Colestyramine for treating wounds, bacterial infections of the skin, and inflammatory skin lesions

Abstract

The invention relates to an agent from the group of anion exchangers, preferably colestyramine, for the care and prophylaxis of wounds and injuries, in particular in the presence of local bacterial infections or critical colonizations, with the goal of biologically neutralizing bacterial toxins which disrupt the healing process during the healing of the wound. The application can be carried out by directly applying the product or in combination with conventional materials and modern simple wound care methods.

Description

[0001] Cholestyramine for the treatment of wounds, bacterial skin infections, and inflammatory skin lesions

[0002] Description

[0003] The present invention relates to the use of anion exchangers, in particular cholestyramine, in wound care.

[0004] Infections in general, but especially localized and chronically infected wounds, have represented a serious medical problem in the history of medicine since its beginning (Hippocrates, 460-370 BC) and continue to this day. This problem also takes on a social dimension when one considers that in Germany alone, approximately 2-3 million people suffer from poorly healing or non-healing wounds. In addition to the personal suffering of affected patients, which can extend over many years, a remarkable approximately 2% of the total healthcare budget in Germany is spent annually on localized infections and poorly healing wounds. (1) In the US, the cost of this treatment is approximately $40 billion per year. With life expectancy increasing by approximately 2 to 3 months per year, this problem will continue to worsen worldwide without measurable progress in treatment.

[0005] Due to the typical colonization of both gram-positive and gram-negative bacteria on the body surface, critical colonization and wound infection occur in skin injuries and burns. Staphylococcus aureus, Escherichia coli, enterococci, MRSA, Proteus mirabilis, Klebsiella, ß-hemolytic streptococci, and Pseudomonas aeruginosa play a key role in this process.

[0006] Wound healing, especially in the cutaneous area, is one of the most complex processes in the human body 1 23) Wound healing normally occurs in regulated phases, but these can be disrupted and delayed in many ways, leading to the development of chronic non-healing wounds. The first, exudative-inflammatory phase initiates the process of healing or impaired healing. This initial healing phase, if successful, is followed by the proliferative phase and later by the phase of tissue remodeling. (1 2)

[0007] The treatment of deep, but also superficial, cutaneous wounds has changed significantly over the past two decades. Drying wounds with the idea of ​​preventing infection is now outdated, as this disrupts tissue repair and thus slows wound healing. The goal of modern wound therapy today is rather to ensure a physiological growth and healing environment in the wound area, thereby preventing pathological wound healing mechanisms and processes. (2 ' 34)

[0008] A first step in this direction was the introduction of hydroactive wound dressings to regulate the moisture balance in the wound area. Despite the wide variety of products available for this purpose, from wound dressings and various drainage devices (endosponages) to vacuum treatment, the superiority of some over others has not yet been proven by evidence. (56)For example, there are currently no binding guidelines for standardizing modern wound management. This is partly due to the fact that, due to its complexity, every wound treatment must be individualized and adapted to the specific patient.

[0009] A wound is defined as the loss of the integrity of an organ due to exogenous or endogenous influences. Depending on the type of wound, local wound factors, systemic mediators, and underlying causes (type of injury, burns, diabetes mellitus, peripheral arterial disease, varicose veins, genetic abnormalities, etc.), wound treatment may require an interdisciplinary therapeutic approach.

[0010] If the physiological process of wound healing is disrupted, particularly during the exudation and initial granulation phase, a chronic wound usually develops due to a prolonged inflammatory reaction. The physiological exudate of a wound is usually characterized by the activation of granulocytes, macrophages, and fibroblasts, by significantly elevated concentrations of cytokines or chemokines (IL-1, IL-6, IL-8, TNF-α, among others), by proteases and elastases, and by an increase in growth factors (FDGF, PDGF), which together are necessary for the unimpaired proliferation of fibroblasts to cover the wound. (3)

[0011] Microbial colonization of the wound leads to a lasting disruption of the physiological environment and also influences the immunological status in loco. This has led to an increasingly intensive use of antiseptics (silver, iodine, etc.) as well as to the almost unbridled administration of antibiotics in wound treatment. However, it was to be expected and is undeniable that the uncontrolled use of such substances, due to their cell and organ toxicity, also leads to significant medical problems. (7 8) and, above all, leads to the development of multi-resistant bacterial strains (MRSA, ORSA, or VRE). Furthermore, the high tissue levels required for such substances often provoke adverse effects, ranging from severe allergies to cell toxicity and severe organ damage. (9 10)There is now a general consensus that the effectiveness of these substances can only be maintained if their medical use is sensitively monitored and not used prophylactically or only in exceptional cases. Of paramount pathophysiological importance in the development of chronically infected and poorly healing wounds, whether superficial, deep, or located in a encapsulated focus, is usually not the bacteria themselves, but rather their toxins, which are produced by killing the bacteria and can trigger negative to severe local and systemic reactions.Depending on the patient's immune status and the concentration of bacterial toxins, these not only negatively impact wound healing itself, but also intensify local inflammatory processes and can spread throughout the body, often very quickly leading to organ failure, multi-organ failure, and even septic shock. Even today, nearly 50% of all affected patients die from this complication. (11 ) Just 100 ng of a bacterial toxin can have significant effects on humans, and a few micrograms can cause death; these are the most toxic biological substances for humans.

