WO2018153514A1

WO2018153514A1 - Composition, especially gel, for use in the urogenital tract

Info

Publication number: WO2018153514A1
Application number: PCT/EP2017/079332
Authority: WO
Inventors: Andreas Meier
Original assignee: Farco-Pharma Gmbh
Priority date: 2017-02-24
Filing date: 2017-11-15
Publication date: 2018-08-30
Also published as: DE202017101350U1; DE102017105010A1

Abstract

The present invention relates to a composition, especially a pharmaceutical composition, which is suitable for the prophylactic and/or therapeutic, especially topical treatment of the urethra for avoiding and/or reducing scars and/or urethral strictures, preferably during and/or after surgical and/or transurethral interventions.

Description

Composition, in particular gel, for use on the genitourinary tract

The present invention relates to the medical field of urology, in particular the field of urological, in particular transurethral interventions or operations.

In particular, the present invention relates to a composition which is preferably suitable for the prophylactic and / or therapeutic treatment of the urethra for the prevention and / or reduction of scars and / or urethral strictures. In addition, the present invention is the use of the composition according to the invention. Furthermore, the present invention relates to a container, a catheter or a syringe, each containing the composition according to the present invention. In addition, the subject of the present invention is a packaging unit or a kit which contain the composition according to the invention.

The urinary organs (Organia urinia) designate a group of organs which serve for the formation and excretion of urine. Together with the sex organs, the urinary organs are summarized as genitourinary tract. The urinary organs include in humans and in most vertebrates kidneys, ureters, urinary bladder and urethra. The urine formed in the kidneys arrives at the urinary bladder via the ureter. The output to the outside finally takes place via the urethra. The urethra is a membranous-muscular tube, which is lined from the inside with urothelium (transitional epithelium). From the inside to the outside follow on the urothelium elastic connective tissue and a blood vessel network (stratum spongiosum), which in turn is surrounded by smooth muscle. The embedding of the urethra in the surrounding tissue is carried out by another outer connective tissue. In women, the urethra is only about 2.5 to 5 cm long, whereas the male urethra has a length of about 20 to 25 cm.

The urethra, especially the inner layer of urothelium, is extremely sensitive, so that it can come due to external mechanical influences as well as due to endogenous causes, such as inflammation, to injuries or changes to the tissue. For reasons of precaution, but also for therapeutic reasons, the implementation of so-called transurethral interventions on the urinary tract, in particular the urethra, may be necessary. Interventions of this kind may, for example, be catheterizations of the urinary bladder for the discharge of urine. Catheterizations are performed especially after surgery for a limited period or incontinence over a longer period. The problem with catheterizations is, in particular, that injuries and injuries to the urothelium and, in addition, inflammation due to infiltration of pathogens can occur.

Furthermore, instrumental interventions on the prostate, such. For example, suprapubic adenoma enucleation, transurethral prostate resection and transurethral incision of the prostate, transurethral, d. H. via the urethra, performed. In addition, interventions on the bladder or kidneys can also be performed by transurethral route, e.g. Bladder or bladder neck resections or kidney stone removal. Even instrumental surgery or catheterization via the urethra can cause damage and injury to the urothelium as well as infiltrating pathogens.

In addition, interventions on the urethra itself, especially in the context of the removal of strictures of the urethra by scarring or urethral strictures may be required. This can on the one hand by bougienage, d. H. a blind dilatation of the urethra, done. On the other hand, urethral strictures can be treated by a so-called slit. Both bougienage and slitting result in urethral urethral injury, and there is also a risk of inflammation due to invasive pathogens.

Overall, there is a considerable risk of inflammation, wound healing problems and pronounced scar formation in transurethral surgery, which in turn can lead to narrowing of the urethra or urethral stricture. The stronger the constriction, the greater the pressure that must be exerted to empty the void (micturition). In the worst case, stricture or stricture due to scarring of the urethra may lead to complete urinary retention. The wound healing of the urothelium in injuries, which can occur in the context of transurethral interventions, takes place in three phases, which may partially overlap. The first phase of wound healing is a cleansing phase in which inflammatory processes in the area of the wound occur. This is followed by the granulation or proliferation phase in which new tissue structures are formed. During this phase, new vessels are created and granulation tissue is formed, so that the wound can be supplied with blood, oxygen and nutrients. Subsequently, the epithelization phase occurs, in which the wound contracts, forming a denser network of collagen fibers ("contraction").

With regard to wound healing, both too little and too much moisture in the area of the wound is unfavorable for the healing process. If the wounds are too dry, growth factors or enzymes are inactivated by the fluid deficiency or reach their target sites only poorly. If the conditions are too humid, fluid congestion can occur, which is also detrimental to supplying the tissue with oxygen and nutrients. In terms of wound healing, it is thus desirable to optimize or balance the moisture content in the wound. A slowed wound healing also promotes a pronounced scarring.

In particular, scarring on the urothelium after transurethral surgery is a common problem as it can lead to constrictions, also referred to as urethral strictures. As previously mentioned, a wound is caused by the so-called contraction, i. H. a contraction of the wound edges during the epithelization phase, closed. Epithelialisation can lead to the formation of keloids and hypertrophic scars. These are benign connective tissue augmentations of the skin, which are the result of a disturbed interaction between cytokines, cells and the extracellular matrix or an increased fibroblast proliferation in the context of the healing process.

In addition, wound healing can be impaired by inflammatory processes, in particular as a result of infiltration of pathogens. By inflammation, on the one hand, the wound healing process is delayed and, on the other hand, increased scarring and thus the formation of urethral strictures is favored. Overall, the known in the prior art measures for the treatment of urethral structures, ie in particular the slit or bougienage, often not to the desired result. On the one hand, they are complex in use and on the other hand associated with a high recurrence rate, so they often have to be repeated several times. In addition, the treatments are painful for the patient and require long-term follow-up care.

In addition, there is a lack of measures that prevent or reduce the occurrence of scars or urethral strictures already preventive or prophylactic, so that the above-mentioned surgical measures or transurethral interventions for the treatment of the urethra are not even necessary. Thus, the present invention has for its object to provide a conception for the prophylactic or therapeutic treatment of the urethra, which avoids the aforementioned disadvantages of the prior art, or at least partially mitigates. In particular, the present invention has for its object to provide easy-to-use measures which prophylactic or therapeutic treatment of the urethra to prevent scars or

Urethral strictures or for the treatment of existing scars or

Urethral stricture and also lead to improved wound healing and a reduction in the risk of inflammation.

To achieve the object described above, the present invention proposes a composition according to claim 1; Further advantageous embodiments are the subject of the relevant dependent claims.

Another object of the present invention is also the use of a composition according to the invention according to the relevant independent claim. Another object of the present invention is also a container according to the invention, which contains a composition according to the invention, according to the relevant independent claim; Further advantageous embodiments are the subject of the relevant dependent claim. Yet another object of the present invention is a syringe according to the invention, which contains a composition according to the present invention, according to the related independent claim. A further subject of the present invention is also a catheter according to the invention, which contains a composition according to the present invention, according to the related independent claim.

In addition, the present invention is a packaging unit according to the invention according to the relevant independent claim.

Finally, the subject of the present invention is a kit according to the invention according to the related independent claim. It goes without saying that the following special embodiments, embodiments or the like, which are described only in connection with an aspect of the invention, apply mutatis mutandis in relation to the other aspects of the invention without this expressly needs mention.

Furthermore, it must be noted in the context of the present invention that those skilled in the art should select each of the abovementioned relative or percentage, in particular weight-related quantities, that the sum of the respective ingredients, active ingredients, additives or auxiliaries or the like is always 100%. result. This is understood by the skilled person but by itself.

Incidentally, the person skilled in the art may deviate from the number, range or quantity information given below, based on the application or the individual case, without departing from the scope of the present invention.

In addition, it is true that all the parameter information or the like mentioned below can in principle be determined or determined using standardized or explicitly stated determination methods or else determination methods familiar to the person skilled in the art. The present invention is thus - according to a first aspect of the invention - a composition, in particular a pharmaceutical composition, preferably for the prophylactic and / or therapeutic, especially topical treatment of the urethra to avoid and / or reduce scars and / or urethral strictures, preferably at and / or after surgical and / or transurethral surgery,

wherein the composition - in each case effective, in particular pharmaceutically effective amounts - as active ingredients, in particular in combination,

(a) onion extract (extract Bulbus cepae) and / or its ingredients ("component (a)");

(B) at least one surface disinfectant, in particular polyhexanide and / or its physiologically acceptable salts, ("component (b)");

(c) optionally panthenol and / or its physiologically tolerated esters and / or pantothenic acid and / or their physiologically tolerated salts, in particular panthenol and / or its physiologically tolerable esters, preferably dexpanthenol, ("component (c)"); and

(d) optionally at least one ectoine derivative, in particular ectoine and / or hydroxyectoine and / or its physiologically acceptable salts, ("component (d)");

contains.

