DE102012000430B4 - Composition for topical use I. - Google Patents

Abstract

Composition for the prevention and / or reduction of scarring for the topical treatment of the urethra during surgical and / or transurethral interventions, the composition being as active ingredients (a) onion extract (extract of bulb cepae) ("component (a)") in an amount in the range from 0.05 to 1% by weight, based on the composition, (b) panthenol and / or its ester and / or pantothenic acid and / or its physiologically acceptable salts (“component (b)”) in an amount in the range of 1.5 to 3% by weight, based on the composition, and (c) ectoin and / or hydroxyectoin (“component (d)”) in an amount in the range from 0.001 to 10% by weight, based on the composition , wherein the onion extract has a drug / extract ratio in the range of 1: 1 to 25: 1, wherein the composition is in the form of a gel, wherein the composition contains at least one gelling agent, and wherein the composition contains the gelling agent in an amount in the range from 1 to 3% by weight, based on on the composition.

Description

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

The present invention relates to a composition which is suitable for the topical treatment of the urethra in surgical or transurethral interventions. In addition, the present invention relates to the use of the composition according to the invention.

The urinary organs (Organia urinia) denote a group of organs that are used for the formation and excretion of urine. Together with the genital organs, the urinary organs are grouped together as the urogenital tract. The urinary organs in humans and most vertebrates include the kidneys, ureters, bladder and urethra. The urine formed in the kidneys is temporarily stored via the ureters in the urinary bladder. It is finally released to the outside via the urethra.

The urethra is a membranous, muscular tube that is lined with urothelium on the inside. From the inside out, the urothelium is followed by elastic connective tissue and a network of blood vessels, which in turn are surrounded by smooth muscles. The urethra is embedded in the surrounding tissue by additional external connective tissue. In women, the urethra is only about 2.5 to 5 cm long, whereas the male urethra is about 20 to 25 cm long.

The urethra, especially the inner urothelial layer, is extremely sensitive, so that both external mechanical influences and endogenous causes, such as inflammation, can lead to injuries or changes to the tissue.

Injuries to the urethra occur particularly frequently as a result of operations or transurethral interventions, for example when removing diseased tissue or tissue to be examined from the bladder or prostate, for example in the case of bladder carcinomas, bladder diverticula or benign prostate tumors. In such a transurethral resection z. B. a wire loop through which an electric current flows, inserted through the urethra into the bladder; the tissue is removed in layers and any bleeding that occurs is then electrically obliterated. The introduction of urological instruments and the resulting friction on the urothelium can cause lesions on the urothelial layer.

Urethral injuries are also common with catheterization for urinary diversion. Catheterization may be necessary due to acute symptoms such as urinary tract infections or urinary retention, after surgery or due to chronic dysfunctions such as bladder emptying disorders or urinary incontinence. The urothelium is often severely damaged by the foreign body, particularly in the case of permanent catheterization.

In addition, inflammation, in particular inflammation triggered by bacterial infections, can lead to changes or injuries to the urethral tissue or urothelium.

The problem with lesions or changes in the urethral urothelium is the formation of indurations and scars. Due to the raised structure of scars, a urethral constriction or a so-called urethral stricture can be formed. The stronger the constriction, the greater the pressure that has to be exerted to empty the bladder (micturition), so that residual ham often remains in the bladder. In extreme cases, a urethral stricture can result in complete urinary retention. H. the bladder can no longer be emptied spontaneously. On the one hand, urinary retention is extremely painful and, on the other hand, it can trigger a backlog of urine in the kidneys, which can be damaged by pressure.

Surgical measures are generally required to treat urethral strictures. The urethrotomy - synonymously also called urethral slit - is an endoscopic procedure in which a small incision is made in the area of the constriction. However, this method can only be used for constrictions over a length of 1 to 4 cm. In the case of long urethral strictures, the use of plastics is necessary, whereby the oral mucosa is first removed from the inside of the upper lip or the cheek and then sewn into the urethra as an enlargement. In the case of short urethral constrictions of less than 2 cm, the narrowed section can also be surgically removed. The two ends are then deserted together. Disadvantage of such However, surgical interventions are associated with a high risk of infection and, moreover, are very painful for the patient. Furthermore, they are complex to carry out and generally require an inpatient hospital stay.

As an alternative to the aforementioned surgical measures, bougienage - i.e. H. a mechanical widening or dilation - of the urethra. For this purpose, rods of increasing thickness are inserted into the urethra, each of which remains in the urethra for a period of several weeks, causing the urethra to expand. Bougienage of the urethra is also very painful for the patient, especially when using thicker sticks. In addition, the long treatment duration of several weeks is extremely impractical and tedious overall.

Overall, the aforementioned measures for the treatment of urethral strictures often do not lead to the desired success. On the one hand, they are complex to use and, on the other hand, they are associated with a high rate of recurrence, so that they often have to be repeated several times. In addition, they are extremely painful for those affected and require long-term follow-up care or treatment.

the U.S. 5,885,581 A relates to a dermatological composition for use in improving the appearance of scars, which comprises 20 to 30% by weight of polyethylene glycol, 0.005 to 0.03% by weight of a preservative, 0.05 to 0.02% by weight of sorbic acid, 0 , 5 to 2% by weight allantoin, 1.3% by weight xanthan, 5 to 15% by weight onion extract, 55 to 65% by weight of a dermatologically compatible aqueous carrier material and optionally perfume oil, the stated amounts in add up to 100% by weight of the sum, and wherein the composition is in the form of a milky gel.

The effects of onion extract and the use of onions or onion extract in topical compositions for scars and contractures are also described in Martindale: "The Complete Drug Reference" 2009, "The Pharmaceutical Press".