[0012] In loco, the presence of bacterial toxins (such as lipopolysaccharide [LPS] of Gram-negative bacteria and / or lipoteichoic acid [LTA] of Gram-positive bacteria, usually in combination) not only activates the coagulation cascade and impairs fibrinolysis, but also releases lysosomal enzymes and peroxide radicals. This results in a massive shift in the mediator balance in the wound exudate. In the complex inflammatory and reparative processes, cytokines, immunomodulators, and growth factors, together and through their interaction, play an important regulatory role. Increased concentrations of bacterial toxins lead to the activation of monocytes, endothelial cells, and neutrophil granulocytes.This results in increased expression of proinflammatory and immunomodulatory cytokines (IL-1β, TNF-α), other inflammatory mediators (histamine, kinins, nitric oxide), and an apoptosis imbalance favoring the apoptosis-promoting members of the Bcl-2 group. 2 ' 3 ' 12 ), as well as profound shifts in the complement system and the coagulation cascade. This explains the negative effect of bacterial toxins on wound growth of fibroblasts, on the reduction of blood supply, and thus on the negative balance of oxygen supply to the infected wound. (2 3)

[0013] The colonization of a wound, especially with problematic pathogens, not only delays wound healing through direct consequences such as abscess formation or tissue necrosis, but also, and especially through the release of LPS and LTA - among other things as a result of antibacterial and bactericidal therapy - the entire healing process and triggers a variety of complications.

[0014] To achieve the therapeutic goal—minimizing the pathologically effective concentration of bacterial toxins in the wound area—modern wound management strategies have so far offered few effective therapeutic approaches. Even a renaissance of traditional methods such as the use of silver ions, maggot treatment, honey treatment, activated charcoal compresses, etc., individually or in combination with modern antibiotics, has failed to produce any demonstrable benefit in reducing the pathologically effective concentration of bacterial toxins in the wound area.

[0015] The object underlying the invention was therefore to sustainably reduce the concentration of bacterial toxins locally using suitable materials or to render the bacterial toxins harmless without simultaneously negatively influencing the physiological environment of the wound, i.e., the natural concentration ratios of the biological mediators in the wound exudate, or disrupting their effect through excessive fluid withdrawal and thus counteracting wound healing. It was also the object of the present invention to bind the bacterial toxins from the onset of infection or critical bacterial colonization in a technically simple, effective, and cost-effective manner, thereby rendering them harmless, without permanently altering the physiological wound environment.Furthermore, the aim was to minimize the undesirable negative effects that are always to be expected in the context of possible simultaneous antibiotic treatment due to the increased release of bacterial toxins when the bacteria are killed.

[0016] Although the agent used according to the invention to achieve these objects is primarily aimed at the local treatment and prophylaxis of infection in skin wounds or susceptible skin areas (e.g. in neurodermatitis, psoriasis, acne), this equally applies to its use in any infected wound areas up to abscesses in body cavities (peritonitis, pleural empyema, etc.), organs (e.g. liver abscess), in bone tissue (e.g. osteomyelitis) or even treatment and prophylaxis of implant infections insofar as an introduction of the agent to the desired site of action is possible and medically sensible.

[0017] WO 2012 / 123363 A1 describes approaches to using bacterial toxin-binding materials as components of wound dressings to improve wound healing. However, these approaches favor complex-to-manufacture wound dressing materials and expensive hollow fiber materials with the greatest possible surface area, to which chemically modified adsorption materials are attached in a specific manner. Such solutions have so far been neither economically nor clinically feasible, primarily due to material costs.

[0018] There is therefore still a great need to improve the care of small and superficial wounds, as well as large or deep wounds, and to provide easy-to-use, effective, and cost-effective treatments for this purpose. Above all, there is still a need for treatments for people with specific and particularly serious injuries that cannot be satisfactorily treated with currently used materials and medications, or whose injuries are so severe that they pose a high risk to life. Such injuries include, in particular, burns, especially large-area burns.

[0019] This object is achieved by providing an agent endowed with properties known from chromatography technology and suitable for therapeutic action even in the treatment of specific skin wounds or injuries through the adsorption and, where appropriate, elimination of bacterial toxins. This applies to the care of wounds and injuries of all kinds, both for the prevention and treatment of the harmful effects of local bacterial infections. According to the invention, materials with the required characteristics comprise anion exchange groups suitable for ionically / physically binding bacterial toxins, in particular lipopolysaccharides and lipoteichoic acids (LPS and LTA), and thereby biologically neutralizing them. The agent according to the invention comprises one or more such anion exchangers as the active ingredient.

[0020] The anion exchangers used according to the invention are preferably polycationic molecules. These have polycation chains that are synthetic, semi-synthetic, or natural, although mixtures of these are also suitable. The polycation chains are present in linear or branched form.

[0021] Preferred cationic groups of the polycation chains are tertiary amino groups and / or, in particular, quaternary ammonium groups. These are, in particular, dialkylaminoalkyl or trialkylammoniumalkyl, dialkylaminoaryl or trialkylammoniumaryl, diarylaminoalkyl or triarylammoniumalkyl, diarylaminoaryl or triarylammoniumaryl radicals.

