patient with two examined ears, see patients 3a and 3b) with chronic otitis media mesotympanalis or otitis media epitympanalis before and after administration of 200 mg 1,8-cineole three times daily (administration period: 14 days of oral 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 bacterial flora, 0 = no germs;
• 6 a graphic representation in the form of a bar chart with an exemplary illustration of the bacterial colonization before and after administration of 200 mg 1,8-cineole three times a day, with evaluation of microbial swabs from the ear canal in three patients before and after oral administration of 200 mg 1,8-cineole three times a day (administration period: 14 days, peroral administration); in these patients too, a reduction in inflammation with otorrhea was observed after administration of 1,8-cineole and an implant was inserted to improve hearing and thus quality of life; testing for pathogens and resistances in routine diagnostics and representation of the shift in microbial colonization based on the medical findings using the scale (y-axis) 5 = massive, 4 = abundant, 3 = moderate, 2 = isolated, 1 = physiological bacterial flora, 0 = no germs.

For further details on the embodiments and exemplary embodiments shown in the figures, in order to avoid unnecessary repetition, reference can also be made to the above statements and to the following supplementary statements on the exemplary embodiments, which apply accordingly with regard to the figures.

Further embodiments, modifications and variations as well as advantages of the present invention are readily apparent and achievable by the person skilled in the art upon reading the description, without departing from the scope of the present invention.

The following embodiments serve only to illustrate the present invention, without however limiting the present invention thereto.

EXAMPLES OF IMPLEMENTATION:

The following 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 patients affected by the disease as shown here.

In the treatment of patients described below, systemic 1,8-cineole in its pure form (together with an excipient based on medium-chain triglycerides (MCT), ie triglycerides of C ₆ -C ₁₂ fatty acids) is used as gastro-resistant, small intestine-soluble capsules (namely the commercial preparation Soledum ^® capsules or Soledum ^® forte capsules, distributed by Cassella-med GmbH & Co. KG or by Maria Clementine Martin Klosterfrau Vertriebsgesellschaft mbH, both in Cologne, Germany).

Example 1:

Bacterial colonization in otitis

In a pilot study, the pathogenic bacterial colonization of patients with otitis For this purpose, microbial swabs were taken from the ear canal of 22 patients with chronic otitis media mesotympanalis or epitympanalis and tested for pathogens and resistance in routine diagnostics. Colonization with pathogenic germs was found in the patients affected by chronic otitis. In patients with chronic otitis media mesotympanalis, in addition to the physiological bacterial flora, pathogenic germs in the form of Pseudomonas aeroginosa and stutzeri, as well as Proteus mirabilis and Staphylococcus aureus were found (although no germs could be detected in one patient). In patients with chronic otitis media epitympanalis in particular, in addition to the physiological bacterial flora, pathogenic germs in the form of Staphylococcus aureus and Stenotrophomonas maltophila were found (although no germs could be detected 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 pathogenic germs occur in patients with otitis media in a corresponding manner in connection with the disease.

Example 2:

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

Investigations of bacterial colonization from the ear 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 particularly chronic otitis media (mesotympanalis or epitympanalis) show clear shifts towards an increased physiological ear colonization, accompanied by a reduced colonization by pathogenic germs, with a particularly clear decrease also being observed for Pseudomonas aeroginosa, with a clear increase also being observed for the physiological bacterial flora. This can also be seen on 1A as well as 1B be referred to.

Example 3:

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

The extremely positive influence of 1,8-cineole on the inflammatory process and the bacterial colonization in the ear of patients with otitis, which was surprisingly found according to the invention, in particular with regard to a significant reduction in otorrhoea and a reduction in pathogenic germs in the ear, made it possible to carry out therapeutic operations on the ear of a patient within the framework of therapeutic applications ( 2 , see Patient 3 according to 5 ), which were not considered possible or were not feasible before the use of 1,8-cineole. 2 which shows the course of the underlying patient (with chronic otitis media mesotympanalis and chronic otorrhoea with colonization by a multi-resistant Pseudomonas aeroginosa germ) before and after taking 1,8-cineol. 2 In the case of the patients shown as examples, a cochlear implant was implanted after administration of 1,8-cineol to patients with previously antibiotic- and therapy-resistant pathogenic germs, with dry ears and physiological germ flora. This is all the more remarkable as the patient had a strong colonization with a multi-resistant Pseudomonas aeroginosa germ (in 2 referred to as MRGN (multi-resistant gram-negative pathogen) with resistance to three groups of antibiotics (3MRGN) or even to four groups of antibiotics (4MRGN).

