WO2020144565A1

WO2020144565A1 - Composition for use in the treatment of skin lesions in cancer patients

Info

Publication number: WO2020144565A1
Application number: PCT/IB2020/050078
Authority: WO
Inventors: Paolo Ferrazza
Original assignee: Paolo Ferrazza
Priority date: 2019-01-10
Filing date: 2020-01-07
Publication date: 2020-07-16
Also published as: IT201900000391A1

Abstract

A composition for use in the treatment of skin lesions comprising: Polyethylene glycol 400 at an amount of 67% by weight; Polyethylene Glycol 4000 at an amount of 26.3%; Micronized allantoin at an amount of 5% by weight; 18-β glycyrrhetinic acid at an amount of 1% by weight; Chlorhexidine gluconate at an amount of 0.5% by weight; Vitamin A acetate at an amount of 0.2% by weight.

Description

“Composition for use in the treatment of skin lesions in cancer patients”

Description Field of the art

The present invention regards the medical industry and in particular to the dermatological industry. In greater detail, the present invention regards a particular composition formulated in ointment to be used typically in the treatment of radiation injuries, exposed metastases, sores and deep wounds, deep surgical wounds and burns found in cancer patients.

Prior art

Despite widespread use of linear accelerators and the general improvement of radiation therapy techniques, such as modulated intensity radiotherapy, having reduced the severity of skin lesions through protective techniques for the same, concomitant use of high-dose chemotherapy and radiotherapy still causes significant problems for patients. The most serious lesions were observed in patients who received high doses for a large irradiated area. Radiation injuries may affect any organ or system which will generally tend to undergo fibrosis and, in the most serious cases, degeneration with ulceration and necrosis.

Actually, organs are sensitive in a different way to radiation and in this respect, we talk about radiosensitivity: in particular, the most radiosensitive organs are the bone marrow, reproductive and gastrointestinal systems, skin, muscles and brain.

In particular, in order to understand the mechanism of creating skin lesions, it is necessary to know not only the radiobiological effects of radiation therapy treatment, but also the way in which healthy skin regenerates. The main function of the skin is to establish an effective physical and immunological barrier against the surrounding environment. The skin consists of two main layers: the epidermis (surface layer) and the dermis (deeper layer). The former consists of layers of keratinocytes, cells with a protective function against attacks of pathogenic organisms, heat, UV radiation, water loss, while the dermis is the layer immediately below the epidermis, which confers the structural scaffold to the skin and it mainly consists of connective tissue produced by fibroblasts.

The skin is particularly susceptible to radiation damage because it is a rapidly and continuously renewed system and radiation can damage the cell reproduction capacity of the basal layer right from the first dose, and therefore given that radiotherapy is carried out through a variable number of treatments based on the total dose to be irradiated and how it is fractionated, subsequent sessions prevent the repopulation process, hence reducing skin integrity. Thus, these repeated exposures do not give the cells time to repair damage to the tissue or to the DNA. The dermis damage is further aggravated by the fact that basal keratinocytes, stem cells of the hair follicle, and melanocytes are highly radiosensitive.

Skin reactions may include mild erythema , dry desquamation and moist desquamation , with the presence of blisters. In particular, lesions can be classified as acute and chronic the former intervene rapidly, sometimes even during radiotherapy, more frequently at the end of radiotherapy, while the latter develop in an average range of time ranging from six months to three years after the end of radiotherapy. Table 1 shows the different acute and chronic lesions depending on the dose received and the onset of the lesion.

Table 1.

One of the most serious consequences of radiation therapy is transepidermal water loss, which is a defence for the integrity of the skin barrier. Serious radiation injuries have also occurred, leading to complete loss of the epidermis up to the presence of exudate.

With regard to the pathogenesis of acute lesions, capillarography reveals an evident vasodilation of the vessels of the basal layer of the epidermis, followed in subsequent sessions by vasoconstriction and subsequently by further vasodilatation toward the end of radiotherapy. It has also been confirmed that the X-ray erythema develops in two phases: the first one within the tenth session, the second one within the twentieth. The first erythema results in the direct release of vasodilators such as prostaglandins (mediators that inhibit platelet aggregation), at doses of approximately 1.5 Gy. This is followed by a reduction in erythema related with the onset of events blocking the further development of erythema and probably the activation of vasoconstrictive processes. The second erythematous phase, around the twentieth session, is characterised by a new vasodilatation which frees intracellular mediators. Whereas the pathogenesis of chronic lesions is to be found where three events occur simultaneously: hypovascularization (consequent to the damage suffered by vessels, in particular arterial vessels), tissue hypoxia (i.e. lack of oxygen), hypocellularity (induced by cell death). Furthermore, although viable the residual cells could undergo a functional damage: osteoblasts remain in place as living cells, but functionally inactive, that is, they are no longer able to produce osteoid substance, similar to chondroblasts that no longer produce chondral matrix.