[0022] A preferred anion exchange moiety contains trimethylbenzylammonium residues. Within the scope of the present invention, the most preferred compound that can be used as an anion exchange moiety is cholestyramine (poly(trimethylammoniomethylstyrene chloride-co-divinylbenzene)). Furthermore, the substance colesevelam, which is also already used pharmaceutically due to its anion exchange activity, is a suitable active ingredient within the scope of the present invention.

[0023] Within the scope of the present invention, it is preferred that the anion exchanger, in particular cholestyramine, be in the form of a powder, fine granules, or processed into a powder, fine granules for incorporation into the agent. Colestyramine is advantageously used in a formulation that can be easily applied to the injury or wound. Any type of formulation, such as a cream, gel, or spray, is particularly suitable for this purpose. Such formulations will be explained in more detail below.

[0024] The effect of cholestyramine is based on the ionic binding of the lipid portion of toxic bacterial components (LPS, LTA). It is an ion exchange resin in the form of small to extremely small particles. Products with various particle diameters down to the nanometer range are commercially available and can be replaced according to the invention.

[0025] Cholestyramine is insoluble, non-absorbable, and neither metabolized nor stored in the body. As a basic substance, it is inexpensive to produce for the healthcare market.

[0026] According to its definition of use, cholestyramine is a medical device and not a drug. It has been used in gastroenterology for decades as an adsorbent for bile acids from the gastrointestinal tract. Adverse effects resulting from cholestyramine's mode of action are not known, even at high doses and with long-term use. Rather, the described adverse effects of oral administration at high doses can be directly attributed to the reduction in bile salts.

[0027] Within the scope of the present invention, it was found that applying the agent according to the invention in the form of a preferably covering layer to the skin area to be treated has extremely positive effects on the healing of a wound or lesion. Thus, in the context of the corresponding clinical studies, with the use of anion exchange materials according to the invention, namely primarily cholestyramine, not only did chronic wounds heal completely, but deep, acute wounds also healed within a very short time, unhindered by the negative effects of bacterial toxins. This accelerated healing tendency has been observed in both humans and animals in therapeutic trials, which is why both human and veterinary use is the subject of the present invention.

[0028] The chromatographically effective anion exchange material, and in particular cholestyramine, used in the inventive treatment of often already infected, critically colonized wounds prevents or reduces the negative effects of these toxins, as described above. Through the adsorptive binding and thus ultimate removal of, in particular, the endotoxins of Gram-negative bacteria, the lipopolysaccharides (LPS), and also the toxins of Gram-positive bacteria, the lipoteichoic acids (LTA), from the wound environment, it is possible to bring about a significant improvement in the pathophysiological conditions in the wound area, allowing natural wound healing to proceed largely unhindered.

[0029] Furthermore, it was found that the application of anion exchangers, in particular cholestyramine, enables biological neutralization and removal of harmful bacterial toxins in an extremely effective manner, but on the other hand, the physiological environment of the wound is hardly negatively influenced, particularly with regard to the concentration ratios of the biological mediators in the wound exudate.

[0030] Surprisingly, it was found within the scope of the present invention that wound healing is very positively influenced by the clinical application of the agent according to the invention, even when no antimicrobial substances are used. In contrast to the previously predominantly used antiseptic treatment of infected wounds, the measures of the present invention can prevent the healing process from being negatively influenced by the increased release of bacterial toxins as a result of such antiseptic treatment and / or antibiotic treatment. If it nevertheless appears appropriate, antibiotics, e.g.When used systemically, the agent according to the invention can prevent a massive, local release of bacterial toxins from entering the bloodstream and thus the entire body of the patient, which triggers the known subsequent cascade that progresses in a partially autoimmune-destructive manner via the activation of mediators and, in severe cases, can even lead to septic manifestations up to septic shock and death of the patient.

[0031] A moist wound environment, which is preferably maintained in the use of cholestyramine according to the invention due to a suitable formulation, enables good contact between the wound secretion and the toxin binding sites and thus guarantees the highest effectiveness of the treatment.

[0032] As already mentioned above, in addition to superficial wounds, deep wounds, wound cavities, and infections (e.g., postoperative), as well as abscess cavities and empyemas, are suitable for treatment with the agent according to the invention. In such wound conditions, the agent according to the invention can be applied to or introduced into the wound, cavity, or region. As with the treatment of superficial wounds, it is essential that the bacterial toxins are bound, do not spread throughout the wound environment, and do not enter the bloodstream.

[0033] In a quite unexpectedly positive way, patients with burns, especially with large-area burns, benefit from the use of the agent according to the invention.

[0034] Burn injuries are damage to the skin and underlying tissue caused by heat, chemicals, electricity, or radiation. The key difference from other acute or chronic wounds is the sometimes extensive damage to the skin's protective barrier. Serious consequences include fluid and electrolyte loss, infections, and other serious complications.

[0035] Even in medical treatment, burns differ from standard wound care. Unlike normal wounds, which can often be treated with modern wound management techniques, burn injuries require specialized care.