The Applicant has surprisingly found that with a combination of active ingredients based on onion extract or its ingredients and polyhexanide and optionally panthenol or pantothenic acid and ectoine derivatives pharmaceutical compositions for topical application in the urethra can be provided, which in a very efficient way the formation of urethral strictures or Avoid or reduce scars on the urothelium, especially during or after transurethral surgery. In other words, with the composition according to the invention, a (renewed) scar formation after transurethral surgery can be controlled or prevented. In addition, on the basis of the combination of active ingredients, inflammation can be prevented and wound healing can be accelerated. The terms "pharmaceutical composition", "pharmaceutical preparation" or the like as used in the present invention are to be understood as being very comprehensive and not only pharmaceutical preparations but also so-called medical products, homeopathic agents, cosmetics or the like ,

The active substance onion extract used according to the invention, also referred to as "extract Bulbus cepae" or "Extractum cepae", is in particular an extract obtained from kitchen onions (botanical Allium cepa). Onion extract is rich in essential oils, thio compounds, flavonoids, especially quercetin, selenium compounds, fructosans and other polyphenols and has a scar-reducing effect. It is assumed in the context of the present invention that the scar reduction is triggered by an inhibition or reduction of the fibroblast proliferation, so that the uncontrolled formation of new tissue is prevented during the application of the composition according to the invention. In addition, onion extract has antimicrobial, anti-inflammatory and antioxidant effects. The aforementioned effects of the onion extract are also based on antioxidant effects as well as the lonenwirkung or osmoregulatory mode of action of the ingredients of the onion extract in the area of the wound - without wishing to be limited to this theory. On this basis, the environmental conditions on the urothelium are improved so that a reliable supply of the tissue or cells to be newly formed takes place with oxygen and nutrients. In particular, the fructans contained in the onion extract - also without wishing to be limited to this theory - act as osmoregulans and on this basis create physiological prerequisites for cell structure and mass transport. In addition, a "displacement effect" prevents the attachment of pathogens, in particular bacteria, to the cells of the urothelium.

The polyhexanide used according to the invention has an antiseptic or antimicrobial action. In chemical terms, the active ingredient polyhexanide is generally polyhexa-methylene biguanide (PHMB), which is also referred to as poly (iminocarbonylimidoyl-iminocarbonylimidoylimino-1,6-hexanediyl) hydrochloride or polyhexanide, and in particular the empirical formula C8H 17N5 and Molecular weight of 183.25 g / mol. Particularly advantageous with respect to polyhexanide is its broad spectrum of activity, which is also directed against the difficult-to-treat hospital germs, such as Staphylococcus aureus. In addition, polyhexanide is effective in extremely low concentrations as it binds directly to the bacterial cell wall and damages it to such an extent that it usually causes cell death. In this way, the effective use of this antiseptic is made possible even in low concentrations, which reduces the risk of the occurrence of side effects accordingly. In addition, polyhexanide is characterized by low systemic absorption, which also minimizes side effects.

The fact that Zwie with extra kt on the one hand and polyhexanide on the other hand in the context of the treatment of the urethra to an excellent efficacy in terms of the prevention of scars and inflammation and beyond accelerate wound healing was quite surprising. Especially with regard to the respective antiseptic mode of action, onion extract and polyhexanide complement each other synergistically.

As far as the active ingredient "panthenol" is concerned, which may optionally be present in the compositions, for the purposes of the present invention this is understood as meaning a chemical compound which belongs to the polyols and amides and has the systematic name 2,4-dihydroxy-N- (3 - hydroxypropyl) -3,3-dimethylbutyramide carries. According to the invention, "panthenol" also means panthenol derivatives, such as esters. In particular, D (+) - panthenol, colloquially also referred to as dexpanthenol, is used in the context of the present invention. The active ingredient develops in the context of the treatment according to the invention in particular a wound healing effect. The wound-healing-promoting effect results - without wishing to be limited to this theory - from the water-binding capacity of panthenol, which leads to moistening of the wound area in the urethra. Panthenol is enzymatically converted into pantothenic acid in the body, which is also known as vitamin B5 and, as a component of coenzyme A, plays a central role in (mucous) skin metabolism. Consequently, in the context of the present invention, pantothenic acid, in which it is chemically N- (2,4-dihydroxy-3,3-dimethyl 1-oxobutyl) -beta-alanine, wherein according to the invention the (R) -form is particularly preferred; especially in the As part of the composition according to the invention pantothenic acid can be used in the form of their physiologically acceptable salts.

The absorption of panthenol or pantothenic acid after topical application increases the moisture retention capacity and, as a consequence, also the elasticity of the treated mucosa. Panthenol or pantothenic acid also supports the formation of mucosal cells within the scope of the present invention, resulting in faster regeneration of damaged tissue. In addition, panthenol and pantothenic acid are anti-inflammatory. For further details on the active ingredient (b) can be made in particular Römpp Chemielexikon, 10th edition, 1999, Georg Thieme Verlag, Stuttgart / New York, keywords "Panthenol" and "Dexpanthenol", pages 927 and 3107-3108, and on the literature referenced therein, the content of which is hereby incorporated by reference in its entirety.

When used in the context of the present invention, component ectoine and hydroxyectoine are chemically to (4S) -2-methyl-1, 4,5,6-tetra ^", hydro-pyhmidin-4-carbo ^-, xysäure.

The ectoine or hydroxyectoin used according to the invention is a natural product belonging to the group of compatible solutes and has strongly water-binding properties. Ectoin occurs in halo or extremophilic bacteria. Without wishing to be bound by theory, Ectoin stabilizes the natural structure of biopolymers, such as proteins, nucleic acids and biomembranes, and protects the skin or mucosa from damage. Ectoin ensures a sustainable hydration, especially when used on mucous membranes. For further comments in this respect with regard to ectoine, in particular with respect to its preparation, reference may be made to the European patent EP 0 887 418 B1, the entire disclosure of which is hereby incorporated by reference.

In the context of the present invention, it was completely surprising that onion extract on the one hand and polyhexanide on the other hand in connection with the reduction or reduction of scar formation, in particular in connection with prophylactic and / or transurethral interventions, in terms of their effectiveness complement each other so that the scarring significantly reduced and the need for surgical or surgical procedures to treat urethral strictures. In addition, inflammation can be prevented and wound healing can be accelerated. The efficiency of action can also be surprisingly increased by the additional use of panthenol or ectoine (derivatives).

The compositions according to the present invention have numerous advantages and particularities, which are described below and which serve as an indication of the existence of an inventive step:

The excellent effectiveness of the onion extract in the compositions according to the invention results - without wishing to be limited to this theory - from the mode of action of the numerous ingredients of onion extract in combination with the other components. Onion extract contains, as stated before, among others fructosans, flavonoids, numerous minerals, polyphenols, selenium compounds and thio compounds. In the context of the use according to the invention, Zwie develops a physicochemical effect on extra kt or its ingredients, as explained below. On the one hand, Zwie acts as an osmoregulan in extra kt and on this basis creates optimal physiological prerequisites for the formation of new tissue structures and the necessary mass transfer. By the other components used according to the invention, in particular panthenol, ectoine and osmotically active substances, the osmoregulatory effect can be increased even further, which leads in particular to accelerated wound healing.

In addition, onion extract has an antioxidant effect, ie the cells are protected against aggressive radical reactions in their environment. In addition, onion extract prevents the formation of extracellular proteoglycans from fibroblasts, so that in particular hypertrophic scars and keloids, ie unwanted forms of scarring, is prevented. Also, fibroblasts are inhibited by onion extract growth (mitogenic inhibitory effect). Furthermore, onion extract acts antiphlogistic, ie the release of inflammatory mediators is prevented. The advantageous effects of onion extract are significantly enhanced by the other active ingredients and auxiliaries of the compositions according to the invention, ie polyhexanide and optionally panthenol and ectoine. On the basis of the combination of active substances according to the invention, occurrence of urinary tract infections or inflammations, in particular after transurethral interventions or catheterizations, is furthermore effectively prevented, since the combination of onion extract and polyhexanide according to the invention has, in addition to the scar-reducing effect, also outstanding antiinflammatory or antiinflammatory and antimicrobial properties ,

In addition, the wound healing promoting effect of the composition according to the invention can be further increased by the additional, optional use of dexpanthenol and ectoine. Without wishing to be limited to this theory, the use of dexpanthenol or ectoine increases the water binding capacity at the urothelium, since panthenol and ectoin act as moisture-retaining osmoregulatory substances. On this basis, a moist wound environment is created, so that a mass transport and a supply of the damaged tissue with oxygen and nutrients can be maintained.