With regard to the incidence of radiation injuries, it has been shown that more than 95% of patients receiving radiation therapy treatments for cancer reveal skin lesions. These patients can be divided into 80-90% who have had erythematous reactions, and about 10-15% who have had moist desquamation. Furthermore, clinical experience has confirmed that, in any case, skin irritations are common to all patients who have been treated radically, and that moist desquamation reactions are not only the most difficult to manage but also, above all, the most painful for patients.

Several factors that affect the degree and duration of skin reactions due to exposure to radiotherapy can be identified. These can be divided into two classes:

• Intrinsic factors : those related to the individual such as age, general skin conditions, nutrition, general health, concomitant diseases and ethnicity.

· Extrinsic factors : these strictly regard treatment such as the dose, the volume, the duration of the individual treatment and the total treatment, the site of treatment, the energy of the beam and the possible adjuvant chemotherapy.

A good result can therefore be achieved on skin health if the degree of risk is taken into account, thus adopting the right strategies.

Treatment of radiation injuries should be chosen based on the degree of severity of the lesion. In any case, it is important that, whatever treatment is chosen, the patient’s comfort should be taken into account, the purpose of treatment should aim at reducing pain, preventing infections and it should not be traumatic in the possible removal of the dressing. According to the Radiation Therapy Oncology Group (RTOG) assessment tool, clinical guidelines recommended by the College of Radiographers, injuries can be classified according to the following RTOG scale:

• RTOG 0: no visible skin change;

• RTOG 1 : faint or dull erythema, mild tightness of skin and itching may occur. Almost all patients suffer from this type of skin reaction;

· RTOG 2a: bright erythema, with or without dry desquamation (loss of superficial skin layers);

• RTOG 2b: patchy moist desquamation, moderate erythema;

• RTOG 3: confluent moist desquamation, strong oedema. In particular, the Society of Radiographers (SOR) guidelines (7) highlight the following recommendations :

• RTOG 1, 2a: wash the skin with lukewarm water and, if desired, with non-perfumed washing bases. Dry by gently buffering. The patient should wear comfortable, lightweight cotton clothing without stitching that could cause friction. To prevent friction and relieve symptoms of inflammation, moisturising products can be used to keep the skin soft and elastic. In particular, a number of randomised studies have evaluated the use of Aloe Vera for the treatment of radiation injuries and it has been found useful not only as a moisturising product but also for its anti-inflammatory and antibacterial properties. In isolated cases, steroid creams can reduce the sensation of itching and inflammation, although they should be used with caution as they may conceal superficial infections. Other topical agents have been evaluated such as ascorbic acid , or moisturising creams containing hyaluronic acid or sucralfate the latter mainly to improve the itching conditions. Liguori et al evaluated the treatment of radiation injuries with the use of hyaluronic acid compared with placebo and the results showed significant improvements not only in the reduction of the degree of injury but also in reduced healing times thanks to the use of hyaluronic acid. For RTOG 1 and 2a grade injuries it is also recommended to avoid any risk of irritation, therefore avoid: the use of soaps, exposure to UV rays, the use of rough clothing and plasters, contact with chlorine (e.g. swimming pool water), shaving with razors.

• RTOG 2b: skin integrity is compromised. Moist desquamation injuries are not easy to manage, not least because reactions often develop in difficult areas such as the armpit, neck and perineum, where dressings cannot be easily applied. One of the most common applications is the use of antiseptic agents , although they make the environment of the wound dry therefore unsuitable for natural repair, which require using dressing systems that guarantee a moist environment, so as to optimise the healing process. Lately there has been a great interest in the use of pharmaceutical forms such as hydrogel. • In particular, it is necessary that the dressings conform to the areas that are difficult to reach, be capable of absorbing variable amounts of serous losses associated with epidermal damage, and that can be removed without disturbing the granulation. In this regard, hydrogels seem to be a viable alternative due to their easy application, ensuring patient comfort and rehydration. Dressings with conventional adhesives should not be used.