[0036] In addition to compensating for fluid / electrolyte losses and intensive pain management (often through induced coma), the priority here is the urgent prevention of infections and serious inflammation. The inflammatory reactions are primarily caused by highly potent bacterial toxins, which massively disrupt the physiological balance required for normal wound healing. A veritable tsunami of inflammation engulfs the tissue. In addition to severe local inflammatory reactions, fulminant courses with sepsis and multiple organ failure can result. Furthermore, pronounced inflammation-related scarring can lead to later severe functional limitations and, not least, to significant psychological problems.

[0037] Early, even prophylactic, intervention can significantly reduce the risk of complications, significantly improve long-term outcomes, and thus help affected patients recover as fully and quickly as possible. However, such options are currently insufficient.

[0038] The use of the agent according to the invention for the treatment of burns, particularly burns with a severity level of II or HB and higher, and especially in patients with extensive burns (from 2-5 cm wound size or diameter up to burns on entire limbs or body parts), represents a novel approach to solving the aforementioned problems. The use of the agent according to the invention, particularly cholestyramine in the appropriate formulation, can make a decisive contribution to preventing infections and serious tissue inflammation in the very specific field of burn treatment. The reason for this is the highly effective binding and thus elimination of bacterial toxins, as already mentioned several times.Due to the large surface area of ​​cholestyramine in the form used according to the invention, in particular as powder, powder or fine granules and in particular microspheres in the nanometer range, considerable amounts of the toxins can be bound and neutralized.

[0039] According to the invention, a water-based gel (hydrogel) in particular can fulfill all the criteria for efficient therapeutic use as a carrier substance for cholestyramine. Accordingly, for the inventive use of cholestyramine in the treatment of patients with severe and / or extensive burns, the use in a hydrogel formulation is a particularly preferred aspect of the present invention. Through the combination with a hydrogel, the active substance, preferably cholestyramine, is evenly distributed over the burn area and fixed at the site of action for an extended period. Furthermore, a hydrogel counteracts burn pain and supports the moisture balance of the tissue.The use of cholestyramine gels according to the invention has been shown to enable healing of even large burns within a very short time, and to proceed completely unhindered by the harmful effects of ubiquitous bacteria, which pose such a high risk for the development of serious complications and ultimately septic conditions in the current treatment regimen for large burns. Surprisingly, additional local antibiotic treatment can be completely dispensed with when using the agent according to the invention, which greatly supports wound healing.

[0040] Radiation damage, which occurs particularly in cancer patients after appropriate treatment, is also among the burns that can be advantageously treated within the scope of the present invention and lead to rapid, complete healing. The corresponding reports in the examples section of the present application demonstrate the exceptionally good effect, particularly in cases of previously therapy-resistant radiation damage. Patients with such radiation damage therefore represent another group of individuals who unexpectedly benefit particularly strongly from the inventive treatment with the cholestyramine products of the present invention.

[0041] A further preferred embodiment of the present invention is in the area of ​​poorly healing and previously at least partially therapy-resistant wounds of various types. Surprisingly, it has been shown that the use of the agent according to the invention also allows the chronic wounds, which are so burdensome for many people, in particular open leg ulcers (ulcus cruris), to heal quickly and completely when the agent according to the invention is used. This is a surprising effect and an unexpected technical effect of the present invention, as patients with such chronic lesions have generally already tried every available treatment method recommended by their doctors. In many cases, however, permanent healing could not be achieved despite the use of a wide variety of wound regimens, including antibiotic treatment.Surprisingly, it was shown that, within the scope of the present invention, outstanding treatment successes could be achieved here as well, and wounds that had existed for years could finally be healed completely.

[0042] The use of the agent according to the invention for the treatment of patients with chronic and long-standing wounds (in particular wounds existing over several months or years) is therefore a further particularly preferred embodiment of the present invention.

[0043] Another patient group whose treatment has so far been very complex and sometimes with little success are bedridden patients with more or less severe pressure ulcers. In these cases, too, current wound treatment methods have unfortunately only achieved limited success. The patients must be laboriously placed in bed and turned frequently. This places a considerable strain on hospital staff, but also on nursing staff in retirement homes and care facilities who also care for long-term bedridden patients. Compared to a "normal wound," a pressure ulcer is subject to constant stress and is often located in areas of the body where an environment detrimental to healing prevails. Pressure ulcer patients are therefore exposed to considerable pain over a long period of time and to negative health effects in addition to their underlying condition.An untreatable pressure ulcer is often a cause of patient death.

[0044] The agent according to the invention can be applied very effectively to body parts affected by pressure ulcers and can also remain in place, particularly if an appropriate covering is applied or some other protection is provided to prevent unwanted removal of the agent. Since experience has shown that healing begins very quickly after application of the agent according to the invention, healing of the pressure ulcer can be observed within a period of days to a few weeks. This outstanding effect of the agent according to the invention must also be considered surprising, since inexpensive, readily available, and uncomplicated materials are ultimately used to meet a long-standing need for medical application. Prophylactic use is also conceivable according to the invention.