On the basis of the ingredients of the composition according to the invention, a protective gel film is formed on the urothelium, which further improves the wound environment, since the supply of the wounds with oxygen, nutrients and the like is further improved. In addition, the wounds are shielded or protected from passing urine. The formation of a gel film also extends the residence time of the active ingredients used according to the invention at the destination. The film formation on the urethral epithelium can be further increased by the targeted use of gelling agents in the form of hydroxyethyl cellulose.

In addition, the recurrence rate with respect to the repeated occurrence of urethral strictures is reduced with the composition according to the invention, since - without wishing to be limited to this theory - the cause of urethral strictures, namely the scarring, especially at the urothelium of the urethra, is combated even before their formation.

In addition, the composition according to the invention is particularly uncomplicated in its application and handling, in particular in comparison with the methods for treating urethral strictures known from the prior art, since it is generally applied purely topically. In addition, the use or the application of the composition according to the invention for the patient with significantly less inconvenience, such as pain, long-term treatment or spontaneously occurring complications. Furthermore, the composition in question is characterized by its particularly good compatibility, since the ingredients are generally free of side effects. In fact, onion extract is a purely herbal natural substance that is at least substantially free of chemical modifications and generally does not trigger allergic reactions or intolerances in humans. The other active ingredients polyhexanide, panthenol or pantothenic acid and ectoine are usually free of significant side effects.

In connection with the advantages and special features of the compositions according to the invention described above, reference is made at this point to the efficacy studies carried out by the Applicant, which demonstrate the aforementioned effects in an impressive manner and are described in detail below. The present invention and its preferred embodiments are described in detail below.

As far as the amount of onion extract used or its ingredients and / or component (a) is concerned, this can vary within wide ranges. Particularly good results in terms of effectiveness are achieved when the composition of component (a) in an amount in the range of 0.00001 to 7 wt .-%, in particular 0.0001 to 5 wt .-%, preferably 0.001 to 2 Wt .-%, preferably 0.005 to 1 wt .-%, particularly preferably 0.01 to 0.5 wt .-%, based on the composition contains.

With regard to the quality of the compositions according to the invention, it is also advantageous if the onion extract or its ingredients are used in the form of a defined extract or are present in the compositions. It has proven particularly suitable in this regard if component (a) is used in the form of dry extract, thick extract, spissum extract and / or fluid extract, in particular in the form of fluid extract and / or thick extract, preferably fluid extract. A particularly constant good quality is obtained if the Zwie is used for extra kt in the form of a fluid extract. In this regard, it may in particular be provided that the fluid extract used in the compositions is provided as component (a) by redilution of a thickness extract, wherein the extractant for the thick extract is preferably water. As solvent for the re-dilution, an ethanol / water mixture which contains 13 to 17% by volume of ethanol has proven to be particularly suitable. Preferably, the onion extract is provided from the plant Allium cepa L.

Furthermore, it has proved to be advantageous if component (a) or the onion extract has a defined drug / extract ratio (DEV). In particular, it can be provided that component (a) has a drug / extract ratio in the range from 10: 1 to 1: 100, in particular in the range from 5: 1 to 1:50, preferably in the range from 2: 1 to 1 : 10, preferably in the range of 1: 1 to 1: 5. Likewise, it can be provided in the context of the present invention that component (a) has a drug / extract ratio of at least 1:50, in particular at least 1:10, preferably at least 1: 5, preferably at least 1: 4, particularly preferably at least 1: 2, has. The so-called drug / extract ratio (DEV) characterizes the (weight-related) ratio of starting drug used to extract obtained. The drug / extract ratio (DEV) thus indicates from which weight-related amount of drug used (eg bulb plants or onions) which weight-related amount of extract is obtained. A drug / extract ratio, for example, of 10: 1 means that one part by weight of extract was obtained from ten parts by weight of the drug. The drug / extract ratio thus indicates how many parts by weight of a drug drug are required for the preparation of the weight-related extract equivalent. The use of extracts with defined drug / extract ratio is particularly relevant in the light of the fact that the quality of the extract has a decisive influence on the overall quality of the pharmaceutical composition. The aim is also to standardize the extract in terms of drug concentration, so that the final pharmaceutical preparation can be provided qualitatively and quantitatively with consistently good levels of active ingredients and ingredients. In addition, the efficacy of the zwie in extra kts in the compositions of the invention can be further improved in view of the reduction of scarring, the promotion of wound healing and the prevention of inflammation, when the onion extract has a defined ash content. According to a preferred embodiment of the present invention, the component (a) has an ash content in the range of 0.01 to 5 wt .-%, in particular 0.05 to 4 wt .-%, preferably 0.1 to 3 wt .-%, based on the component (a), on. The ash content of the onion extract indicates the mineral content of the onion extract. An ash content in the aforementioned amounts in the onion extract improves the environmental conditions in the area of the wound. In addition, the minerals act on the ion environment, resulting in improved conditions for mass transport and supply of the tissue to be formed, which in turn has a positive effect on wound healing and the lowest possible scar formation.

The amount of component (b) or of the at least one surface disinfectant, preferably in the form of polyhexanide, can also vary widely in the compositions according to the invention. According to a preferred embodiment of the present invention, the composition contains component (b) in an amount in the range of 0.00001 to 1 wt .-%, in particular 0.00005 to 0.5 wt .-%, preferably 0.0001 to 0 , 1 wt .-%, preferably 0.001 to 0.01 wt .-%, based on the composition.

With regard to the amount of panthenol or pantothenic acid used, it is also advantageous if the composition contains component (c) in an amount in the range from 0.01 to 10% by weight, in particular 0.05 to 8% by weight. , preferably 0.1 to 5 wt .-%, preferably 1 to 3 wt .-%, based on the composition contains. Particularly good results are also obtained when component (c) is dexpanthenol.

The amount of component (d) based on at least one ectoine derivative, in particular in the form of ectoine and / or hydroxyectoine, is variable. According to the invention, it is preferred if the composition of component (d) in an amount in the range of 0.001 to 10 wt .-%, in particular 0.01 to 8 wt .-%, preferably 0.1 to 5 wt .-%, preferably 0.5 to 2.5 wt .-%, based on the composition contains. In addition, it has proved to be advantageous if component (d) is ectoine and / or hydroxyectoine. According to the invention, component (d) may thus be formed by ectoine or hydroxyectoine, but equally by a mixture of ectoine and hydroxyectoine.

In addition to the amounts of the abovementioned components as such, their respective proportions to one another have proved to be decisive with regard to the effectiveness of the compositions according to the invention.

With regard to the ratio of onion extract to surface disinfectant, in particular polyhexanide, the composition according to the invention may contain component (a) and component (b) in a weight-related quantitative ratio of component (a) to component (b) [component (a): Component (b)] in the range of 1: 1 to 1 .000: 1, in particular 2: 1 to 500: 1, preferably 5: 1 to 100: 1, preferably 10: 1 to 80: 1, particularly preferably 20: 1 to 60: 1, included.

In addition, it can be provided according to the invention that the composition comprises component (a) and component (c) in a weight-related quantitative ratio of component (a) to component (c) [component (a): component (c)] in the range from 1 : 1, 500 to 10: 1, in particular 1: 1 .000 to 1: 1, preferably 1: 500 to 1: 10, preferably 1: 250 to 1: 20, particularly preferably 1: 150 to 1: 50 contains.

Moreover, it can be provided in the context of the present invention that the composition comprises component (a) and component (d) in a weight-related quantitative ratio of component (a) to component (d) [component (a): component (d) ] in the range from 1: 1 .000 to 50: 1, in particular 1: 500 to 30: 1, preferably 1: 250 to 10: 1, preferably 1: 100 to 1: 1, particularly preferably 1: 75 to 1:10 , contains.