Example 4:

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

Furthermore, 3 exemplary course of another patient (with chronic granulating otitis media and cholesteatoma as well as foetid otorrhea colonized by Proteus mirabilis) ( 3 , see Patient 5 according to 5 ). The patient presented with a medical history of multiple ear operations (over the past ten years) for recurrent cholesteatoma. After administration of 1,8-cineole, a tympanoplasty (type III) with Vibrant Soundbridge implantation was performed in the presence of physiological bacterial flora, with the operations being performed under antibiotic protection.

Example 5:

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

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

The patient collective was made up of patients aged between 27 and 75 years (30% female and 70% male). Before treatment, seven cases had chronic otitis media mesotympanalis, one case had a perforated eardrum, another had chronic Eustachian tube dysfunction, and yet another case had chronic otitis media mesotympanalis with mastoiditis, with the right ear being affected in four cases and the left ear in six cases. With regard to the underlying diseases, one case also had very severe hearing loss and six cases had severe hearing loss. One further case had moderate hearing loss and two cases had slight hearing loss.

As in 4 As shown, a significant improvement in otorrhoea ("wet ear") was found in the patient questionnaires (20% of cases reported occasional ear runny ear before therapy and 80% reported constant ("always") ear runny ear). In 70% of cases, it was reported that ear runny ear had improved after therapy. In 30% of cases, a strong improvement was even reported after therapy. A significant improvement was found, particularly with regard to the severe impairment of patients caused by a "wet ear" or otorrhoea.

Furthermore, the patient questionnaires also showed positive effects of the therapy with 1,8-cineole in terms of improving ear pain and the (feeling of) pressure in the ear. The evaluation of the questionnaires also showed that before the therapy, all patients had limitations in their everyday lives (namely 60% of patients had major limitations and 40% had very major limitations), while after the therapy, the patients were highly satisfied with the treatment. In particular, the limitations in everyday life were significantly reduced after the therapy, with 90% of patients reporting minor limitations and only 10% of patients still reporting very major limitations.

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

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

Example 6:

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

The effectiveness of 1,8-cineole in reducing pathogenic germs or pathogenic bacteria in patients with chronic otitis media is also being investigated on the basis of 5 which provides an overview of the patients examined in this regard. In particular, a reduction in pathogenic germs or pathogenic bacteria can be observed as a result of treatment with 1,8-cineole, and this even applies to multi-resistant pathogenic germs or bacteria.

Example 7:

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

Both 6 three patients mentioned as examples (see also relevant patients according to 5 ) treatment with 1,8-cineole resulted in a significant reduction in inflammation and infection with pathogenic germs, which made it possible to surgically insert a cochlear implant or a Vibrant Soundbridge implant. This in turn leads to a significant improvement in hearing and thus in the quality of life of the affected patients.

Example 8:

Overview of exemplary clinical disease and therapy courses Below is an overview of exemplary clinical disease and therapy courses and the successful influence of 1,8-cineole in relation to two patients.

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

Regarding the patient with chronic otitis media mesotympanalis, after two weeks of oral administration (preoperatively) of 200 mg 1,8-cineol three times daily for previously refractory otorrhea (local and systemic After administration of antibiotics (see section 4.1), a reduction in otorrhea was observed, which made ear surgery possible. After tympanoplasty, a renewed otorrhea with recurrent perforation was observed. After further administration of 200 mg of 1,8-cineole three times a day over a period of four weeks, a reduction in this otorrhea and spontaneous closure of the eardrum were also observed.

With regard to the patient with chronic otitis media epitympanalis or cholesteatoma, after preoperative administration of 200 mg of 1,8-cineole three times a day (duration of administration: 2 weeks, oral administration) in the case of previously therapy-refractory otorrhea (local and systemic antibiotics), a reduction in the accompanying otorrhea was observed, making an operation on the ear possible. In particular, there was a positive effect on the inflamed mucous membrane of the middle ear and with regard to a mastoid (although the cholesteatoma masses were not significantly reduced, however - and this is relevant for therapy - the inflammatory nature and aggressiveness of the inflammation of the cholesteatoma could be inhibited or treated). In the post-tympanoplasty condition, otorrhea with recurrent perforation occurred; after administration of 200 mg of 1,8-cineole three times daily (administration period: 4 weeks, peroral administration), the otorrhea subsided and the tympanic membrane spontaneously closed in this case as well.