[0045] The active ingredient of the agent according to the invention can be applied neat to the area to be treated, particularly when the anion exchanger is present as a powder or fine powder. In this embodiment, the agent according to the invention consists solely of the one or more anion exchangers; no carriers or excipients are present. In another embodiment, which is considered preferred for many applications, the active ingredient is present in a liquid to semi-solid or solid carrier base (e.g. in the form of a suspension, gel, cream, lotion, ointment, paste, spray / adhesive spray, powder, etc.). This carrier base is a pharmaceutically or galenically acceptable base. Such base products for any dosage form are known to the person skilled in the art. Particularly preferred within the scope of the invention are formulations with hydrogels, i.e. in particular cholestyramine in finely divided form incorporated into a gel base.

[0046] The agent according to the invention can be applied directly to the wound or previously incorporated into modern wound management materials (e.g. hydrofiber, foam dressing, alginate, etc.). Furthermore, the area to be treated can be protected after application of the agent according to the invention by placing a conventional wound dressing over it and, if necessary, securing it. This can be a compress, a plaster, or any other dressing material. This dressing material can be permeable to air, but should reliably hold the applied agent in place. Such a wound dressing can also protect against contamination, mechanical damage, drying out, unwanted wetness, or the like. Suitable materials are known to those skilled in the art. In a particularly preferred embodiment of the invention, the agent according to the invention, preferably the cholestyramine gel, is applied to a material that is impermeable to the gel. This can, for example, beFor example, it could be a film onto which a layer of gel is applied, allowing this product to be packaged ready for use and, preferably, offered in sterile form. Especially for large burns, the simple application of such a ready-to-use product facilitates application and thus reduces discomfort for the patient.

[0047] The concentration of the active ingredient according to the invention (preferably cholestyramine) in the carrier base is determined from clinical experience in the respective application form. In preferred, but non-limiting, embodiments of the invention, the agent contains the active ingredient in a carrier base at a concentration of 0.5 to 20 wt.%, although other concentrations may also be indicated depending on the application form. Concentrations of 1 to 15 wt.%, 2 to 10 wt.%, and especially 3 to 8 wt.% are more preferred, particularly for gels, creams, lotions, and ointments. As already mentioned above, the active ingredient can also be used neat, resulting in a 100% active ingredient concentration.When used as a powder or paste with appropriate carriers, which then also fall under the definition of a suitable carrier base, high concentrations of active ingredient can also be present, for example up to 95%, 90%, 80%, 75%, 50%, in each case based on the weight, or the above concentrations of 0.5 to 20% by weight can also be suitable for these dosage forms.

[0048] Finally, it is also conceivable, particularly for infection prophylaxis, to embody the agent in the form of a shower gel, shampoo, or other body cleansing or body care product. For this purpose, suitable substances, such as detergents, are included in the formulation of the agent according to the invention.

[0049] For application as a gel, suitable gelling agents or gelling agent mixtures known to those skilled in the art can be used. The gel base can contain, for example, substances, particularly from the group consisting of alginates, hyaluronic acid and hyaluronates, polyacrylic acid such as Carbopol® polymers, propylene glycol, carboxymethylcellulose, gum tragacanth, silicon dioxide, gelatin, methylcellulose, poloxamers, or povidone. It may also be desirable to use a commercially available gel base. Gel bases that form at least a temporary layer on the wound or skin are particularly suitable. Other suitable gel bases are hydrogels made from water and a water-insoluble polymer, or those based on a colloid / sol.

[0050] In a further preferred embodiment of the invention, the agent according to the invention is introduced into a moisture- or liquid-permeable container of suitable dimensions, which is suitable for application to the area to be treated. The container can be a pouch, a cushion or a bag, a cushion attached to a plaster, or similar products. In this embodiment of the invention, the agent according to the invention is not applied directly to the wound or lesion; rather, due to its moisture permeability, the active ingredient in the container is in exchange with the wound / wound secretion and can also bind bacterial toxins with high effectiveness in this embodiment.

[0051] The agent according to the invention can, if desired, contain one or more additional active ingredients. Such active ingredients can preferably be selected from the group comprising analgesics, anti-inflammatories, antiseptics, antibiotics, antimycotics, antiallergics, and antiviral substances. Mixtures of these substances, as well as other supporting substances, can also be added to the agent according to the invention. Examples that can be mentioned as preferred according to the invention include: silbenones, zinc oxide, povidone-iodine, activated carbon, ibuprofen, acetylsalicylic acid, diclofenac, dexpanthenol, and mixtures of two or more of these substances. The formulation of an agent according to the invention also corresponds to the above possibilities in this case. Depending on the additional active ingredient and its properties, the agent can therefore be used pure, i.e., undiluted and without carriers or excipients.Alternatively, the other dosage forms can be used using suitable carrier bases and additives as explained above. In particular, suitable preservatives can also be added.

[0052] Due to its good binding properties for LPS and LTA, cholestyramine, which is preferably used as the active ingredient according to the invention, can be used surprisingly well in combination with antibiotics or other bactericidal agents without the associated increased release of toxins causing undesirable effects. Thus, therapy with antibiotics (systemic or local) or other bactericidal agents can be supported by the agent according to the invention, thus significantly improving wound healing.

[0053] The inventive agent is intended for use in the prevention of infection in acute wounds and the accelerated healing of chronic, superficial, and deep wounds with critical bacterial colonization or infection. Corresponding treatment options exist, in particular, for dermatitis in general, including neurodermatitis, skin eruptions, burns, folliculitis, boils, carbuncles, acne, decubitus ulcers, subcutaneous and deeper infections, abscesses, and empyemas, among others.