Finally, the wound healing-promoting properties of the compositions according to the invention can be further increased by a targeted adjusted ratio of the skin care and moisturizing components based on panthenol or pantothenic acid on the one hand and Ectoinderivaten on the other hand. In this context, it has proven to be particularly advantageous if the composition of the Component (c) and component (d) in a ratio by weight of component (c) to component (d) [component (c): component (d)] in the range from 1: 200 to 200: 1, in particular 1: 100 to 100: 1, preferably 1: 50 to 50: 1, preferably 1: 10 to 20: 1, particularly preferably 1: 1 to 10: 1 contains.

As far as the consistency of the composition according to the invention is concerned, the composition according to a preferred embodiment of the present invention is liquid, in particular viscous and / or gelatinous, and / or in the form of a lubricating gel, in particular hydrogel, and / or lubricant. Similarly, it may be provided that the composition is formed as a liquid, in particular viscous and / or gelatinous application and / or dosage form. The provision of the composition according to the invention in viscous or gel form has the advantage that the handling and applicability of the composition are improved. In particular, leakage of the composition from the urethra after application is prevented and, in addition, better adhesion of the composition at its target site, i. the urothelium of the urethra, which also results in an overall improved efficacy due to the extended duration of action.

In this connection, according to a preferred embodiment, it may be provided that the composition contains at least one gelling agent. By using a gelling agent at the destination, i. H. on the urothel, a gel film formed. The gel film ensures the formation of a moist wound environment or a moist wound treatment, which is associated with faster wound healing and less scarring. In addition, the urothelium is shielded from passing urine.

As far as the amounts of gelling agent in the compositions are concerned, they can vary widely. Particularly good results are obtained if the composition comprises the at least one gelling agent in an amount in the range from 0.01 to 20% by weight, in particular 0 to 1 to 10% by weight, preferably 0.5 to 5% by weight. , preferably 1 to 3 wt .-%, based on the composition contains. According to a preferred embodiment of the present invention, the gelling agent is selected from the group of bentonites, silicic acids, polyacrylic acids, carbomers, polyvinylpyrrolidones, cellulose and cellulose derivatives, xanthanes and mixtures thereof, preferably cellulose and cellulose derivatives.

According to another, more particularly preferred embodiment of the present invention, the gels may also be selected from modified celluloses, in particular chemically modified celluloses, more preferably methylcellulose, hydroxymethylcellulose, carboxymethylcellulose and / or hydroxyethylcellulose, most preferably hydroxyethylcellulose.

The use of hydroxyethylcellulose - without wishing to be limited to this theory - depending on the ambient humidity or the ambient conditions, especially on the wet, the wound side facing added water in the hydroxyethylcellulose based film. On this basis, a moist wound environment or a moist wound treatment can be ensured. The use of hydroxyethylcellulose regulates the moisture content in the wound by supplying moisture to dry wounds ("hydrogel effect") and removing moist wounds from moist wounds ("hydrocolloid effect"). Based on this moisture balance system, exudate management is enabled; H. On the one hand, the wound film can release moisture to the wound and, on the other hand, absorb excess exudate, which in turn accelerates the healing process and reduces the risk of scarring.

With regard to the consistency of the compositions, it may in particular be provided that the composition has a defined viscosity, in particular dynamic viscosity, at a temperature of 20 ° C. in the range from 100 to 100,000 mPas, in particular 500 to 75,000 mPas, preferably 750 to 50,000 mPas , preferably 1 .000 to 10,000 mPas, particularly preferably 2,000 to 6,000 mPas, preferably determined according to the method according to Ph. Eur. [Pharmacopoea Europaea] 7th edition, Grundwerk 201 1, Section 2.2.8.

A defined viscosity in the stated ranges causes good applicability of the compositions without causing the composition to run out of the urethra after application. In addition, it may be provided that the composition has a viscosity, in particular dynamic viscosity, at a temperature of 20 ° C. in the range of at least 100 mPas, in particular at least 500 mPas, preferably at least 1, 000 mPas, preferably at least 2,000 mPas, particularly preferred at least 4,000 mPas, preferably determined according to the method according to Ph. Eur. [Pharmacopoea Europaea] 7th edition, basic text 201 1, section 2.2.8.

The determination of the viscosity is carried out by methods known per se to the person skilled in the art. In particular, the viscosity, in particular the dynamic viscosity, can be determined according to the method according to Ph. Eur. [Pharmacopoea Europaea] 7th Edition, Grundwerk 201 1, Section 2.2.38.

Furthermore, it can be provided that the composition is aqueous or aqueous-alcoholic, especially aqueous, based. Similarly, it may be provided that the composition contains at least one preferably polyhydric alcohol.

With regard to an aqueous-alcoholic composition, it may in particular be provided that the polyhydric alcohol is selected from the group of polyvinyl alcohols, glycerol, glycols and (poly) alkylene glycols and combinations and mixtures thereof, preferably alkylene or polyalkylene glycols, particularly preferably (poly) propylene glycol is selected. Most preferably, the polyhydric alcohol is propylene glycol.

Moreover, it has proven to be advantageous in this context if the composition comprises the preferably polyhydric alcohol in an amount in the range from 10 to 90% by weight, in particular 15 to 70% by weight, preferably 20 to 60% by weight, based on the composition contains.

In addition, it may be provided, in particular with regard to an aqueous composition, that the composition contains water. In particular, the composition according to the invention may comprise water in an amount of at least 10% by weight, in particular at least 20% by weight, preferably at least 30% by weight, preferably at least 40% by weight, based on the composition. Similarly, in the compositions, water in an amount ranging from 10 to 99 wt .-%, in particular 20 to 98 wt .-%, preferably 30 to 97 wt .-%, preferably 40 to 95 wt .-%, based on the composition, be contained.

In addition, it can be provided according to the invention that the composition has an electrical conductivity in the range of 1 to 30 mS / cm, in particular 2 to 20 mS / cm, preferably 5 to 15 mS / cm, preferably determined according to the method according to Ph. Eur [Pharmacopoea Europaea] 7th edition, basic text 201 1, section 2.2.38. The determination of the conductivity is carried out by methods known per se to the person skilled in the art. In particular, the determination of the conductivity can be determined according to the method according to Ph. Eur. [Pharmacopoea Europaea] 7th Edition, Grundwerk 201 1, Section 2.2.38. In addition, it can be provided that the composition of the invention contains at least one physiologically acceptable, osmotically active substance and / or at least one physiologically acceptable osmolyte. In this context, it has proved to be particularly advantageous if the composition of the at least one physiologically acceptable, osmotically active substance or the at least one physiologically acceptable osmolyte in an amount in the range of 0.001 to 5 wt .-%, in particular 0.01 to 3 wt .-%, preferably 0.05 to 2 wt .-%, preferably 0.1 to 1 wt .-%, based on the composition contains. As far as the selection of the osmotically active substance or the osmolyte, it may be provided that the osmotically active substances or the osmolytes from the group of ions of physiologically acceptable salts (ie salt ions), in particular alkali ions , in particular sodium ions and / or potassium ions, and / or chloride ions, preferably sodium ions and chloride ions, are selected. According to a particularly preferred embodiment, the osmotically active substances or the osmolytes are sodium ions and chloride ions, in particular in the form of sodium chloride. Through the use of sodium chloride, the ion environment in the area of the wounds and the associated osmotic effect can be improved. On this basis, in particular the mass transfer and the supply of the wound with nutrients and oxygen can be improved, which in turn leads to accelerated wound healing. In view of the stability and the physiological compatibility of the composition according to the invention, it has also proven to be advantageous if the composition has at least one buffer system. According to a preferred embodiment, the buffer system is selected from physiologically acceptable buffer systems, preferably citric acid / citrate buffer or acetic acid / acetate buffer, preferably citric acid / citrate buffer. As also demonstrated by the exemplary embodiments discussed below, the buffer system further improves the stability of the compositions according to the invention.

The amount of the pH buffer system used can vary within wide limits. According to a preferred embodiment, the composition contains at least one pH buffer system in an amount in the range of 0.00001 to 5 wt.%, In particular 0.0001 to 1 wt.%, Preferably 0.001 to 0.1 wt. based on the composition.

For the term of the chemical buffer or the chemical buffer system, reference may be made in particular to RÖMPP Lexikon Chemie, 10th edition, Georg Thieme Verlag, Stuttgart / New York, Volume 5, 1998, pages 3618/3619, keyword: "buffer", as well as the literature referenced there.

In the context of the present invention, the chemical buffer system is used in particular for adjusting and / or keeping the pH of the composition according to the invention constant. As stated above, this leads to the fact that an undesirable degradation of the active ingredients is effectively counteracted during storage over a longer period of time and in this way the shelf life of the composition according to the invention is improved.

