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WO2018153514A1 - Composition, en particulier gel, pour application au tractus urogénital - Google Patents

Composition, en particulier gel, pour application au tractus urogénital Download PDF

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Publication number
WO2018153514A1
WO2018153514A1 PCT/EP2017/079332 EP2017079332W WO2018153514A1 WO 2018153514 A1 WO2018153514 A1 WO 2018153514A1 EP 2017079332 W EP2017079332 W EP 2017079332W WO 2018153514 A1 WO2018153514 A1 WO 2018153514A1
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Prior art keywords
composition
component
composition according
range
extract
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German (de)
English (en)
Inventor
Andreas Meier
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Farco Pharma GmbH
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Farco Pharma GmbH
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
    • A61K36/8962—Allium, e.g. garden onion, leek, garlic or chives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A61K9/0039—Devices retained in the uterus for a prolonged period, e.g. intrauterine devices for contraception
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes

Definitions

  • 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.
  • 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.
  • the present invention is the use of the composition according to the invention.
  • the present invention relates to a container, a catheter or a syringe, each containing the composition according to the present invention.
  • the subject of the present invention is a packaging unit or a kit which contain the composition according to the invention.
  • the urinary organs 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).
  • the urethra 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.
  • endogenous causes such as inflammation, to injuries or changes to the tissue.
  • transurethral interventions on the urinary tract in particular the urethra
  • 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.
  • 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.
  • 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.
  • the epithelization phase occurs, in which the wound contracts, forming a denser network of collagen fibers ("contraction").
  • 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.
  • scarring on the urothelium after transurethral surgery is a common problem as it can lead to constrictions, also referred to as urethral strictures.
  • 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.
  • keloids 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.
  • wound healing can be impaired by inflammatory processes, in particular as a result of infiltration of pathogens.
  • 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.
  • 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.
  • 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.
  • the treatments are painful for the patient and require long-term follow-up care.
  • 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.
  • 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
  • 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.
  • the present invention is a packaging unit according to the invention according to the relevant independent claim.
  • 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,
  • composition in each case effective, in particular pharmaceutically effective amounts - as active ingredients, in particular in combination,
  • component (b) at least one surface disinfectant, in particular polyhexanide and / or its physiologically acceptable salts, ("component (b)");
  • 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
  • component (d) optionally at least one ectoine derivative, in particular ectoine and / or hydroxyectoine and / or its physiologically acceptable salts, ("component (d)");
  • 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.
  • a (renewed) scar formation after transurethral surgery can be controlled or prevented.
  • inflammation can be prevented and wound healing can be accelerated.
  • 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 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.
  • 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 lonen Koch 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • PHMB polyhexa-methylene biguanide
  • 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.
  • 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.
  • polyhexanide is characterized by low systemic absorption, which also minimizes side effects.
  • panthenol 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.
  • panthenol also means panthenol derivatives, such as esters.
  • 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.
  • 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.
  • 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.
  • panthenol or pantothenic acid 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.
  • panthenol and pantothenic acid are anti-inflammatory.
  • component ectoine and hydroxyectoine are chemically to (4S) -2-methyl-1, 4,5,6-tetra ", hydro-pyhmidin-4-carbo -, xyklare.
  • 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.
  • European patent EP 0 887 418 B1 the entire disclosure of which is hereby incorporated by reference.
  • 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).
  • 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:
  • Onion extract contains, as stated before, among others fructosans, flavonoids, numerous minerals, polyphenols, selenium compounds and thio compounds.
  • Zwie develops a physicochemical effect on extra kt or its ingredients, as explained below.
  • 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.
  • panthenol, ectoine and osmotically active substances the osmoregulatory effect can be increased even further, which leads in particular to accelerated wound healing.
  • onion extract has an antioxidant effect, ie the cells are protected against aggressive radical reactions in their environment.
  • 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.
  • fibroblasts are inhibited by onion extract growth (mitogenic inhibitory effect).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the composition in question is characterized by its particularly good compatibility, since the ingredients are generally free of side effects.
  • 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.
  • component (a) 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.
  • 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.
  • 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.
  • an ethanol / water mixture which contains 13 to 17% by volume of ethanol has proven to be particularly suitable.
  • the onion extract is provided from the plant Allium cepa L.
  • component (a) or the onion extract has a defined drug / extract ratio (DEV).
  • 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.
  • 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 characterizes the (weight-related) ratio of starting drug used to extract obtained.
  • the drug / extract ratio 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the composition contains at least one gelling agent.
  • 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.
  • the urothelium is shielded from passing urine.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the composition is aqueous or aqueous-alcoholic, especially aqueous, based.
  • the composition contains at least one preferably polyhydric alcohol.
  • 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.
  • 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.
  • the composition contains water.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the composition of the invention contains at least one physiologically acceptable, osmotically active substance and / or at least one physiologically acceptable osmolyte.
  • 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.
  • 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.
  • the osmotically active substances or the osmolytes are sodium ions and chloride ions, in particular in the form of sodium chloride.
  • the composition has at least one buffer system.
  • 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.
  • 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.
  • 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.
  • 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.
  • the composition has a physiologically acceptable pH.
  • 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, Grundtechnik 201 1, Section 2.2.3.
  • the determination of the pH can be carried out by methods known per se to those skilled in the art.
  • 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.
  • 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.
  • 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.
  • 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.
  • composition 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
  • the composition is at least substantially free of pharmaceutically acceptable preservatives.
  • 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.
  • the absence of preservatives in the compositions according to the invention increases the compatibility of the compositions even further.
  • the composition contains at least one further active ingredient or ingredient.
  • 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.
  • the composition also contains at least one further pharmaceutical additive and / or adjuvant.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • bougies 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.
  • 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.
  • 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.
  • 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.
  • the container is in the form of a catheter, in particular urinary catheter or fistula catheter.
  • the container according to the invention contains the composition according to the present invention as a sub-sterile, preserved composition.
  • 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.
  • 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.
  • 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.
  • the container may be present in an outer package that protects against contamination.
  • 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.
  • kits according to the invention 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.
  • compositions of the invention provided by the Applicant are compared with various comparative compositions.
  • the following tables give the recipes for the compositions provided.
  • 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)
  • a model system based on collagen gels with seeded fibroblasts i. H. Connective tissue cells from the dermis.
  • the model system is intended for the investigation of unwanted scarring.
  • TGF-beta cytokine transforming growth factor
  • hypertrophic scars and keloids 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.
  • 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 ⁇ g / 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.
  • 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,
  • compositions 4 to 6 lead.
  • Hyaluronic acid which has a moisturizing effect, has little effect on the contraction of fibroblasts (Composition 7).
  • compositions 8 and 9 which contain the active ingredients onion extract, dexpanthenol and ectoine according to the invention
  • composition 1 a marked reduction in contraction by activated fibroblasts and thus also a reduction in scar formation can be achieved.
  • the addition of dexpanthenol and ectoin can significantly increase the scar-reducing effect (compo- sitions 2 and 3).
  • compositions 8 and 9 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.
  • compositions 1 to 3 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.
  • 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.
  • 3-aminopropanol or its ammonium salt and D-pantolactone are characteristic decomposition products of dexpanthenol.
  • 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.
  • Stability tests were carried out on a batch of the composition according to the invention in accordance with recipe 3 described above.
  • 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.
  • 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.
  • 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.
  • 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.
  • compositions were prepared according to Formulation 3 except that the pH for a first test composition was adjusted to 5.0.
  • 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).
  • 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.
  • compositions based on formulation 3 were provided, which instead of citric acid / citrate contained a buffer system based on acetic acid / acetate or phosphate.
  • 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).
  • compositions 3, 8 and 9 were used.
  • Composition 3 contains polyhexanide as an antiseptic
  • composition 8 contains octenidine
  • composition 9 contains chlorhexidine.
  • the stability of composition 3 reference is made to the above statements under a), which prove the excellent long-term stability of the composition.
  • 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.