[0054] The treatment according to the invention can be performed both acutely and for infection prophylaxis, the latter particularly in the case of burns, pressure ulcers, leg ulcers, and atopic dermatitis. The agent according to the invention also offers good treatment results for leg ulcers (leg ulcers), pressure ulcers, and other chronic wounds, particularly those caused by diabetes mellitus, peripheral arterial disease, and varicose veins, as well as for their prevention once the first lesions appear.

[0055] The invention represents a completely new and cost-effective concept for wound treatment, which has already proven extremely effective in use on selected patients.

[0056] In addition to the agent according to the invention, combinations with other anion exchangers as active ingredients, as well as with other agents and products known in wound management, are also the subject of the invention.

[0057] In addition to the medical applications mentioned above, the agent according to the invention is also of particular interest for cosmetic applications. While clinically relevant acne often requires the treatment of open and already infected wounds, mild cases of acne in both adolescents and adults are more likely to be considered a cosmetic problem. In the early stages of the development of pimples, pustules, or blackheads, a hair follicle duct becomes blocked for various reasons, resulting in the formation of a retention cyst. If this cyst becomes inflamed, a purulent pustule forms. Such a pustule usually opens spontaneously or can be easily opened manually. Treatment is indicated especially after the pustule has opened in order to promote rapid healing without scarring or to prevent the infection from spreading to other areas of the skin. However, treatment of a closed pustule may also be indicated, e.g.This prevents bacteria from entering during the opening process. Furthermore, a retention cyst that has not yet been infected can also be treated with the agent according to the invention.

[0058] The agent according to the invention is particularly suitable for these cosmetic applications because it can be applied easily and simply, and even applying it generously beyond the actual area of ​​the skin impurity is completely unproblematic.

[0059] These advantages in use apply to the agent in powder form as well as to a product in semi-solid or liquid form (e.g., as a spray or tincture). By allowing the formulation to dry quickly on open skin and preferably by including film-forming excipients or carriers, the agent according to the invention can remain at the site of action for a sufficiently long time without causing visual impairment.

[0060] A further subject of the invention is therefore the non-therapeutic, cosmetic use of the agent according to the invention for skin impurities of all kinds, especially mild to moderately impure skin or acne, or an agent for use in the aforementioned cases.

[0061] The invention is illustrated by the following examples and treatment reports.

[0062] Examples

[0063] Example 1: In vitro adsorption and elimination of LPS and LTA from a simulated wound exudate in the presence of cytokines and a growth factor

[0064] Comparison of cholestyramine with another anion exchange resin

[0065] The simulated wound exudate consisted of human albumin (2 wt%), calcium chloride (0.02 M), sodium chloride (0.4 M), and trimethylamine (0.08 M) dissolved in distilled water. The pH was adjusted to 7.5.

[0066] The following bacterial toxins, human cytokines and a representative growth factor were added to the simulated wound exudate:

[0067] A. Lipopolysaccharide (LPS, 2 µl / mL, E. coli 055: B5 endotoxin;

[0068] BioWhitaker)

[0069] B. Lipoteichoic acids (LTA, 1 pg / mL, Streptococcus pyogenes; Sigma Aldrich)

[0070] C. Recombinant human tumor necrosis factor alpha (rh TNF-α, 10 pg / ml; Biomol)

[0071] D. Recombinant human interleukin-6 (rh IL-6, 50 pg / mL; Biomol)

[0072] E. Recombinant human platelet-derived growth factor A (rhPDGF A;

[0073] 50 ng / ml; Biomol)

[0074] An aliquot (5 mL) of the simulated wound exudate or wound exudate supplemented with bacterial toxins and human cytokines as well as with a growth factor was mixed with 100 mg of each of the adsorbents listed below, incubated for 4 hours at 37°C and then centrifuged at 1000 g.

[0075] Adsorbents used:

[0076] 1. Colestyramine (Quantalan, Bristol Meyer Squibb)

[0077] 2. DEAE-modified polyamide hollow fiber (according to DE 10258944 A1; B. Braun Melsungen AG) The substances added to the simulated wound exudate (AE) have the following molecular weights: A and B) common lipid A subunit ~ 2000 Dalton; C) ~ 50000 Dalton; D) ~ 25000 Dalton; E) ~ 30000 Dalton.

[0078] Determination methods:

[0079] LPS was determined using the chromogenic kinetic Limulus amoebocyte lysate test (LAL-QCL, Cambrex).

[0080] LTA detection was performed indirectly using a whole blood stimulation assay. Freshly collected heparinized whole blood from a healthy donor was mixed with untreated or treated prepared wound exudate in a ratio of 6:1 (v / v) and incubated for 24 hours at room temperature. Following centrifugation (3000 g for 10 min) and collection of the corresponding plasma fraction, the LTA-stimulated interleukin-6 (IL-6) biosynthesis rate was determined. Recombinant human interleukin-6 (IL-6) and rh PDGF-A were quantified using a corresponding ELISA assay (Biomol GmbH).