In addition, it can be provided according to the invention that the composition has a physiologically acceptable pH. According to a preferred embodiment of the present invention, the composition has a pH in the range from 4 to 9, in particular 5 to 8.5, preferably 5.5 to 8, preferably determined according to the method according to Ph. Eur. [Pharmacopoea Europaea ] 7th Edition, Grundwerk 201 1, Section 2.2.3. In the context of the present invention, the determination of the pH can be carried out by methods known per se to those skilled in the art. In particular, the determination of the pH can be carried out in accordance with the method according to Ph. Eur. [Pharmacopoea Europaea] 7th Edition, Grundwerk 201 1, Section 2.2.3.

As stated above, the composition according to the invention has excellent stability or long-term stability, in particular storage stability, owing to the measures according to the invention. According to a preferred embodiment, it may thus be provided that the composition is storage stable, in particular wherein the composition at room temperature (20 ° C) and ambient pressure (1 .013,25 hPa) for a period of at least 6 months, in particular at least 12 months , preferably at least 24 months, preferably at least 36 months, is storage stable.

The stability of the composition according to the invention can be characterized by the presence or content of the degradation products of the active substance panthenol or pantothenic acid. The degradation products characteristic of panthenol or pantothenic acid are, in particular, 3-aminopropanol or D-pantolactone.

In the context of the present invention, it can thus be provided that the composition has a content of decomposition product (s) of the active ingredient (c), ie panthenol or pantothenic acid, in particular 3-aminopropanol and / or D-pantolactone, in each case at most 5% by weight. -%, in particular of in each case at most 3 wt .-%, preferably in each case at most 2 wt .-%, particularly preferably in each case at most 1 wt .-%, based on component (c), especially after storage of the composition Temperatures in the range of 20 ° C to 50 ° C, at a pressure of 1 .013,25 mbar and at a relative humidity in the range of 50% to 90% over a period of at least 6 months, in particular at least 12 months, preferably at least 24 months, preferably at least 36 months. Moreover, it may be provided according to the invention that the composition is at least substantially free of pharmaceutically acceptable preservatives. In the context of the present invention, it is surprisingly successful, the composition free of preservatives without causing unwanted degradation of the active ingredients or microbiological deterioration before the expiry of a storage period of 36 months. In addition, the absence of preservatives in the compositions according to the invention increases the compatibility of the compositions even further.

In addition, it may be provided that the composition contains at least one further active ingredient or ingredient. In particular, the one further active ingredient or ingredient may be a substance which is selected from the group of skin protection agents, antiseptics, local anesthetics, vitamins, trace elements, minerals, micronutrients and combinations thereof.

Likewise, it may be provided that the composition also contains at least one further pharmaceutical additive and / or adjuvant. According to a preferred embodiment, the at least one further additive or adjuvant from the group of processing aids, stabilizers, emulsifiers, antioxidants, preservatives, humectants, pH adjusters, pH puff substances, thickeners, antiseptics, dyeing, buffer, Fragrance, fragrance, stretching, binding, wetting and / or preservatives and their combinations selected.

With regard to the dosage form or dosage form, it may also be provided that the composition is present ready to be dosed in containers, in particular with volume sizes in the range of 1 to 1000 ml, in particular 2 to 500 ml, preferably 3 to 50 ml, particularly preferably 4 to 30 ml, most preferably 5 to 20 ml.

The present invention thus relates to a composition for use in the prophylactic and / or therapeutic, in particular topical, treatment of the urethra for the prevention and / or reduction of scars and / or urethral strictures, preferably during and / or after surgical and / or transurethral interventions. In particular, the composition of the present invention is for use in and / or after bougies, urethral slits, (urethral stricture) cleavages, transurethral renal calculus resections, in particular by endoscopic, laser or transoral, transurethral Prostate resections, transurethral bladder neck resections, transurethral electroresections or coagulations, transvaginal endoscopic procedures, (intermittent) catheterizations or endourological procedures.

In addition, the composition may also be used for use in intubations, endoscopies in general and for the prevention of iatrogenic injury to the rectum and / or colon. Furthermore, the present invention according to a second aspect of the present invention relates to the use of a composition as described above for the prophylactic and / or therapeutic, in particular topical, treatment of the urethra for the prevention and / or reduction of scars and / or urethral strictures. preferably during and / or after surgical and / or transurethral interventions.

In particular, of the use according to the invention or the surgical and / or transurethral interventions are bougies, urethral slits, urethral strictures, transurethral kidney stone resections, in particular by means of endoscope, laser or catching baskets, transurethral prostate resections, transurethral bladder neck resections, transurethral electroresections or coagulation, transvaginal endoscopic procedures, (intermittent) catheterizations or endourological procedures.

In addition, the uses of the invention also encompass use of the compositions in intubations and endoscopies in general and use to prevent iatrogenic injury to the rectum and / or colon.

For further details on the use according to the invention, reference may be made to the preceding statements relating to the composition according to the invention, which also apply correspondingly with regard to the use according to the invention. Yet another object of the present invention - according to a third aspect of the present invention - is a container, in particular an application device, which contains the composition described above.

As regards the container in particular, it may be in the form of a tube, bottle, can, a pump and / or dosing dispenser or a syringe, more preferably in the form of a syringe. Similarly, it may be provided that the container is in the form of a catheter, in particular urinary catheter or fistula catheter.

According to a preferred embodiment of the present invention, it can be provided in this context, in particular, that the container according to the invention contains the composition according to the present invention as a sub-sterile, preserved composition.

For further details with respect to the container according to the invention, reference may be made to the above statements on the other aspects of the invention, which also apply with regard to the container according to the invention.

Another object of the present invention is also - according to a fourth aspect of the invention - a syringe containing a composition described above, for use in the prophylactic and / or therapeutic, especially topical treatment of the urethra to avoid and / or reduce scars and / or urethral strictures.

For further details of the syringe according to the invention, reference may be made to the above remarks on the other aspects of the invention, which also apply correspondingly with regard to the syringe according to the invention. A further subject of the present invention is also, according to a fifth aspect of the invention, a bladder catheter or fistula catheter containing a composition as described above, in particular wherein the composition is applied to a body lumen, in particular into the urethra or into an artificial fistula for urinary diversion , insertable and / or insertable portion of the catheter, preferably for use in the prophylactic and / or therapeutic, in particular topical treatment of the urethra for the prevention and / or reduction of scars and / or urethral strictures.

For further details on the catheter according to the invention, reference may be made to the above remarks on the other aspects of the invention, which also apply with regard to the catheter according to the invention. In addition, the subject of the present invention is - according to one of the aspects of the present invention - a packaging unit which contains a container as described above.

In particular, the container may be present in an outer package that protects against contamination.

For further details of the application device according to the invention, reference may be made to the above remarks on the other aspects of the invention, which apply correspondingly with regard to the packaging unit according to the invention.

Finally, subject of the present invention - according to a seventh aspect of the present invention - a kit which as spatially separated components on the one hand a catheter, in particular a bladder or fistula catheter, and / or a syringe and on the other hand, a composition as described above, includes.

For further details on the kit according to the invention, reference may be made to the above remarks on the other aspects of the invention, which apply correspondingly with regard to the kit according to the invention. Preferred embodiments of the present invention are described below on the basis of the exemplary embodiments, which, however, are by no means to be understood as limiting.

WORKING EXAMPLES

1 . Preparation Examples

In order to investigate the effectiveness of the compositions of the invention, the compositions of the invention provided by the Applicant are compared with various comparative compositions. The following tables give the recipes for the compositions provided.