It also affects the WO 03/004043 A1 an (oil) containing agent based on onion extract, which is used for the care or treatment of damaged skin tissue, e.g. B. after operations, biopsies, cuts, burns or other accidents, as well as for the treatment of scars, is used, the composition having an oil base on the one hand and onion extract on the other hand.

the DE 10 2004 004 034 A1 relates to an extract from fresh or dried onions which contains at least 10%, preferably 20 to 60%, quercetin or quercetin derivatives.

Furthermore concerns the DE 10 2008 022 712 A1 a hair cleaning agent, which gives the hair more firmness, grip and tensile strength as well as improved combability when dry or wet. The hair cleaning agent is based on a cosmetically acceptable carrier and also contains 0.1 to 35% by weight of at least one surfactant and 15 to 85% by weight of at least one fruit or vegetable juice.

the WO 2012/175626 A1 relates to a composition based on onion extract for the treatment of scars, wherein at least part of the onion extract is encapsulated in liposomes and can be present in combination with pathenol.

the WO 96/10387 relates to the use of water-soluble salts of potassium, copper and / or zinc, flavones or flavone derivatives, xanthines, mucopolysaccharides, fat-soluble vitamins, citrus root, ginger and / or cinnamon oil and allyl-based plant extracts, e.g. B. onion or garlic extracts as hair stimulants.

the US 2004/0137023 A1 relates to a cosmetic method for the treatment of dry skin or dry scalp by topical application of a composition which contains in a physiologically acceptable medium at least one of 5-cholesten-3beta, 25-diol-7-one and esters and ethers thereof on the skin or scalp.

the DE 20 2007 001 059 U1 relates to a composition for the treatment of inflammatory diseases of the urogenital tract, preferably interstitial cystitis, the composition containing in combination: hyaluronic acid or its salts, preferably with an average molar mass (molecular weight) of less than 200 kDa with at least one other different glycosaminoglycan , preferably chondroitin sulfate.

With regard to the treatment of urethral strictures, conservative measures that can prevent scar formation or reduce existing scars and thus reduce the need for operative or surgical measures would be desirable.

The present invention is therefore based on the object of providing a new concept for the treatment of urethral strictures which at least partially avoids or at least partially mitigates the aforementioned disadvantages of the prior art.

In particular, the present invention is based on the object of providing easy-to-use or topical measures in relation to the treatment of urethral strictures which at least partially avoid or at least partially mitigate the aforementioned disadvantages of the prior art.

Furthermore, the present invention is based on the object of providing a composition which is suitable for the topical treatment of the urethra in surgical and / or transurethral interventions and which serves to avoid and / or reduce scar formation.

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

Finally, the subject of the present invention is the use of the composition according to the invention according to the relevant independent claims.

It goes without saying that in the following special configurations, embodiments or the like, which are only described in connection with one aspect of the invention, also apply accordingly with regard to the other aspects of the invention, without this needing to be explicitly mentioned.

Furthermore, with all of the relative or percentage, in particular weight-related, quantitative information mentioned below, it should be noted that within the scope of the present invention these are to be selected by the person skilled in the art in such a way that in the sum of the respective ingredients, active ingredients, additives or auxiliaries or the like, always 100% result. However, this goes without saying for the expert.

In addition, it applies that the person skilled in the application or in individual cases can deviate from the figures, ranges or quantities given below without departing from the scope of the present invention.

In addition, it applies that all of the parameter information or the like mentioned below can in principle be determined or determined using standardized or explicitly stated determination methods or with determination methods that are known per se to the person skilled in the art.

1. (a) Zwiebelextrakt (Extrakt Bulbus cepae) („Komponente (a)“) in einer Menge im Bereich von 0,05 bis 1 Gew.-%, bezogen auf die Zusammensetzung,
2. (b) Panthenol und/oder dessen Ester und/oder Pantothensäure und/oder deren physiologisch unbedenkliche Salze („Komponente (b)“) in einer Menge im Bereich von 1,5 bis 3 Gew.-%, bezogen auf die Zusammensetzung, und
3. (c) Ectoin und/oder Hydroxyectoin („Komponente (d)“) in einer Menge im Bereich von 0,001 bis 10 Gew.-%, bezogen auf die Zusammensetzung,

umfasst,
wobei der Zwiebelextrakt ein Droge/Extrakt-Verhältnis im Bereich von 1 : 1 bis 25 : 1 aufweist,
wobei die Zusammensetzung als Gel vorliegt, wobei die Zusammensetzung mindestens einen Gelbildner enthält, und wobei die Zusammensetzung den Gelbildner in einer Menge im Bereich von 1 bis 3 Gew.-%, bezogen auf die Zusammensetzung, enthält.The present invention thus - according to a first aspect of the invention - a composition for avoiding and / or reducing scar formation for the topical treatment of the urethra in surgical and / or transurethral interventions, the composition being used as active ingredients

1. (a) Onion extract (Bulbus cepae extract) ("Component (a)") in an amount in the range from 0.05 to 1% by weight, based on the composition,
2. (b) panthenol and / or its ester and / or pantothenic acid and / or its physiologically harmless salts (“component (b)”) in an amount in the range from 1.5 to 3% by weight, based on the composition, and
3. (c) Ectoin and / or hydroxyectoin ("component (d)") in an amount in the range from 0.001 to 10% by weight, based on the composition,

includes,
wherein the onion extract has a drug / extract ratio in the range from 1: 1 to 25: 1,
wherein the composition is in the form of a gel, wherein the composition contains at least one gelling agent, and wherein the composition contains the gelling agent in an amount in the range from 1 to 3% by weight, based on the composition.