Example 9:

Further information on patient data and examinations

In industrialized nations, otitis media is one of the diseases that most frequently leads to visits to the doctor, prescriptions of antibiotics and operations. Chronic recurrent inflammation of the middle ear (COM) results in significant effects on the quality of life of patients, e.g. through ear discharge, hearing loss, delayed speech development, etc., and even total deafness and dizziness. The particularly aggressive form, cholesteatoma (cf. chronic otitis media epitympanalis), behaves like a malignant tumor, because it evades antibiotic therapy through progressive inflammatory destructive processes in the middle ear and destroys the surrounding structures.

The patient population that was treated with Soledum ^® forte capsules preoperatively and in individual cases postoperatively as part of the present invention was recruited from this collective. 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 the overall success of the operation into question.

Surprisingly, otitis media, particularly middle ear infections, with chronic runny ears, could be successfully treated with Soledum ^® forte capsules. Patients with very persistent otorrhea due to chronic otitis media mesotympanalis or epitympanalis were successfully treated with Soledum ^® forte capsules (three times 1 capsule each containing 200 mg 1,8-cineole daily) over a period of 14 days. In all preoperative cases, there was a significant reduction in otorrhea, so that a timely operation was possible and was then successful in each case. In some cases, patients were also successfully treated postoperatively with Soledum ^® forte capsules.

Surprisingly, treatments with Soledum ^® forte capsules in patients with often long-standing chronic otitis media mesotympanalis with accompanying otorrhea and complete resistance in the antibiogram for pathogens carried out by the microbiology department before therapy were also successful.

Overall, based on the applicant's surprisingly discovered findings, cineole, in particular 1,8-cineole, is therefore efficiently suitable for use in 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, 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 (46)