Table 1: Recipe 1

Ingredient Amount in g per amount in wt.%,

100 ml gel d = 1, 0145 g / cm ³

Allium cepa 0.020 0.020

(Onion extract)

Polyhexanide 0.025 0.025

(20% solution)

Hydroxyethyl cellulose 1, 928 1, 900

Sodium chloride 0.507 0.500

Citric acid 0.005 0.005

Purified water ad 100 ml ad 100% by weight

Table 2: Recipe 2

Ingredient Amount in g per amount in wt.%,

100 ml gel d = 1, 0145 g / cm ³

Allium cepa 0.020 0.020

(Onion extract)

Polyhexanide 0.025 0.025

(20% solution)

Dexpanthenol 2.536 2.500

Hydroxyethyl cellulose 1, 928 1, 900

Sodium chloride 0.507 0.500

Citric acid 0.005 0.005

Purified water ad 100 ml ad 100% by weight

Table 3: Recipe 3

Ingredient Amount in g per amount in wt.%,

100 ml gel d = 1, 0145 g / cm ³

Allium cepa 0.020 0.020

(Onion extract)

Polyhexanide 0.025 0.025

(20% solution)

Dexpanthenol 2.536 2.500

Ectoin 1, 015 1, 000

Hydroxyethyl cellulose 1, 928 1, 900

Sodium chloride 0.507 0.500

Citric acid 0.005 0.005

Purified water ad 100 ml ad 100% by weight Table 4: Formulation 4

Table 5: Recipe 5

Ingredient Amount in g per amount in wt.%,

100 ml gel d = 1, 0145 g / cm ³

Dexpanthenol 2.536 2.500

Hydroxyethyl cellulose 1, 928 1, 900

Sodium chloride 0.507 0.500

Citric acid 0.005 0.005

Purified water ad 100 ml ad 100% by weight

Table 6: Recipe 6

Ingredient Amount in g per amount in wt.%,

100 ml gel d = 1, 0145 g / cm ³

Ectoin 1, 015 1, 000

Hydroxyethyl cellulose 1, 928 1, 900

Sodium chloride 0.507 0.500

Citric acid 0.005 0.005

Purified water ad 100 ml ad 100% by weight

Table 7: Recipe 7

Ingredient Amount in g per amount in wt.%,

100 ml gel d = 1, 0145 g / cm ³

Hyaluronic acid 0.233 0.200

Hydroxyethyl cellulose 1, 928 1, 900

Sodium chloride 0.507 0.500

Citric acid 0.005 0.005

Purified water ad 100 ml ad 100% by weight Table 8: Recipe 8

The compositions listed above are prepared by methods known to those skilled in the art. The onion extract used on the basis of a fluid extract recovered from thick extract has a drug / extract ratio of 1: 1, 8 and an ash content in the range of 0.3 to 2 wt .-%, based on the onion extract on. The compositions are in the form of a clear colorless gel having a viscosity of at least 4,000 mPas. The viscosity is determined by the method according to Ph. Eur. 2.2.8. The compositions are also adjusted to a pH in the range of 5.5 to 8. The measurement or checking of the pH takes place according to Ph. Eur. 2.2.3. The density is determined by the method according to Ph. Eur. 2.2.5. certainly. Preclinical examinations (in w ^' fro tests)

To investigate the efficacy of the above compositions in vitro, a model system based on collagen gels with seeded fibroblasts, i. H. Connective tissue cells from the dermis, used. The model system is intended for the investigation of unwanted scarring.

In wounds or tissue injuries growth factors are usually released, which activate fibroblasts. The growth factors are mainly the cytokine transforming growth factor (TGF-beta), which is considered to be the cause of the increased proliferation and matrix synthesis or matrix contraction of the fibroblasts. The increased proliferation of fibroblasts initially has a positive effect on the repair of tissue damage.

An unwanted scarring, d. H. the formation of hypertrophic scars and keloids is caused by fibroblasts which, after closure of the wound, do not return to normal proliferation and matrix formation, but remain in the activated state for longer than necessary. As a consequence, excessive wound edges result from excessive synthesis of extracellular matrix and altered skin surface structures due to contracting forces of the fibroblasts in hypertrophic scars.

To investigate the scar-reducing effect of the above compositions, fibroblast-populated collagen gels were used as a model for contraction of wound edges. A reduced contraction in the collagen gels by the fibroblasts is considered an indicator of a scar-reducing effect.

The in vitro assays were performed as follows: fibroblast populated collagen gels were treated with the test compositions over a period of six days. The test compositions were each used at a concentration of 200 μg / ml. The monetary diameter was measured after six days and compared to the initial size of 22.3 mm (100%). The smaller the diameter after six days, the stronger was the contraction by the fibroblasts. Eight collagen gels colonized with fibroblasts were used per composition to be tested, with four of the eight gels additionally stimulated with TGF-beta. In addition, for control purposes, an untreated batch (ie, eight collagen gels, thereof four stimulated with TGF-beta). The results were then averaged. The results obtained can be taken from the table below.

Table 10: Results of in vitro studies

From the in vitro studies on collagen gels populated with fibroblasts, it is evident that compositions 1 to 3 according to the invention lead to a significantly reduced contraction in the collagen gels in comparison to the mono compositions based on onion extract,

Dexpanthenol or ectoine (compositions 4 to 6) lead. Hyaluronic acid, which has a moisturizing effect, has little effect on the contraction of fibroblasts (Composition 7). With the comparison compositions 8 and 9, which contain the active ingredients onion extract, dexpanthenol and ectoine according to the invention

Combination with an antiseptic based on octenidine or chlorhexidine, a reduction of the contraction could also be achieved, although this was significantly weaker than the contraction reduction. tion, which could be achieved with the inventive composition 3, which contains as an antiseptic polyhexanide.

Overall, it can be seen from the investigations that even with a composition based solely on onion extract and polyhexanide, a marked reduction in contraction by activated fibroblasts and thus also a reduction in scar formation can be achieved (composition 1). The addition of dexpanthenol and ectoin can significantly increase the scar-reducing effect (compo- sitions 2 and 3). It is also apparent from a comparison of the results of composition 3 with compositions 8 and 9, respectively, that polyhexanide leads to a significant increase in efficacy in reducing scarring as compared to the antiseptics octenidine and chlorhexidine.

application tests

In order to examine the efficacy and tolerability of compositions 1 to 3 according to the invention, a panel of volunteers based on 30 men between the ages of 55 and 70 years who are subject to transurethral surgery is used. Three groups of 10 subjects each are treated with compositions 1, 2 and 3, respectively. The treatment is performed postoperatively by the attending physician.

The application schedule is as follows: Up to 7 days after the procedure or surgery, the composition to be tested is applied once a day after bladder emptying by instilling it in the urethra.

In all 30 subjects fast regeneration of the consequences of the procedure can be observed. In none of the subjects inflammation in the context of wound healing is observed. After completion of the treatment, all subjects are virtually free of pain and complaints. An occurrence of urethral strictures due to transurethral surgery is not observed. In addition, no adverse reactions occurred in any subject. stability studies

The results of a large number of stability studies are reproduced below.

For this purpose, in each case under defined storage conditions, as indicated below, long-term stability tests were carried out on the relevant compositions, after which specific test parameters in the compositions were measured and compared with the relevant specification (eg appearance of the composition, pH Value and content of impurities). Unless otherwise stated below, storage was at a defined temperature of 25 ° C ± 2 ° C and at a relative ambient humidity of 60% ± 5%.

A characteristic measure of the stability of a composition is, on the one hand, the constancy of the pH and the constancy of the content of active ingredients. Furthermore, the content of decomposition products of the active ingredients can be determined in order to assess the stability of the composition.

As described above, 3-aminopropanol or its ammonium salt and D-pantolactone are characteristic decomposition products of dexpanthenol. In the following description of the results of the stability studies, the percentages of the active ingredient dexpanthenol are given by weight percentages with respect to the composition, whereas the percentage contents of the impurities are in each case referred to as percentages by weight with respect to the original active substance, d. H. the content of 3-aminopropanol or its ammonium salt and D-pantolactone as percent by weight with respect to dexpanthenol.

In other words, in the case of impurities, the percentages by weight do not relate to the composition, but to the content of the active substance concerned, the breakdown of which results in contamination. a) Stability studies

Stability tests were carried out on a batch of the composition according to the invention in accordance with recipe 3 described above. For this purpose, both the content of the ingredients dexpanthenol and ectoine and the content of the degradation products pantolactone and 3-aminopropanol was determined, after storage periods of 3 months, 6 months, 9 months, 12 months, 18 months, 24 Months and 36 months. On the other hand, the pH was determined for the same storage period for the aforementioned storage periods.

The pH was determined by the method according to Ph. Eur. 2.2.3. certainly. The content of dexpanthenol, ectoine or hydroxyectoine, pantolactone and 3-aminopropanol was determined by HPLC. The measurement of the active ingredient content by means of HOLC is known in principle to the person skilled in the art. In addition, the compositions were assessed for their microbiological quality by determining the content of aerobic microbes and yeasts by the method described in Ph. Eur. 2.6.12. certainly. Furthermore, according to Ph. Eur. 2.6.13. also the content of Pseudomonas aeruginosa and Staphylococcus aureus measured.