The applicant has found, surprisingly, that the particularly synergistic combination of onion extract on the one hand and panthenol or pantothenic acid on the other hand can significantly reduce scarring, especially in the urethra, after transurethral or surgical interventions or already existing scars can be reduced. In this context, it has been shown in particular that the individual active ingredients complement one another in a synergistic manner, since the effect of the combination according to the invention significantly exceeds the effect of the individual active ingredients.

The terms “pharmaceutical composition”, “pharmaceutical preparation” or the like, as used in the context of the present invention, are to be understood very comprehensively and denote not only pharmaceutical preparations or pharmaceuticals, but also so-called medical products, homeopathic agents, cosmetics or the like .

The active ingredient onion extract used according to the invention, also referred to as “Bulbus cepae extract” or “Extractum cepae”, is in particular an extract containing active ingredients obtained from so-called kitchen onions (botanically Allium cepa). Onion extract is rich in essential oils, sulfur-containing compounds and flavonoids, especially quercetin, and has a scar-reducing effect. In the context of the present invention it is assumed that the scar reduction is triggered by an inhibition or reduction of the fibroblast proliferation. In addition, onion extract has an antiproliferative effect, so that the uncontrolled new formation of tissue is prevented in the context of the application of the composition according to the invention. In addition, onion extract has antimicrobial, anti-inflammatory and antioxidant effects.

As far as the active ingredient "panthenol" is concerned, this is understood in the context of the present invention to be a chemical compound which is one of the polyols and amides and has the systematic name 2,4-dihydroxy-N- (3-hydroxypropyl) -3,3- dimethylbutyramide carries. According to the invention, “panthenol” is also understood to mean esters of panthenol. In particular, in the context of the present invention, preference is given to using D (+) - panthenol, also known colloquially as dexpanthenol. In the course of the treatment according to the invention, the active ingredient develops, in particular, an effect that promotes wound healing. Panthenol is enzymatically converted in the body into pantothenic acid, which is also known as vitamin B5 and, as a component of coenzyme A, plays a central role in skin metabolism. Consequently, in the context of the present invention, instead of panthenol or else in combination with panthenol as component (b) of the composition according to the invention, pantothenic acid can be used, which chemically is N- (2,4-dihydroxy-3,3-dimethyl -1-oxobutyl) -beta-alanine, the (R) form being particularly preferred according to the invention; In particular, pantothenic acid can be used in the form of its physiologically harmless salts in the context of the composition according to the invention.

The absorption of panthenol or pantothenic acid after topical application increases the moisture retention capacity and consequently also the elasticity of the treated skin or mucous membrane. Furthermore, within the scope of the present invention, panthenol or pantothenic acid supports the regeneration of the treated mucous membrane cells, so that damaged tissue is regenerated more quickly. In addition, panthenol and pantothenic acid have anti-inflammatory and antipruritic effects. For further details on the active ingredient (b), reference can be made in particular to Römpp Chemielexikon, 10th edition, 1999, Georg Thieme Verlag, Stuttgart / New York, keywords “Panthenol” and “Dexpanthenol”, pages 927 and 3107-3108, and to the literature referenced therein, the relevant content of which is hereby fully incorporated by reference.

In the context of the present invention, it was completely surprising that onion extract on the one hand and panthenol on the other hand in connection with the reduction or reduction of scarring, in particular in surgical and / or transurethral interventions, complement each other in terms of their effectiveness, in particular act synergistically, that the need for operative or surgical interventions to treat urethral strictures due to scarring can be significantly reduced or reduced.

The present invention also has numerous other advantages and special features which distinguish it from the prior art and are described in detail below.

The composition according to the invention is - especially in comparison to the methods known from the prior art for treating urethral strictures - particularly uncomplicated with regard to its application and handling, since it is used purely topically. In addition, the use or application of the composition according to the invention for the patient is significantly less Inconveniences such as pain, long-term treatment times or spontaneously occurring complications.

Furthermore, with the composition according to the invention, the recurrence rate with regard to the recurrence of urethral strictures is reduced, since - without wishing to be limited to this theory - the cause of urethral strictures (namely scar formation, especially on the urothelium) is combated before they develop.

The composition according to the invention also effectively prevents the occurrence of urinary tract infections or inflammation, especially after transurethral interventions, since the combination of onion extract and panthenol according to the invention has excellent anti-inflammatory and antimicrobial properties in addition to the scar-reducing effect. Through the additional, optional use of fusafungin in the composition, these effects can moreover be increased even further, as will be described below.

Another particularly advantageous property of the composition according to the invention lies in the acceleration of the regeneration of the tissue, in particular the urothelium, after transurethral interventions. This effect is even reinforced by the additional use of ectoin, as described below.

Furthermore, the composition in question is characterized by its particularly good tolerance, since the ingredients are generally free from side effects. Onion extract is a purely plant-based natural substance, which is at least essentially free of chemical modifications and generally does not trigger any allergic reactions or intolerance in humans. Panthenol or pantothenic acid as vitamin B5 is also free of side effects.

In connection with the advantages and special features described above, reference is already made at this point to the effectiveness studies carried out by the applicant, which impressively demonstrate the aforementioned effects and are described in detail below.

The present invention can be designed in a variety of ways, preferred embodiments being described in detail below for better understanding.

With regard to component (a) or the onion extract in detail, the use of extracts with a high drug / extract ratio has proven to be particularly effective with regard to the scar-reducing effect. The drug / extract ratio (DEV) is a fixed pharmaceutical term that is used in particular in connection with phytopharmaceuticals and specifies the required initial amount of drug for the preparation of a certain amount of the extract. For an extract with a drug / extract ratio of 10: 1, this means that 1 part of extract is obtained from 10 parts of drug. With regard to a high concentration of active ingredient, it is therefore advantageous if the extract used has a large drug / extract ratio or an extract with a high drug / extract ratio is used. In the context of the present invention, the onion extract used has a drug / extract ratio in the range from 1: 1 to 25: 1.