• RTOG 3: observe the general skin treatment guidelines as mentioned above. Wet with lukewarm saline solution, if necessary. Choose a non-traumatic dressing, taking into account the amount of exudate, appearance, condition, position and size of the area to be treated. Follow best practice principles to ensure healing in a moist environment, preventing infection, reducing pain and trauma, and improving patient comfort. The recent College of Radiographers 2011 guidelines recommend the use of alginate fibres. These dressings are not only capable of converting into a hydrophilic gel upon contact with the wound, but they are also capable of promoting granulation. However, they reveal a major practical problem: the fact that dressings must be removed for radiotherapy to reduce the possibility that the additional volume of the dressing creates a‘bolus’ effect and thus increases the dose for the skin. Re-epithelialization usually starts a week after the end of the radiation therapy treatment.

• As mentioned above, it is necessary for the dressings to be comfortable and to relieve symptoms such as pain, itching or infection. It is therefore important to manage and evaluate pain, with the possible prescription of appropriate analgesics. Furthermore, anti-inflammatory drugs can often be extremely effective, and they can also relieve the discomfort associated with itching and swelling around the skin reaction. Antihistamines may also be useful in the treatment of severe itching, although possible contraindication regarding drowsiness which may be caused by them should be taken into account. Furthermore, if there is suspicion of infection, extensive investigations should be undertaken to determine whether antibiotic or antifungal therapy is required. Early management of an infection can quickly reduce the intensity of a severe skin reaction.

• Skin metastases may spread from an internal cancer or skin cancer, usually melanoma; their incidence is difficult to establish but has been reported in more than 9% of cancer patients. Cutaneous metastases are defined by the British Columbia Cancer Agency (2001), such as:“a cancerous lesion involving the skin, which is open and may be draining’ \

• As previously mentioned, skin metastases may appear in several primary malignancies: Table 2

In most cases cutaneous metastases develop after initial diagnosis of primary malignant tumour, and during the course of the disease. In very rare cases, skin metastases may occur simultaneously or before primary cancer has been diagnosed and it could be the reason for further in-depth investigations.

Clinical recognition of cutaneous metastases is difficult to diagnose because cutaneous metastases occur in different forms and appearance depending on the primary tumour from which they originate. Based on the distance from primary melanoma, cutaneous metastases can be described as‘in-transit diseases’, or‘distant’ cutaneous melanoma that originates from haematogenous dissemination. The typical clinical appearance is pigmented papules and/or nodules, although shapes and appearance may be heterogeneous and a broad morphological spectrum of lesions have been described. For example, in the case of breast cancer, the metastases usually occur on the anterior thoracic wall both as direct extension of the underlying tumour and as lymphatic or blood diffusion, but often they are ambiguous to identify in that they mimic common processes such as cellulitis or lymphedema (lymphatic swelling caused by an accumulation of interstitial fluids). On the other hand, in the case of skin melanoma, cutaneous metastases are more frequent on the face and scalp. The onset of cutaneous metastases is, regardless of the type of primary tumour, a symptom of a widespread systemic disease and therefore of a negative prognosis: an average survival of 57 months for breast cancer with cutaneous metastases was estimated. Therefore, the treatment of cutaneous metastases must have two main objectives: to seek to obtain a control of the disease in order to be able to lengthen life expectancy and to optimise the quality of life by trying to manage the symptoms better. A cutaneous metastasis represents a difficult wound to treat for several reasons:

• The patient has a terminal illness and may also have other treatment needs;

• These wounds have a tendency to bleed copiously;

• If infected with anaerobes, they produce a characteristic unpleasant odour that can be a source of embarrassment and discomfort to the patient;

• large amounts of exudate are often a problem;

• due to their appearance, they can be difficult to conceal under modem low-profile dressings, especially if they are found on the face or neck.

In order to plan for the proper treatment of skin metastases, the doctor must be guided by the most important problems for the patient that can be ascertained through a keen assessment of the patient. The latter should include the size, shape, position and condition of the wound bed and the surrounding skin, which may have been damaged if the patient has received radiotherapy as part of the treatment of the disease. What matters is to consider the level of pain experienced by the patient at the wound site or at the change of dressing, same case allowing to the amount of exudate while the presence of odour should not be overlooked. Therefore, the following should be considered for a complete evaluation of the metastasis and for the choice of the best therapy:

• The patient’s clinical and social history;

• Cause and stage of the disease;

• Site of the primary tumour and its characteristics;

• Treatment and prognosis;

• Knowledge of the diagnosis by the patient’s family;

• Nutritional evaluation;

• Psychological impact of the wound on the patient;

• Impact of the injury on the quality of life;

• Availability of resources and social support network.