The measurements carried out have shown that the composition according to the invention did not show any changes in the pH over the entire observation period. The content of dexpanthenol or ectoine and hydroxyectoine was over the entire observation period at 90 to 1 10 wt .-%, based on the originally used amount of the respective active ingredient. The content of the decomposition products D-pantolactone and 3-aminopropanol of dexpanthenol was less than 5% by weight, based on the originally used amount of dexpanthenol. Pseudomonas aeruginosa and Staphylococcus aureus could not be detected in the compositions even after a storage period of 36 months. The content of aerobic microbes or yeasts was below the maximum permissible value of 2 - 102 KbE / g or 2 - 101 KbE / g even after 36 months.

The results prove the excellent storage stability, in particular over a long period of at least 36 months, of the composition according to the invention.

In addition, further stability studies with the comparative compositions or changed parameters were carried out. b) influence of pH

To study the effect of pH on the stability of the compositions, Compositions were prepared according to Formulation 3 except that the pH for a first test composition was adjusted to 5.0. In addition, a second composition with a pH of 8.5 was provided. The compositions in question were investigated over a period of 36 months, like the compositions according to the invention described under a). In both compositions, a decomposition of dexpanthenol in pantolactone or 3-aminopropanol was observed after only 12 months. The content of both degradation products was already after 12 months more than 10 wt .-%, based on the originally used amount of dexpanthenol. The content of dexpanthenol and ectoine or hydroxyectoine had already fallen after 12 months to 77 or 80% by weight, based on the amount of active ingredients originally used, respectively. The reduced stability was also shown by slight clouding.

c) influence of the type of buffer system

Furthermore, investigations were carried out with different buffer systems based on formulation 3. For this purpose, compositions based on formulation 3 were provided, which instead of citric acid / citrate contained a buffer system based on acetic acid / acetate or phosphate. With regard to the stability of composition 3, which contains a citric acid / citrate-based buffer, reference is made to the above statements under a), which prove the excellent long-term stability of the composition. The composition with the acetic acid / acetate buffer was investigated analogously to the procedure described under a). When using acetic acid / acetate or phosphate based buffer systems, the content of dexpanthenol or ectoine and hydroxyectin decreased to less than 80% by weight, based on the originally used amount of ingredients, after 24 months within the observation period. The degradation products of dexpanthenol, ie D-pantolactone and 3-aminopropanol, however, were after 24 months in an amount of more than 10 wt .-%, based on the original amount of dexpanthenol detected. d) Influence of the antiseptic

Furthermore, the influence of the antiseptic on the stability of the compositions was investigated. In this regard, compositions 3, 8 and 9 were used. Composition 3 contains polyhexanide as an antiseptic, whereas composition 8 contains octenidine and composition 9 contains chlorhexidine. With regard to the stability of composition 3, reference is made to the above statements under a), which prove the excellent long-term stability of the composition. Analogous to the procedure described under a), the compositions 8 and 9 were also examined with regard to their stability. Up to a period of 24 months, the compositions 8 and 9 also exhibited a stability corresponding to the requirements. At the time of measurement after 36 months, however, the content of dexpanthenol and ectoine or hydroxyectoine had fallen to 82% by weight (dexpanthenol) and 79% by weight (ectoine or hydroxyectoine). The content of pantolactone or 3-aminopropanol was more than 7 wt .-%, based on the originally used amount of dexpanthenol.

The results indicate that chlorhexidine and octenidine do not provide storage stability over a period of 36 months without the use of additional preservatives. With polyhexanide as antiseptic, however, can be dispensed with the additional use of preservatives, since polyhexanide as such already leads to a sufficient stabilization of the compositions.

As the above results of the stability studies indicate, intensive research effort has been required to find a stable composition for the therapeutic or prophylactic treatment of urethral strictures in accordance with the present invention.

The stability studies reported above show the complexity of the approach found by the Applicant. These include the joint presence of polyhexanide as an antiseptic and a defined buffer system with adjustment of a pH in the range of 5.5 to 8.

Claims

claims:

Composition, in particular pharmaceutical composition, preferably for the prophylactic and / or therapeutic, in particular topical treatment of the urethra for the prevention and / or reduction of scars and / or urethral strictures, preferably during and / or after surgical and / or transurethral procedures,

a) Onion extract (extract Bulbus cepae) and / or its ingredients ("component (a)");

b) at least one surface disinfectant, in particular polyhexanide and / or its physiologically acceptable salts, ("component (b)");

c) optionally panthenol and / or its physiologically tolerated esters and / or pantothenic acid and / or their physiologically tolerated salts, in particular panthenol and / or its physiologically tolerable esters, preferably dexpanthenol, ("component (c)"); and d) optionally at least one ectoine derivative, in particular ectoine and / or hydroxyectoine and / or physiologically acceptable salts thereof, ("component (d)");

contains.

2. A composition according to claim 1, wherein the composition comprises component (a) in an amount in the range of 0.00001 to 7% by weight, in particular 0.0001 to 5% by weight, preferably 0.001 to 2% by weight. , preferably 0.005 to 1 wt .-%, particularly preferably 0.01 to 0.5 wt .-%, based on the composition contains.

3. Composition according to claim 1 or 2,

wherein component (a) is used in the form of dry extract, thick extract, spissum extract and / or fluid extract, in particular in the form of fluid extract and / or thick extract, preferably fluid extract; and or wherein component (a) has a drug / extract ratio in the range from 10: 1 to 1: 100, in particular in the range from 5: 1 to 1:50, preferably in the range from 2: 1 to 1:10, preferably in the range from 1: 1 to 1: 5; and or

wherein component (a) has a drug / extract ratio of at least 1:50, in particular at least 1:10, preferably at least 1: 5, preferably at least 1: 4, particularly preferably at least 1: 2; and or

wherein component (a) has an ash content in the range from 0.01 to 5% by weight, in particular 0.05 to 4% by weight, preferably 0, 1 to 3% by weight, based on component (a) , having.

A composition according to any one of the preceding claims wherein the composition comprises component (b) in an amount ranging from 0.00001 to 1% by weight, especially 0.00005 to 0.5% by weight, preferably 0.0001 to 0 , 1 wt .-%, preferably 0.001 to 0.01 wt .-%, based on the composition contains.

Composition according to one of the preceding claims,

wherein the composition comprises component (c) in an amount in the range of 0.01 to 10 wt .-%, in particular 0.05 to 8 wt .-%, preferably 0, 1 to 5 wt .-%, preferably 1 to 3 Wt .-%, based on the composition contains; and or

wherein component (c) is dexpanthenol.

Composition according to one of the preceding claims,

wherein the composition comprises component (d) in an amount in the range of 0.001 to 10 wt .-%, in particular 0.01 to 8 wt .-%, preferably 0, 1 to 5 wt .-%, preferably 0.5 to 2 , 5 wt .-%, based on the composition contains; and or

wherein component (d) is ectoine and / or hydroxyectoine. Composition according to one of the preceding claims,

wherein the composition comprises component (a) and component (b) in a weight ratio of component (a) to component (b) [component (a): component (b)] in the range of 1: 1 to 1, 000: 1, in particular 2: 1 to 500: 1, preferably 5: 1 to 100: 1, preferably 10: 1 to 80: 1, particularly preferably 20: 1 to 60: 1, contains; and or

wherein the composition comprises component (a) and component (c) in a weight ratio of component (a) to component (c) [component (a): component (c)] in the range of 1: 1, 500 to 10: 1, in particular 1: 1 .000 to 1: 1, preferably 1: 500 to 10: 1, preferably 1: 250 to 1: 20, particularly preferably 1: 150 to 1: 50, contains; and or

wherein the composition comprises component (a) and component (d) in a weight ratio of component (a) to component (d) [component (a): component (d)] in the range of 1: 1000 to 50: 1, in particular 1: 500 to 30: 1, preferably 1: 250 to 10: 1, preferably 1: 100 to 1: 1, particularly preferably 1: 75 to 1: 10, contains; and or

wherein the composition comprises component (c) and component (d) in a weight ratio of component (c) to component (d) [component (c): component (d)] in the range of 1: 200 to 200: 1, in particular 1: 100 to 100: 1, preferably 1: 50 to 50: 1, preferably 1: 10 to 20: 1, particularly preferably 1: 1 to 10: 1.

8. Composition according to one of the preceding claims,

wherein the composition is liquid, in particular viscous and / or gel-shaped, and / or in the form of a lubricant, in particular hydrogel, and / or lubricant, and / or

wherein the composition is formed as a liquid, in particular viscous and / or gelatinous application and / or dosage form. Composition according to one of the preceding claims, wherein the composition contains at least one gelling agent, in particular in an amount in the range of 0.01 to 20 wt .-%, in particular 0.1 to 10 wt .-%, preferably 0.5 to 5 wt .-%, preferably 1 to 3 wt .-%, based on the composition.