As far as the amount of onion extract (extract Bulbus cepae) used is concerned, it varies in the range from 0.05 to 1% by weight. For a good effectiveness it has been found to be particularly favorable that the composition contains onion extract in an amount in the range from 0.05 to 1% by weight, based on the composition.

In addition, it can be provided according to the invention that the composition onion extract (extract Bulbus cepae) is preferred in an absolute amount in the range from 0.1 to 1,000 mg, in particular in the range from 1 to 500 mg, preferably in the range from 2 to 250 mg in the range from 3 to 100 mg, particularly preferably in the range from 5 to 80 mg, even more preferably in the range from 10 to 50 mg, the aforementioned derived amounts in particular relating to an application unit and / or in particular to an application amount.

An application unit or an application amount is to be understood in particular as the amount of composition according to the invention which is used in the context of an individual treatment (unit), in particular of the urethra. In this context, it can also be provided in particular that the composition according to the invention is used as an application unit or with the corresponding application amount is already present in a container, for example a syringe, for single use.

As far as component (b) or panthenol and / or its ester and / or pantothenic acid or its physiologically acceptable salts are concerned, the amount used varies in the range from 1.5 to 3% by weight. With regard to the effectiveness, in particular the support of the urothelium during regeneration, it has proven to be particularly efficient that the composition according to the invention contains component (b) (ie panthenol and / or its ester, and / or pantothenic acid and / or its physiologically harmless salts) in an amount in the range from 1.5 to 3% by weight, based on the composition.

In order to achieve a particularly efficient effectiveness of component (b), it has also proven to be advantageous if panthenol is contained in the composition in the form of dexpanthenol. Dexpanthenol is the biologically active form of panthenol, which is enzymatically converted to pantothenic acid (vitamin B5) in the body when it comes into contact with the skin.

With regard to the synergistic effect of onion extract on the one hand and panthenol on the other hand, it has proven to be particularly effective when component (a) and component (b) in a weight-related ratio of [(a): (b)] in the range of 1 : 1 to 100: 1, in particular in the range from 1.2: 1 to 80: 1, preferably in the range from 2: 1 to 60: 1, preferably in the range from 3: 1 to 30: 1, particularly preferably in the range of 4: 1 to 20: 1, very particularly preferably in the range from 5: 1 to 15: 1, are present in the composition.

According to a particularly preferred embodiment of the present invention, it can also be provided that the composition contains fusafungin and / or a fusafungin derivative (“component (c)”) as further component (c).

Fusafungin is a natural antibiotic which is synthesized by fungi of the genus Fusarium, in particular the species Fusarium lateritium, preferably WR strain 437, or other Fusarium species. From a chemical point of view, fusafungin is a heat-stable depsipeptide. It is an ionophore peptide antibiotic, which is a mixture of ennitatin A, B, C and possibly other components; Enniantins are cyclic depsipeptides with a circular backbone with peptide and ester bonds. Fusafungin is a solid which melts at 125 to 129 ° C, is almost insoluble in water, but is soluble in glycols and fats.

Fusafungin has hitherto only been used in the prior art for the treatment of infections of the upper respiratory tract. The applicant has surprisingly found that within the scope of the composition according to the invention, fusafungin or its derivatives in combination with the other active ingredients develop a particularly good effect and surprisingly increase the effect of the two basic components - onion extract and panthenol or pantothenic acid.

Fusafungin is particularly effective against gram-positive bacteria such as streptococci, pneumococci and staphylococci, but also against gram-negative bacteria and, moreover, against the fungus Candida albicans and against mycoplasmas without cell walls. The bacteriostatic or bactericidal effect of fusafungin is based - without wishing to be bound by a specific theory - on the ionophoric properties of the antibiotic, through which the permeability of the membrane of the pathogens for sodium and potassium ions is increased due to its function as an alkali cation transporter Way that the ion concentration gradient, which is essential for the bacteria, is broken down. In addition to the bacteriostatic or bactericidal effect, fusafungin also has an anti-inflammatory effect in the context of the composition according to the invention. Fusafungin derivatives are to be understood as meaning, in particular, its physiologically tolerable salts and its esters, ethers and amides. For more details on the active ingredient “Fusafungin” can, for example, be referred to Römpp Chemielexikon, 10th edition, 1999, Georg Thieme Verlag, Stuttgart / New York, keyword “Fusafungin”, page 1442 , as well as the literature referenced therein, the relevant content of which is hereby fully incorporated by reference.

In the context of the present invention it has surprisingly been found that fusafungin on the one hand and the combination of onion extract and panthenol or pantothenic acid on the other hand complement each other in their effect in a synergistic manner. The antimicrobial and anti-inflammatory properties of onion extract are further enhanced by the additional use of fusafungin, in particular, the overall effect of all of the aforementioned active ingredients, when applied together, significantly exceeds the effect of the respective individual active ingredients.

As far as the amounts of fusafungin used are concerned, these are also variable. It has proven to be particularly effective if the composition contains fusafungin and / or at least one fusafungin derivative in an amount in the range from 0.0001 to 5% by weight, in particular in the range from 0.001 to 3% by weight, preferably in the range from Contains 0.01 to 2% by weight, preferably in the range from 0.1 to 1% by weight, based on the composition.

Furthermore, it can be provided according to the invention that the composition fusafungin and / or at least one fusafungin derivative is preferred in an absolute amount in the range from 0.1 to 1,000 mg, in particular in the range from 1 to 500 mg, preferably in the range from 5 to 250 mg in the range from 10 to 100 mg, particularly preferably in the range from 20 to 80 mg, very particularly preferably in the range from 30 to 70 mg, the aforementioned amounts in particular relating to an application unit and / or in particular to an application amount.