[0081] The concentration of recombinant human TNF-α was determined using an EIA kit (Biomol GmbH).

[0082] Results:

[0083] After incubation with the prepared wound exudate and removal of the used adsorbents by centrifugation, the percentage depletion (elimination rate) of the added components (AE, i.e., bacterial toxins, cytokines, and growth factor) was determined in the respective supernatant. The following elimination rates [%] were obtained:

[0084] This example demonstrates a level of effectiveness for cholestyramine equivalent to that of materials known for LPS / LTA adsorption. Other substances, such as cytokines and growth factors, are not bound in significant quantities, leaving the physiological mediators of wound healing virtually unaffected.

[0085] Example 2: Therapy reports from clinical application:

[0086] Patient 1 presents with a condition following open abdominal surgery with healing and a remaining scar of approximately 8x12 cm.

[0087] After initiating tumor therapy, severe ulcerations recurred (Fig. 1A, see black outline). Treatment was then initiated with a gel according to the invention (6% cholestyramine in a gel base (aqua, propylene glycol, panthenol, sodium carbomer, sodium hydroxide, phenoxyethanol, ethylhexylglycerin, sodium hyaluronate)), which was applied in a thin layer (approximately 1 mm) to the wound.

[0088] After 2 weeks, there is a significant reduction in signs of inflammation and a visible reduction in the wound area (Fig. 1 B, see black border).

[0089] After a further 4 weeks of treatment, complete wound closure was achieved despite continued tumor therapy (Fig. 1 C).

[0090] Patient 2 suffers from locally advanced breast cancer. Severe dermatitis developed during radiation therapy (Fig. 2A, see black outline). Despite receiving specialized wound care for months, the patient still complains of severe burning pain.

[0091] Treatment with gel (6% cholestyramine in a gel base (aqua, propylene glycol, panthenol, sodium carbomer, sodium hydroxide, phenoxyethanol, ethylhexylglycerin, sodium hyaluronate)) was then initiated. A thin layer (approximately 1 mm) was applied to the wound. After 2 weeks, there was a significant reduction in signs of inflammation and symptoms (Fig. 2B).

[0092] After a further 4 weeks of treatment with the cholestyramine gel according to the invention, a further reduction in the signs of inflammation is observed (Fig. 2 C), and the patient is almost symptom-free.

[0093] Patient 3, female, age 51, sustained a burn on her forearm and hand with redness, skin injury and blistering while adding wood to an open fireplace on an iron part. This burn was a stage II burn with redness on a skin area of ​​approximately 2 x 10 cm on the forearm and approximately 2 x 4 cm on the hand, and blistering over 70-80% of the wound area. Treatment began on the same day. The patient applied a thin layer of the gel according to the invention (6% cholestyramine in a gel base (aqua, propylene glycol, panthenol, sodium carbomer, sodium hydroxide, phenoxyethanol, ethylhexylglycerin, sodium hyaluronate) to the entire injured skin area. The application was repeated twice daily. After just 2 days, the patient was pain-free, and after 5 days, the burn wounds had completely healed (verbal report from the patient who applied the cholestyramine gel herself).

[0094] Patient 4, a male, had been treated as an inpatient in a trauma clinic for several weeks following an accident. He was bedridden and had developed a large pressure ulcer, which was then treated with the gel according to the invention (6% cholestyramine, aqua, propylene glycol, panthenol, sodium carbomer, sodium hydroxide, phenoxyethanol, ethylhexylglycerin, sodium hyaluronate). Within a few days, the pressure ulcer began to heal, and after three weeks of treatment, the pressure ulcer had already shrunk considerably, to approximately 50% of its original size. After two more weeks, the pressure ulcer had completely healed.

[0095] Patient 5, a 56-year-old male, suffers from prurigo nodularis with chronic ulcerative dermatitis. His status after 8 months of treatment with modern wound management is shown in Figure 3A. After 3.5 months of treatment with colstyramine hydrogel (6% cholestyramine, aqua, propylene glycol, panthenol, sodium carbomer, sodium hydroxide, phenoxyethanol, ethylhexylglycerin, sodium hyaluronate), almost complete wound closure was achieved (Figure 3B).

[0096] Patient 6, an 80-year-old female, suffered from a post-traumatic right leg ulcer with venous insufficiency. After a split-thickness skin graft with partial graft rejection and prolonged wound treatment with modern wound management techniques, the treatment status was extremely unsatisfactory, as shown in Figure 4A.

[0097] After 8 weeks of treatment with the cholestyramine gel according to the invention (6% cholestyramine, aqua, propylene glycol, panthenol, sodium carbomer, sodium hydroxide, phenoxyethanol, ethylhexylglycerin, sodium hyaluronate), complete wound closure was observed (Fig. 4B). References:

[0098] 1. J. Heinlin et al.

[0099] Wound healing - therapeutic interventions

[0100] Dermatologist 2010, 61 :611 -628

[0101] 2. Y. Winkler

[0102] Endotoxin binding, bactericidal efficacy and cytotoxicity of silver-containing wound dressings

[0103] Inaugural dissertation, Ernst Moritz Amtt University of Greifswald, 2010

[0104] 3. M. Schäffer, H.-D. Becker

[0105] Immune regulation of wound healing

[0106] Surgeon 1999, 70:897-908

[0107] 4. H. Lippert

[0108] Wound Atlas: Compendium of Complex Wound Treatment

[0109] Georg Thieme Verlag KG, Stuttgart / New York, 2006

[0110] 5. M. Voshege et al.