Composition according to Claim 9,

wherein the gelling agent is selected from the group of bentonites, silicas, polyacrylic acids, carbomers, polyvinylpyrrolidones, cellulose and cellulose derivatives, xanthanes and mixtures thereof, preferably cellulose and cellulose derivatives; and or

wherein the gelling agent is selected from modified celluloses, in particular chemically modified celluloses, particularly preferably methylcellulose, hydroxymethylcellulose, carboxymethylcellulose and / or hydroxyethylcellulose, very particularly preferably hydroxyethylcellulose. Composition according to one of the preceding claims,

wherein the composition has a viscosity, in particular dynamic viscosity, at a temperature of 20 ° C. in the range from 100 to 100,000 mPas, in particular 500 to 75,000 mPas, preferably 750 to 50,000 mPas, preferably 1 .000 to 10,000 mPas, particularly preferably 2,000 to 6,000 mPas, preferably determined according to the method according to Ph. Eur. [Pharmacopoea Europaea] 7th edition, basic text 201 1, section 2.2.8; and or

wherein the composition has a viscosity, in particular dynamic viscosity, at a temperature of 20 ° C in the range of at least 100 mPas, in particular at least 500 mPas, preferably at least 1, 000 mPas, preferably at least 2,000 mPas, more preferably at least 4,000 mPas, preferably determined according to the method according to Ph. Eur. [Pharmacopoea Europaea] 7th edition, basic text 201 1, section 2.2.8.

Composition according to one of the preceding claims, wherein the composition is aqueous or aqueous-alcoholic, in particular aqueous, based and / or wherein the composition contains at least one preferably polyhydric alcohol.

13. The composition according to claim 12,

wherein the polyhydric alcohol is selected from the group of polyvinyl alcohols, glycerol, glycols and (poly) alkylene glycols and their

Combinations and mixtures, preferably alkylene or polyalkylene glycols, particularly preferably (poly) propylene glycol, and / or wherein the preferably polyhydric alcohol is propylene glycol; and or

wherein the composition preferably contains the polyhydric alcohol in an amount in the range of 10 to 90 wt .-%, in particular 15 to 70 wt .-%, preferably 20 to 60 wt .-%, based on the composition. 14. A composition according to any one of the preceding claims, wherein the composition contains water, in particular in an amount of at least 10 wt .-%, in particular at least 20 wt .-%, preferably at least 30 wt .-%, preferably at least 40 wt .-% , based on the composition, and / or in particular in an amount in the range of 10 to 99 wt .-%, in particular 20 to 98 wt .-%, preferably 30 to

97 wt .-%, preferably 40 to 95 wt .-%, based on the composition.

15. A composition according to any one of the preceding claims, wherein the composition has an electrical conductivity in the range of 1 to 30 mS / cm, in particular 2 to 20 mS / cm, preferably 5 to 15 mS / cm, preferably determined according to the method of Ph Eur. [Pharmacopoea Europaea] 7th edition, basic text 201 1, section 2.2.38. 16. The composition according to any one of the preceding claims, wherein the composition contains at least one physiologically acceptable, osmotically active substance and / or at least one physiologically acceptable osmolyte, in particular in an amount in the range of 0.001 to 5 wt .-%, in particular 0.01 to 3 wt .-%, preferably 0.05 to 2 wt .-%, preferably 0, 1 to 1 wt .-%, based on the composition.

17. Composition according to claim 16,

wherein the osmotically active substances and / or the osmolytes are selected from the group of ions of physiologically acceptable salts (i.e., salt ions), in particular alkali ions, in particular sodium ions and / or

Potassium ions, and / or chloride ions, preferably sodium ions and chloride ions; and or

wherein the osmotically active substances and / or the osmolytes are sodium ions and chloride ions, in particular in the form of sodium chloride.

18. Composition according to one of the preceding claims, wherein the composition comprises at least one pH buffer system, in particular wherein the buffer system is selected from physiologically acceptable buffer systems, preferably citric acid / citrate buffer or acetic acid / acetate buffer, preferably citric acid / citrate buffer. Buffer.

19. A composition according to any one of the preceding claims wherein the composition comprises at least one pH buffering system in an amount ranging from 0.00001 to 5% by weight, more preferably 0.0001 to 1% by weight, preferably 0.001 to 0.1 Wt .-%, based on the composition contains.

20. The composition according to any one of the preceding claims, wherein the composition has a physiologically acceptable pH, in particular a pH in the range of 4 to 9, in particular 5 to 8.5, preferably 5.5 to 8, preferably determined according to Method according to Ph. Eur. [Pharmacopoea Europaea] 7th edition, basic text 201 1, section 2.2.3.

21. Composition according to one of the preceding claims, wherein the composition is storage stable, in particular wherein the composition at room temperature (20 ° C) and ambient pressure (1 .013,25 hPa) for a period of at least 6 months, especially at least 12 months, preferably at least 24 months, preferably at least 36 months, is stable on storage. Composition according to one of the preceding claims, wherein the composition has a content of degradation product (s) of the active ingredient (c), in particular 3-aminopropanol and / or D-pantolactone, in each case at most 5 wt .-%, in particular of at most 3 wt. -%, preferably of at most 2 wt .-%, particularly preferably at most 1 wt .-%, based on component (c) contains, in particular after storage of the composition at temperatures in the range of 20 ° C to 50 ° C, at a pressure of 1 .013,25 mbar and at a relative humidity in the range of 50% to 90% over a period of at least 6 months, in particular at least 12 months, preferably at least 24 months, preferably at least 36 months.

A composition according to any one of the preceding claims wherein the composition is at least substantially free of pharmaceutically acceptable preservatives.

Composition according to one of the preceding claims, wherein the composition contains at least one further active ingredient and / or ingredient, in particular selected from the group of skin protection agents, antiseptics, local anesthetics, vitamins, trace elements, minerals, micronutrients and combinations thereof.

Composition according to one of the preceding claims, wherein the composition contains at least one further pharmaceutical adjuvant and / or adjuvant, in particular selected from the group of processing aids, stabilizers, emulsifiers, antioxidants, preservatives, humectants, pH adjusters, pH buffer substances, thickeners , Antiseptics, coloring, buffering, scent, fragrance, extender, binding, wetting and / or preservatives and their combinations.

Composition according to one of the preceding claims, wherein the composition is present ready to be dosed in containers, in particular with volume sizes in the range of 1 to 1, 000 ml, in particular 2 to 500 ml, preferably 3 to 50 ml, particularly preferably 4 to 30 ml, very particularly preferably 5 to 20 ml.

27. A composition according to any one of the preceding claims for use in the prophylactic and / or therapeutic, especially topical, treatment of the urethra to prevent and / or reduce scars and / or urethral strictures, preferably during and / or after surgical and / or transurethral procedures.

28. Use of a composition according to any one of the preceding claims for prophylactic and / or therapeutic, especially topical treatment of the urethra for the prevention and / or reduction of scars and / or urethral strictures, preferably during and / or after surgical and / or transurethral surgery.

29. Container, in particular application device, comprising a composition according to one of the preceding claims.

30. Container according to claim 29 in the form of a tube, bottle, can, a pump and / or dosing dispenser, a syringe, particularly preferably in the form of a syringe, and / or in the form of a catheter, in particular bladder catheter or fistula catheter.

31. A syringe containing a composition according to any one of claims 1 to 28 for use in the prophylactic and / or therapeutic, especially topical treatment of the urethra to prevent and / or reduce scars and / or urethral strictures, preferably at and / or after operative and / or or transurethral interventions.

32. Catheter, in particular bladder catheter or fistula catheter, containing a composition according to one of claims 1 to 28, in particular wherein the composition on a in a body lumen, in particular in the urethra or in an artificial fistula for urinary diversion, insertable and / or insertable portion of the catheter is applied, preferably for use in the prophylactic and / or therapeutic, especially topical treatment of the urethra for the prevention and / or reduction of scars and / or urethral strictures, preferably during and / or after surgical and / or transurethral surgery.

33. Packaging unit, containing at least one container according to claim 29 or 30, in particular wherein the container is present in a protective against contamination outer packaging. 34. Kit, comprising as spatially separated components a catheter, in particular a bladder or fistula catheter, and / or a syringe, and a composition according to any one of claims 1 to 28.