In order to achieve a particularly efficient effect, it is particularly advantageous if the components “onion extract” (component (a)) and “fusafungin” (component (c)) are included in the composition in a specific weight-related ratio. In this context, it can in particular be provided that the composition contains component (a) and component (c) in a weight ratio of [(a): (c)] in the range from 1:10 to 10: 1, in particular in Range from 1: 5 to 5: 1, preferably in the range from 1: 4 to 4: 1, preferably in the range from 1: 3 to 3: 1, particularly preferably in the range from 1: 2 to 2: 1.

According to the present invention, it is also provided that the composition contains ectoine and / or hydroxyectoine (“component (d)”) as further component (d). The active ingredient ectoin is advantageous in the composition according to the invention, in particular with regard to a further acceleration of the regeneration of the urothelium after transurethral or surgical interventions.

The component ectoin used in the context of the present invention is chemically (4S) -2-methyl-1,4,5,6-tetrahydropyrimidine-4-carboxy acid according to the following structural formula:

The ectoin used according to the invention is a natural substance belonging to the group of compatible solutes, which has strong water-binding properties. Ectoin occurs in halophilic and extremophilic bacteria. Without wanting to be tied to a specific theory, Ectoin stabilizes the natural structure of biopolymers, such as proteins, nucleic acids and biomembranes, and protects the skin or mucous membrane from damage. Ectoin ensures a sustainable build-up of moisture, especially when used on mucous membranes. For further explanations in this regard with regard to ectoin, in particular with regard to its production, reference can be made to the European patent specification EP 0 887 418 B1 , the entire disclosure content of which is hereby incorporated by reference.

The amount of ectoin used varies in the range from 0.001 to 10% by weight. Particularly good results with regard to the effectiveness of the composition according to the invention are obtained if the composition contains ectoine and / or hydroxyectoine in an amount in the range from 0.001 to 10% by weight, in particular in the range from 0.001 to 9% by weight, preferably in the range from 0.01 to 8% by weight, preferably in the range from 0.1 to 6.5% by weight, particularly preferably in the range from 1.5 to 3% by weight, based on the composition .

As far as the further configuration, in particular the basic or carrier substances, of the composition according to the invention is concerned, this is variable. Preferred embodiments are described below.

With regard to the consistency of the composition according to the invention, it is advantageous if the composition has a viscous and / or pasty consistency. With regard to uncomplicated applicability, the composition is in the form of a gel.

In order to further improve the applicability in the urethra, it can be provided according to the invention in particular that the composition has a Brookfield viscosity at a temperature of 25 ° C in the range from 500 to 100,000 mPas, in particular in the range from 750 to 50,000 mPas, preferably in Range from 1,000 to 10,000 mPas, particularly preferably in the range from 1,500 to 8,000 mPas, very particularly preferably in the range from 2,000 to 6,000 mPas. By setting viscosities in the aforementioned ranges, the composition according to the invention is, on the one hand, sufficiently thin to enable easy application without exerting great pressure. On the other hand, good adhesion to the urothelium is achieved, so that the active components are in contact with the urothelium over a longer period of time and can be absorbed in order to develop their effect.

In addition, it is advantageous if the composition according to the invention has a physiologically compatible pH. In particular, it can be provided in this context that the composition according to the invention has a pH in the range from 3 to 8, in particular in the range from 4 to 7.5, preferably in the range from 5 to 7, particularly preferably in the range from 6 to 7 , having.

Furthermore, it can be provided within the scope of the present invention that the composition according to the invention has an electrical conductivity in the physiological range. In this regard, it is particularly advantageous if the electrical conductivity is in the range from 1 to 20 mS / cm, in particular in the range from 2 to 15 mS / cm, preferably in the range from 5 to 15 mS / cm.

As far as the further configuration of the composition according to the invention is concerned, it is usually provided that the composition is aqueous or aqueous-alcoholic.

In this context it has proven to be particularly advantageous if the composition has at least one preferably polyhydric alcohol.

As far as the preferably polyhydric alcohol is concerned, it can be 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. The preferably polyhydric alcohol propylene glycol is particularly preferred.

The amounts of the preferably polyhydric alcohol used can vary within wide ranges. It has proven to be particularly advantageous if the composition contains the preferably polyhydric alcohol in an amount in the range from 10 to 80% by weight, in particular in the range from 15 to 70% by weight, preferably in the range from 20 to 60% by weight. , based on the composition.

In addition, it can usually be provided within the scope of the present invention that the composition contains water, in particular in an amount of at least 10% by weight, in particular at least 20% by weight, preferably at least 30% by weight, based on the Composition. In particular, the composition can contain water in an amount in the range from 10 to 90% by weight, in particular in the range from 20 to 85% by weight, preferably from 30 to 80% by weight, based on the composition.

With a view to setting the desired consistency or viscosity of the composition according to the invention, the composition has at least one gel former.

As far as the gel former is concerned in particular, it can advantageously be selected within the scope of the present invention from the group of bentonites, silicas, polyacrylic acids, carbomers, polyvinylpyrrolidones, cellulose and cellulose derivatives, xanthan gums and mixtures thereof, preferably cellulose and cellulose derivatives. In particular, the gel former can be selected from modified celluloses, in particular chemically modified celluloses, particularly preferably methyl cellulose, hydroxymethyl cellulose, carboxymethyl cellulose and / or hydroxyethyl cellulose. Particularly good results are achieved when the gelling agent is hydroxymethyl cellulose.

The composition contains the gelling agent in amounts in the range from 1 to 3% by weight, based on the composition.