[0111] Was ist evidenzbasiert in der Behandlung chronischer Wunden? Gefäßchir 2003, 8:269-276,

[0112] 6. P. K. Baier et al.

[0113] Subcutaneous Redon drains do not reduce the incidence of surgical site infections after laparotomy. A randomized controlled trial on 200 patients

[0114] Int J Colorectal Dis 2010, 25:639-643

[0115] 7. S. Trambe et al.

[0116] In vitro evaluation of the risk of developing bacterial resistance to antiseptics Atimicrob Chemother 2001 , 47:589-598 P. Appelgren et al.

[0117] A prospective study of infections in bum patients

[0118] Bums 2002, 28:39-46 G. Müller et al.

[0119] Biocompatibility index of antiseptic agents by parallel assessment of antimicrobial activity and cellular cytotoxicity

[0120] J Antimicrob Chemother 2008, 61 :1281 -1287 W. Lineaweaver et al.

[0121] Topical antimicrobial toxicity

[0122] Arch Surg 1985, 120:267-270 R. Stone

[0123] Search for sepsis drugs goes on despite past failures

[0124] Science 1994, 264:365-367 Z. Metzger et al.

[0125] The effect of bacterial endotoxin on the early tensile strength of healing surgical wounds

[0126] J Endod 2002, 28:30-33 Xin Liu et al.

[0127] In vivo wound healing and antibacterial performances of electrospun nanofibre membranes

[0128] J Biomed Mater Res A. 2010, 94:499-508

Claims

Claims: A composition for use in the treatment of wounds or lesions of the skin and / or underlying tissues, in particular for the prevention and / or treatment of adverse effects in local bacterial infections or critical colonization in the wound or lesion area, characterized in that it comprises as an active ingredient an anion exchanger suitable for binding bacterial toxins and thereby biologically neutralizing them. A composition for use according to claim 1, characterized in that the wounds or lesions of the skin and / or underlying tissues are burns of grade 2 or higher, in particular grade 2 or 2b. A composition for use according to claim 1, characterized in that the wounds or lesions of the skin and / or underlying tissues are chronic wounds, in particular leg ulcers.A composition for use according to claim 1, characterized in that the wounds or lesions of the skin and / or underlying tissues are pressure ulcers, in particular pressure ulcers of stage 2 or stage 3. A composition for use according to any one of the preceding claims, characterized in that it contains cholestyramine and / or colesevelam, preferably cholestyramine, as the active ingredient. A composition for use according to any one of claims 1 to 5, characterized in that the active ingredient is available as a crude substance or in a... A composition for use according to any one of claims 1 to 6, characterized in that it is applied or placed directly onto the infected or inflamed area, or is introduced in a moisture- and / or fluid-permeable container, for example, a pouch, pad, or bag, or is applied to a moisture- and / or fluid-impermeable film or other substrate. A composition for use according to any one of claims 1 to 6, characterized in that it is integrated into a conventional wound dressing. A composition for use according to claims 1 to 6, characterized in that the active ingredient is incorporated into a matrix that forms an adhesive layer on the wound or skin.A composition for use according to any of the preceding claims, characterized in that it contains, in addition to the anion exchanger, one or more further active ingredients in combination. A composition for use according to claim 10, characterized in that the combination comprises one or more further active ingredients selected from the group consisting of antibiotics, analgesics, anti-inflammatories, antiseptics, antifungals, antiallergics, antiviral substances, silbenones, zinc oxide, povidone-iodine, activated charcoal, ibuprofen, acetylsalicylic acid, diclofenac, local anesthetics, dexpanthenol, and mixtures thereof. A means for use according to any of the preceding claims, characterized in that the wound or lesion to be treated is a superficial or deep wound, an open, infected acute or chronic wound, a subcutaneous infection, a deep-lying infected region, possibly also after implantation of a foreign body, a skin efflorescence, a burn, folliculitis, a boil, acne, dermatitis, neurodermatitis, or a pressure ulcer. A means for use according to any of the preceding claims, characterized in that, in cases of particular genetic predisposition, as well as in cases of predisposition to neurodermatitis, burns, or pressure ulcers, it is also used for prophylactic application to prevent critical colonization or bacterial infection.Non-therapeutic use of a composition containing an anion exchanger, in particular cholestyramine, as an active ingredient for cosmetic purposes, wherein the composition is preferably characterized as in claims 5 to 13. Non-therapeutic use of a composition according to claim 14 for the treatment or prophylaxis of mild to moderate acne, pimples, pustules, and blackheads. Method for treating wounds or lesions of the skin and / or underlying tissues, in particular for the prevention and / or treatment of adverse effects of local bacterial infections or critical colonization in the wound or lesion area, characterized in that it comprises an anion exchanger as an active ingredient, which is suitable for binding bacterial toxins and thereby biologically neutralizing them.

17. Use according to claim 16, characterized in that the agent is characterized as in claims 5 to 13.

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