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Abstract

La présente invention concerne une composition, en particulier une composition pharmaceutique appropriée pour le traitement préventif et/ou thérapeutique, en particulier topique, de l'urètre afin d'empêcher et/ou réduire l'apparition de cicatrices et/ou de sténoses urétrales, de préférence pendant ou après des interventions chirurgicales et/ou transurétrales.
PCT/EP2017/079332 2017-02-24 2017-11-15 Composition, en particulier gel, pour application au tractus urogénital Ceased WO2018153514A1 (fr)

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DE102017105010.8A DE102017105010A1 (de) 2017-02-24 2017-03-09 Zusammensetzung, insbesondere Gel, zur Anwendung im Urogenitaltrakt

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US12383700B2 (en) 2019-06-13 2025-08-12 Hollister Incorporated Reusable urinary catheter products
US12440644B2 (en) 2020-06-23 2025-10-14 Hollister Incorporated Reusable urinary catheter products

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DE102020129363A1 (de) 2020-11-06 2022-05-12 Selina Jakumeit Schutzvorrichtung als temporäre Versiegelung während sexueller Aktivitäten zur Vermeidung von Harnwegs- und Blasenentzündungen

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US12383700B2 (en) 2019-06-13 2025-08-12 Hollister Incorporated Reusable urinary catheter products
US12440644B2 (en) 2020-06-23 2025-10-14 Hollister Incorporated Reusable urinary catheter products

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