In order to keep the pH of the composition according to the invention constant, in particular in the context of its application, it is preferred according to the invention if the composition contains at least one acid and / or base, in particular to form a buffer system. In this context it can be provided that the composition contains at least one buffer system. In particular, it is advantageous if the composition preferably has at least one base; The base can preferably be selected from the group of amines, carboxylates, alkali and / or alkaline earth metal hydroxides and mixtures and combinations thereof, in particular alkali and alkaline earth metal hydroxides, preferably sodium hydroxide.

In addition, it can be provided according to the invention that the composition has at least one further active ingredient and / or ingredient, which can in particular be selected from the group of skin protection agents, antiseptics, local anesthetics, vitamins, trace elements, minerals, micronutrients and combinations thereof.

In particular, it can also be provided within the scope of the present invention that the composition contains at least one customary pharmaceutical additive and / or auxiliary substance, which can in particular be selected from the group of processing aids, stabilizers, emulsifiers, antioxidants, preservatives, humectants, pH adjusters , pH buffer substances, thickeners, antiseptics, coloring, buffering, fragrancing, fragrancing, stretching, binding, wetting and / or preserving substances and combinations thereof.

1. (a) Zwiebelextrakt (Extrakt Bulbus cepae) in einer Menge im Bereich von 0,05 bis 1 Gew.-%, bezogen auf die Zusammensetzung,
2. (b) Panthenol und/oder dessen Ester, und/oder Pantothensäure und/oder deren physiologisch unbedenkliche Salze in einer Menge im Bereich von 1,5 bis 3 Gew.-%, bezogen auf die Zusammensetzung,
3. (c) gegebenenfalls Fusafungin und/oder mindestens ein Fusafunginderivat in einer Menge im Bereich von 0,0001 bis 5 Gew.-%, insbesondere im Bereich von 0,001 bis 3 Gew.-%, vorzugsweise im Bereich von 0,01 bis 2 Gew.-%, bevorzugt im Bereich von 0,1 bis 1 Gew.-%, bezogen auf die Zusammensetzung,
4. (d) Ectoin und/oder Hydroxyectoin in einer Menge im Bereich von 0,001 bis 10 Gew.-%, insbesondere im Bereich von 0,001 bis 9 Gew.-%, vorzugsweise im Bereich von 0,01 bis 8 Gew.-%, bevorzugt im Bereich von 0,1 bis 6,5 Gew.-%, besonders bevorzugt im Bereich von 1,5 bis 3 Gew.-%, bezogen auf die Zusammensetzung,

aufweist.According to a further particularly preferred embodiment, the subject matter of the invention is a composition, in particular a pharmaceutical composition, which is used to avoid and / or reduce scarring for the topical treatment of the urethra in surgical and / or transurethral interventions, the composition being used as active ingredients

1. (a) Onion extract (extract Bulbus cepae) in an amount in the range from 0.05 to 1% by weight, based on the composition,
2. (b) panthenol and / or its esters, and / or pantothenic acid and / or its physiologically acceptable salts in an amount in the range from 1.5 to 3% by weight, based on the composition,
3. (c) optionally fusafungin and / or at least one fusafungin derivative in an amount in the range from 0.0001 to 5% by weight, in particular in the range from 0.001 to 3% by weight, preferably in the range from 0.01 to 2% by weight. -%, preferably in the range from 0.1 to 1% by weight, based on the composition,
4. (d) Ectoin and / or hydroxyectoin in an amount in the range from 0.001 to 10% by weight, in particular in the range from 0.001 to 9% by weight, preferably in the range from 0.01 to 8% by weight, preferably im Range from 0.1 to 6.5% by weight, particularly preferably in the range from 1.5 to 3% by weight, based on the composition,

having.

As far as the preparation of the composition according to the invention is concerned, this can be carried out using customary methods which are known per se to the person skilled in the art. Production takes place in particular by mixing or homogenizing the individual active ingredients or ingredients, followed by subsequent processing into the desired application form of a gel for topical use. This is known as such to the person skilled in the art, so that no further explanations in this regard are required.

Furthermore, it is particularly advantageous if the composition is ready-to-dose in containers, in particular with volume sizes in the range from 1 to 1,000 ml, in particular in the range from 2 to 500 ml, preferably in the range from 2 to 100 ml, preferably in the range from 3 to 50 ml, particularly preferably in the range from 4 to 30 ml, very particularly preferably in the range from 5 to 20 ml. In particular, it can be provided in this context that the volume size corresponds to an application amount and / or an application unit.

According to the invention, it is possible in particular to use the composition as described above in the field of pharmacy, medicine or cosmetics.

In this context, it is provided that the composition in the prophylactic and / or therapeutic treatment of the urethra for topical treatment of the urethra in surgical and / or transurethral surgery to avoid and / or reduce scarring in the urethra.

The composition according to the invention is usually present in a container, the container being in particular in the form of a tube, bottle, can, a pump and / or metering dispenser, a syringe or the like, preferably in the form of a syringe.

For further details on this aspect of the invention, to avoid unnecessary repetition, reference can be made to the above statements on the first aspect of the invention, which apply accordingly in relation to this aspect of the invention.

Finally, the subject matter of the present invention - according to a second aspect of the invention - is the use of a composition as defined above for the prevention and / or reduction of scarring for the topical treatment of the urethra in surgical and / or transurethral interventions and / or for the production of a medicament or therapeutic agent for the prevention and / or reduction of scarring for the topical treatment of the urethra during surgical and / or transurethral interventions.

For further details on this aspect of the invention, in order to avoid unnecessary repetition, reference can be made to the above statements on the other aspects of the invention, which apply accordingly in relation to this aspect of the invention.

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

The present invention is illustrated with the aid of the following exemplary embodiments, which, however, in no way limit the present invention.