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 otorrhea, 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 accompanying otorrhea. Cineole, preferably 1,8-cineole, after claim 1 , 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 otorrhea. Cineole, preferably 1,8-cineole, after claim 1 or 2 , for use in the prophylactic and/or therapeutic treatment of otitis media with accompanying otorrhea. Cineole, preferably 1,8-cineole, according to one of the preceding claims, for use in reducing the load and/or the number of pathogenic germs, in particular pathogenic bacteria, located 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 of pathogenic germs, in particular pathogenic bacteria, located 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 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 otorrhea. Cineole, preferably 1,8-cineole, for use according to one of the preceding claims, wherein the cineole, preferably 1,8-cineole, is used or employed to reduce the load and/or the number of germs, in particular pathogenic bacteria, located in the ear, in particular in the middle and/or outer ear, preferably in the middle ear; and/or where the cineole, preferably 1,8-cineole, is used or employed to reduce the proportion of pathogenic germs, in particular pathogenic bacteria, located in the ear, in particular in the middle and/or outer ear, preferably in the middle ear; and/or wherein the pathogenic germs are selected from the group of germs that cause and/or exacerbate inflammatory diseases of the ear, in particular inflammatory diseases of the middle and/or outer ear, preferably the middle ear, preferably with accompanying otorrhea, and/or otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying otorrhea, and/or are associated with this; and/or wherein 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. Cineole, preferably 1,8-cineole, for use according to one of the preceding claims, wherein the cineole, preferably 1,8-cineole, is further and/or additionally and/or equally used or employed to increase the number, proliferation or support of physiological germs, in particular physiological bacteria, located and/or localized in the ear, in particular in the middle and/or outer ear, preferably in the middle ear. Cineole, preferably 1,8-cineole, for use according to one of the preceding claims, wherein the disease is a therapy-refractory and/or therapy-resistant, in particular drug- and/or pharmaceutical-resistant, preferably antibiotic-resistant, disease. Cineole, preferably 1,8-cineole, for use according to one of the preceding claims, wherein the disease is a therapy-refractory and/or therapy-resistant, in particular drug- and/or pharmaceutical-resistant, preferably antibiotic-resistant, disease. Cineole, preferably 1,8-cineole, for use according to any one of the preceding claims, wherein the otitis is acute otitis or chronic otitis, in particular chronic otitis, preferably chronic polypous otitis or chronic granular otitis. Cineole, preferably 1,8-cineole, for use according to any one of the preceding claims, wherein the otitis is a recurrent otitis or chronic recurrent otitis, in particular a chronic otitis, preferably a chronic polypous otitis or a chronic granular otitis. Cineole, preferably 1,8-cineole, for use according to any one of the preceding claims, wherein the otitis is an otitis media epitympanalis or an otitis media mesotympanalis, preferably an otitis media epitympanalis. Cineole, preferably 1,8-cineole, for use according to 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 otorrhea, preferably otitis media epitympanalis, is accompanied by or is associated with inflammatory mediation, in particular upregulation and/or increased production or increased release of particularly proinflammatory cytokines, preferably TNF-alpha and/or interleukin-1, preferably TNF-alpha. Cineole, preferably 1,8-cineole, for use according to one of the preceding claims, wherein the cineole, preferably 1,8-cineole, exerts a suppressive or attenuating effect against an inflammatory mediation occurring in the context of inflammatory diseases of the ear and/or otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying otorrhea, preferably otitis media epitympanalis, in particular wherein the cineole, preferably 1,8-cineole, causes and/or induces a down-regulation and/or a reduced production and/or a reduced secretion of in particular pro-inflammatory cytokines, preferably TNF-alpha and/or interleukin-1beta, preferably TNF-alpha. Cineole, preferably 1,8-cineole, for use according to one of the preceding claims, wherein the cineole, preferably 1,8-cineole, is furthermore and/or additionally and/or equally used or employed as an anti-inflammatory active agent, in particular as a locally and/or systemically acting anti-inflammatory active agent. Cineole, preferably 1,8-cineole, for use according to one of the preceding claims, wherein the cineole, preferably 1,8-cineole, is furthermore and/or additionally and/or equally used or employed for the prevention and/or avoidance and/or for the prophylactic and/or therapeutic treatment of secondary and/or concomitant diseases associated with and/or caused by inflammatory diseases of the ear and/or otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying otorrhea, in particular selected from the group of mastoisitis, labyrinthitis, meningitis, sinus vein thrombosis, sepsis, facial nerve paralysis and tinnitus, and combinations thereof. Cineole, preferably 1,8-cineole, for use according to one of the preceding claims, wherein the cineole, preferably 1,8-cineole, is used or employed preoperatively and/or for preoperative preparation and/or to enable surgical interventions, in particular therapeutic-surgical interventions, on the ear, in particular on the middle and/or outer ear, preferably on the middle ear, such as tympanoplastic operations and/or implantation operations. Cineole, preferably 1,8-cineole, for use according to one of the preceding claims, wherein the cineole, preferably 1,8-cineole, is used or employed postoperatively and/or for the postoperative aftercare of surgical interventions, in particular therapeutic-surgical interventions, on the ear, in particular on the middle and/or outer ear, preferably on the middle ear, such as tympanoplastic operations and/or implantation operations. Cineole, preferably 1,8-cineole, 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 otorrhea, and/or for use in the prophylactic and/or therapeutic treatment of otitis interna and/or otitis media with accompanying inner ear inflammation, in each case preferably with accompanying otorrhea. Cineole, preferably 1,8-cineole, for use according to one of the preceding claims, wherein the otitis is an otitis interna and/or an otitis media with accompanying inner ear inflammation, in each case preferably with accompanying otorrhea. Cineole, preferably 1,8-cineole, for use according to one of the preceding claims, but excluding use in reducing pathogenic germs or pathogenic agents in the human intestine, in particular in the human intestinal flora, and/or but excluding use in reducing the colonization of the human intestine, in particular the human intestinal flora, with pathogenic germs or pathogenic agents. Cineole, preferably 1,8-cineole, for use according to one of the preceding claims, wherein the cineole, preferably 1,8-cineole, is administered systemically, in particular orally or parenterally, preferably orally, and/or wherein the cineole, preferably 1,8-cineole, is prepared for systemic, in particular orally or parenterally, preferably orally, administration. Cineole, preferably 1,8-cineole, for use according to one of the preceding claims, wherein the cineole, preferably 1,8-cineole, is administered in the form of a dosage form to be administered orally and/or wherein the Cineole, preferably 1,8-cineole, in a dosage form for oral administration. Cineole, preferably 1,8-cineole, for use according to one of the preceding claims, wherein the cineole, preferably 1,8-cineole, is administered as a gastric juice-resistant but small intestine-soluble systemic dosage form, preferably as a capsule, dragee, pill, tablet or the like, and/or wherein the cineole, preferably 1,8-cineole, is prepared for administration as a gastric juice-resistant but small intestine-soluble systemic dosage form, preferably capsule, dragee, pill, tablet or the like. Cineole, preferably 1,8-cineole, for use according to any of the Claims 1 until 20 , wherein 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, and/or wherein the cineole, preferably 1,8-cineole, is prepared in a dosage form to be administered topically, in particular auricularly and/or in the ear. 