Embodiments:

In the context of exemplary embodiments or effectiveness studies carried out by the applicant, the outstanding effect of compositions according to the present invention in relation to the avoidance or reduction of scar formation due to surgical or transurethral interventions has been proven.

For this purpose, a composition according to the invention (see composition C below) was compared with comparison compositions which contained active ingredient combinations not according to the invention (see composition A, composition B, composition D and composition E below) with respect to their effectiveness.

In this context, it was possible in particular to demonstrate the synergistic effect of the combination according to the invention.

The compositions in detail:

All the compositions described below had the same basic formulation on an aqueous-alcoholic gel base with the gel-forming agent hydroxymethyl cellulose in a relative amount of 2% by weight, based on the total composition (10 ml), and consequently only differed in the presence or absence of individual active ingredients .

Composition A (comparison):

• 30 mg Zwiebelextrakt
• 2 Gew.-% Dexpanthenol

The composition A not according to the invention contained the active ingredient components mentioned below in the amounts mentioned below, relative amounts being based on the total composition (10 ml):

• 30 mg onion extract
• 2% by weight dexpanthenol

The remaining constituents (to 100% by weight) were based on a gel base, the gel being aqueous-alcoholic and also containing hydroxymethyl cellulose as a gel-forming agent in a relative amount of 2% by weight, based on the total composition.

Composition B (comparison):

• 30 mg Zwiebelextrakt
• 2 Gew.-% Dexpanthenol
• 50 mg Fusafungin

Composition B, not according to the invention, contained the active ingredient components mentioned below in the amounts mentioned below, relative amounts being based on the total composition (10 ml):

• 30 mg onion extract
• 2% by weight dexpanthenol
• 50 mg of fusafungin

The remaining constituents (to 100% by weight) were based on a gel base, the gel being aqueous-alcoholic and also containing hydroxymethyl cellulose as a gel-forming agent in a relative amount of 2% by weight, based on the total composition.

Composition C (according to the invention):

• 30 mg Zwiebelextrakt
• 2 Gew.-% Dexpanthenol
• 50 mg Fusafungin
• 2 Gew.-% Ectoin

Composition C according to the invention contained the active ingredient components mentioned below in the amounts mentioned below, relative amounts being based on the total composition (10 ml):

• 30 mg onion extract
• 2% by weight dexpanthenol
• 50 mg of fusafungin
• 2 wt% ectoin

The remaining constituents (to 100% by weight) were based on a gel base, the gel being aqueous-alcoholic and also containing hydroxymethyl cellulose as a gel-forming agent in a relative amount of 2% by weight, based on the total composition.

Composition D (comparison):

• 30 mg Zwiebelextrakt

Composition D not in accordance with the invention contained the following active ingredient as the only active ingredient in the following amount (based on 10 ml of total composition):

• 30 mg onion extract

The remaining constituents (to 100% by weight) were based on a gel base, the gel being aqueous-alcoholic and also containing hydroxymethyl cellulose as a gel-forming agent in a relative amount of 2% by weight, based on the total composition.

Composition E (comparison):

• 2 Gew.-% Dexpanthenol

The composition E not according to the invention contained the following active ingredient as the only active ingredient in the following amount (based on 10 ml of total composition):

• 2% by weight dexpanthenol

The remaining constituents (to 100% by weight) were based on a gel base, the gel being aqueous-alcoholic and also containing hydroxymethyl cellulose as a gel-forming agent in a relative amount of 2% by weight, based on the total composition.

Effectiveness studies:

In order to examine the effectiveness of the composition according to the invention with the effectiveness of the comparison compositions, a series of tests was carried out with a test group of 75 patients.

The test group comprised 75 patients between the ages of 62 and 84, of whom 48 were male and 27 were female, who had to be catheterized regularly to completely empty the urinary bladder due to bladder emptying disorders. In order to compare the effectiveness of the compositions provided, the test subjects each received one of the compositions as part of each catheterization carried out as a catheter lubricant gel, with 15 test subjects being treated with one of the compositions A, B, C, D or E in each case. The treatment with the respective composition took place over a period of two months.

• • Verhinderung von Harnröhrenvernarbungen bzw. -strikturen
• • Regeneration des Gewebes nach der Katheterisierung
• • Verhinderung bzw. Reduzierung von Infektionen bzw. Entzündungen infolge der häufigen Katheterisierungen.

Following this treatment period, the evaluation of the effectiveness of the respective composition was carried out with regard to

• • Prevention of urethral scarring or strictures
• • Regeneration of the tissue after catheterization
• • Prevention or reduction of infections or inflammations as a result of frequent catheterizations.

The results in this regard are shown in the table below. The evaluation of the respective composition was carried out according to the school grading system with grades from 1 = very good to 6 = unsatisfactory. Table: Assessment of the compositions according to the school grading system composition A. B. C. D. E. Avoiding scarring 2.0 1.9 1.7 3.9 4.4 Regeneration of tissue injured by catheterization 1.9 1.9 1.8 3.5 3.2 Avoiding inflammation or infection 2.3 1.7 1.5 3.9 4.2

The above results show the excellent effect of the composition according to the invention over the comparative compositions. With the composition C according to the invention, the best results were obtained, which had a combination of onion extract, dexpanthenol, fusafungin and ectoin.

In particular, the results make it clear that the active ingredients complement each other in a synergistic manner, since the effect of onion extract on the one hand and panthenol on the other hand, when used in combination, significantly exceeds the effect of the respective monopreparations. This is particularly clear from the results or the assessments of the non-inventive composition A with the non-inventive comparative compositions D and E, which each contained the active ingredients onion extract and dexpanthenol as monoactive ingredients. With the composition A, not according to the invention, which contained the combination of onion extract and panthenol, excellent results were achieved with regard to avoiding scar formation, rapid regeneration of the urothelium and avoiding inflammation and infections. With the comparative compositions D and E, however, the results were not satisfactory.

In addition, the effect of the composition according to the invention can be increased even further by using fusafungin and ectoin as additional components. Through the additional use of fusafungin, in particular the reduction of inflammations or infections can be further improved, as the results of composition B show. The additional use of ectoin leads to an even faster regeneration of urethral tissue, in particular of the urothelium, which was injured or damaged as a result of the catheterization, which can be seen from the results obtained with composition C.

Summary:

Overall, it can be stated that within the scope of the present invention, a composition could be provided for the first time, which enables an easy-to-use measure for the topical treatment of the urethra in surgical or transurethral interventions and is suitable for avoiding or reducing scar formation. Up to now it has generally been necessary to counteract the formation of scars, in particular urethral constrictions or urethral strictures, with operative or surgical therapeutic measures in order to enable the patient to perform complete urination again.

Furthermore, the composition according to the invention also brings about a faster regeneration of the tissue and an avoidance of infections, as they often occur in the context of transurethral interventions. Such a composition is hitherto not known from the prior art.

Claims (10)

Composition for the prevention and / or reduction of scarring for the topical treatment of the urethra during surgical and / or transurethral interventions, the composition being used as active ingredients (a) Onion extract (Bulbus cepae extract) ("Component (a)") in an amount in the range from 0.05 to 1% by weight, based on the composition, (b) panthenol and / or its ester and / or pantothenic acid and / or its physiologically harmless salts (“component (b)”) in an amount in the range from 1.5 to 3% by weight, based on the composition, and (c) ectoin and / or hydroxyectoin ("component (d)") in an amount in the range from 0.001 to 10% by weight, based on the composition, wherein the onion extract has a drug / extract ratio in the range from 1: 1 to 25: 1, wherein the composition is in the form of a gel, wherein the composition contains at least one gelling agent, and wherein the composition contains the gelling agent in an amount in the range from 1 to 3% by weight, based on the composition. Composition according to Claim 1 wherein component (b) is dexpanthenol. Composition according to Claim 1 or 2 , the composition being used as further component (c) fusafungin (“component (c)”) in an amount in the range from 0.0001 to 5% by weight, in particular in the range from 0.001 to 3% by weight, preferably in the range from 0.01 to 2% by weight, preferably in the range from 0.1 to 1% by weight, based on the composition. Composition according to any one of the preceding claims, wherein component (d) is hydroxyectoin. Composition according to any one of the preceding claims, wherein the composition has a viscous and / or pasty consistency; and wherein the composition has a Brookfield viscosity at a temperature of 25 ° C. in the range from 500 to 100,000 mPas, in particular in the range from 750 to 50,000 mPas, preferably in the range from 1,000 to 10,000 mPas, particularly preferably in the range from 1,500 to 8,000 mPas , very particularly preferably in the range from 2,000 to 6,000 mPas; and the composition having a physiologically acceptable pH value and / or a pH value in the range from 3 to 8, in particular in the range from 4 to 7.5, preferably in the range from 5 to 7, particularly preferably in the range from 6 to 7, having; and wherein the composition has an electrical conductivity in the physiological range and / or an electrical conductivity in the range from 1 to 20 mS / cm, in particular in the range from 2 to 15 mS / cm, preferably in the range from 5 to 15 mS / cm. Composition according to one of the preceding claims, wherein the composition is aqueous or aqueous-alcoholic based and / or wherein the composition contains at least one preferably polyhydric alcohol; in particular where the preferably 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 where the preferably polyvalent Alcohol is propylene glycol; and / or in particular where the composition contains the preferably polyhydric alcohol in an amount in the range from 10 to 80% by weight, in particular in the range from 15 to 70% by weight, preferably in the range from 20 to 60% by weight on the composition. Composition according to any one of the preceding claims, wherein the composition contains water, in particular in an amount of at least 10% by weight, in particular at least 20% by weight, preferably at least 30% by weight, based on the composition, and / or in particular in an amount in the range of 10 up to 90% by weight, in particular in the range from 20 to 85% by weight, preferably in the range from 30 to 80% by weight, based on the composition. Composition according to any one of the preceding claims, wherein the gel former is selected from the group of bentonites, silicas, polyacrylic acids, carbomers, polyvinylpyrrolidones, cellulose and cellulose derivatives, xanthan gums and mixtures thereof, preferably cellulose and cellulose derivatives, in particular where the gel former is preferably selected from modified celluloses, in particular chemically modified celluloses, especially preferably methyl cellulose, hydroxymethyl cellulose, carboxymethyl cellulose and / or hydroxyethyl cellulose, very particularly preferably hydroxymethyl cellulose. Composition according to any one of the preceding claims, where the composition contains at least one acid and / or base, in particular to form a buffer system, and / or where the composition contains at least one buffer system and / or where the composition preferably has at least one base, in particular where the base is selected from the group of Amines, carboxylates, alkali and / or alkaline earth metal hydroxides and mixtures and combinations thereof, in particular alkali and alkaline earth metal hydroxides, preferably sodium hydroxide; and / or 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; and or the composition also having at least one customary pharmaceutical additive and / or auxiliary, in particular selected from the group of processing aids, stabilizers, emulsifiers, antioxidants, preservatives, humectants, pH adjusters, pH buffer substances, thickeners, antiseptics, coloring agents, buffers , Fragrances, fragrances, extenders, binders, wetting agents and / or preservatives and combinations thereof. Use of a composition according to one of the preceding claims for the prevention and / or reduction of scarring for the topical treatment of the urethra during surgical and / or transurethral interventions and / or for the production of a medicament or therapeutic agent for the avoidance and / or reduction of scarring for the topical treatment the urethra during surgical and / or transurethral interventions.