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, is prepared 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 prepared for administration at a daily dose in the range of 1 mg/diem to 5,000 mg/diem, in particular in the range of 2 mg/diem to 3,000 mg/diem, preferably in the range of 5 mg/diem to 2,500 mg/diem, preferably in the range of 10 mg/diem to 2,000 mg/diem, particularly preferably in the range of 50 mg/diem to 1,500 mg/diem, very particularly preferably in the range of 100 mg/diem to 1,200 mg/diem, further preferably in the range of 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. 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. Cineole, preferably 1,8-cineole, for use according to one of the preceding claims, wherein the cineole, preferably 1,8-cineole, is present and/or administered in or in the form of a composition, in particular a pharmaceutical composition, in particular together with at least one pharmaceutically acceptable and/or physiologically acceptable excipient; wherein the composition contains the cineole, preferably 1,8-cineole, as the sole active ingredient, in particular as the sole pharmaceutical active ingredient, 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 of 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 in liposome-enclosed and/or liposomally packaged form. Cineole, preferably 1,8-cineole, for use according to one of the preceding claims, wherein the cineole, preferably 1,8-cineole, is present and/or administered and/or prepared for administration as a single active ingredient and/or as a monopreparation; and/or where the cineole, preferably 1,8-cineole, is present and/or administered and/or prepared for administration without and/or in the absence of further active ingredients, different from cineole, preferably 1,8-cineole. 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 otorrhea. Cineole, preferably 1,8-cineole, for use in the prophylactic and/or therapeutic treatment of otitis media with accompanying otorrhea. Cineole, preferably 1,8-cineole, for use in reducing the load and/or number of pathogenic germs present 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 of pathogenic germs present 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 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 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 otorrhea, 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 accompanying otorrhea, but excluding use in reducing pathogenic germs in the human intestine, in particular in the human intestinal flora, and/or but excluding use in reducing the colonization of the human intestine, in particular the human intestinal flora, with pathogenic germs. 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 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 otorrhea. Use of cineole, preferably 1,8-cineole, for producing a medicament or drug 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 otorrhea, and/or use of cineole, preferably 1,8-cineole, for producing a medicament or drug for the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying 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 of the middle ear, preferably with 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 otorrhea. Use of cineole, preferably 1,8-cineole, for producing 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 of the middle ear, preferably with accompanying otorrhea, and/or use of cineole, preferably 1,8-cineole, for producing 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 otorrhea. Drug or medicament, in particular 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 otorrhea, and/or for the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with accompanying otorrhea, wherein the drug or medicament, in particular antiviral agent, contains cineole, preferably 1,8-cineole, together with at least one pharmaceutically acceptable and/or physiologically acceptable excipient, and wherein the drug or medicament contains the cineole, preferably 1,8-cineole, as the sole active ingredient and/or as a single active ingredient. Medicine or drug, especially ear treatment product, after claim 40 , wherein the drug or medicament 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, most particularly preferably at least at least 99% by weight, more preferably at least 99.5%, based on the cineole, preferably 1,8-cineole, and/or preferably free from other terpenes. Medicinal product or drug, in particular ear treatment product, according to one of the Claims 40 until 41 , wherein the drug or medicament does not contain any other active ingredients other than cineole, preferably 1,8-cineole, and/or wherein the drug or medicament is free from active ingredients other than cineole, preferably 1,8-cineole, and/or wherein the drug or medicament is not present and/or administered and/or prepared for administration in combination with other active ingredients other than cineole, preferably 1,8-cineole. Composition, in particular pharmaceutical composition, 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 otorrhea, and/or for the prophylactic and/or therapeutic treatment of otitis, in particular otitis media and/or otitis externa, preferably otitis media, preferably with 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, and wherein the composition contains the cineole, preferably 1,8-cineole, as the sole active ingredient and/or as a single active ingredient. Composition, in particular pharmaceutical composition, according to claim 43 , 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. Composition, in particular pharmaceutical composition, according to one of the Claims 43 or 44 , wherein the composition does not contain any other active ingredients other than cineole, preferably 1,8-cineole, and/or wherein the composition is free from active ingredients other than cineole, preferably 1,8-cineole, and/or wherein 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. Cineole, preferably 1,8-cineole, for use according to any of the Claims 1 until 37 , Use according to one of the Claims 38 until 41 , medicinal product or drug according to any of the Claims 40 until 42 and composition according to one of the Claims 43 until 45 , wherein the cineole, preferably 1,8-cineole, in particular the drug or medicament or the composition, is prepared for administration 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 administered systemically or topically, in particular systemically, preferably orally.

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