As regards the odour-related problem, the use of impregnated carbon dressings may be useful but also the use of topical Metronidazole in gel form can also be useful in the fight against the odour associated with anaerobic infection.

Simple measures can be taken to minimize odour, such as:

• changing the daily dressing using simple dressings, so that the patient can change it independently;

• If the general condition of the patient permits, the shower may be useful for the self esteem of the patient and may help to clean the wound from aggressive material. However, it should be observed that the washing action on the lesion should be delicate so as minimise trauma and bleeding.

Another characteristic to be taken into account in the choice of dressing lies in the volume and consistency of exudate. In this perspective alginates and foams are useful; adhesive dressings must instead be used with caution, since their incorrect removal could cause trauma to the skin. If the lesion has little exudate, it can be covered with a sterile and dry gauze and a non-stick dressing. Metastases that exude blood may be contained using haemostatic agents , such as absorbable gelatine and collagen products or alginate dressings. External radiotherapy may be capable of providing a local control of skin metastases for purely palliative purposes, although it cannot be used on previously irradiated areas due to the cumulative dose.

Local therapies (surgery, isolated limb perfusion, electrochemotherapy) can be the first choice in patients with regional loco-localization, where satellite or‘in-transit’ cutaneous metastases have grown between the primary melanoma site and the regional lymph node, due to their relatively positive prognosis, as opposed to metastases with distant cutaneous involvement, i.e. in the presence of cutaneous localizations beyond the regional lymph node. Recently, the efficacy of electrochemotherapy in the treatment of melanoma has been clearly highlighted. In a work previously published by P. Savoia et al, a positive response in 93% of cases was obtained with electrochemotherapy, with 58% complete remission and no evidence of relapse during a 21 -month median follow-up. Moreover, the treatment was generally well tolerated, with less adverse effects with respect to limb perfusion and, in addition, it requires only minimal general sedation; electrochemotherapy sessions can also be repeated at short intervals. Therefore, electrochemotherapy can be a valuable therapeutic resource, especially for patients with regional cutaneous metastases.

On the other hand, patients with disseminated cutaneous metastases may benefit from more aggressive systemic treatments. Unfortunately, cutaneous and visceral melanoma metastases are relatively chemo-resistant. At present, the percentage of patients with disseminated metastatic cutaneous disease who achieve complete remission is less than 5% and the number of patients with durable response is even lower. Therefore, the combination of local and systemic treatments is strongly recommended in these patients.

The treatment of cutaneous metastases therefore has some particular needs, different from the treatment of non-oncological lesions, since the patient often suffers from a terminal illness. Palliative care of these wounds, however, should reflect the same principles as those used for the treatment of any wound, i.e.: healing is assisted by the presence of a moist environment, the prevention of adhesion and/or trauma during the dressing stages, always keeping in mind the patient’s comfort, cosmetic acceptability and the absorbent capacities of the dressings.

The surgical wound is a tissue continuity solution produced by a mechanical agent. In clinical practice there are 2 main types of surgical wounds:

• wounds that heal by primary intention in which the edges have been approached by stitching. They repair rapidly generally developing a linear scar that is often not very visible;

· wounds that heal by secondary intention in which the edges are not often approached due to an infection. Healing is slow and the scar that forms can take on varying dimensions. Dehiscence of the surgical wound indicates a post-operative complication represented by the spontaneous reopening of a previously sutured wound. It may be partial and thus involve one or more stitches or full. A very serious form, regards non- laparotomy wounds, in which the complete opening of all the layers of the wall entails the removal of the movable viscera outside the abdominal cavity or evisceration. Optimal treatment of surgical wounds is achieved through proper preparation of the skin and patient for the operation and local treatment of the wound through dressing. The difference between lesion, wound and ulcer should be emphasised, in particular:

· Lesion: reversible or irreversible alteration of the anatomy and histological characteristics of a tissue or organ that alters the integrity of the organism;

• Wound: a continuous solution, with or without loss of substance, of cutaneous or internal tissue, caused by various external factors;

• Ulcer: A skin lesion characterised by deep loss of substance and poor healing tendency that occurs leading to scars. It is the expression of degenerative processes caused by inflammatory, infectious events, circulatory disorders or by tissue damage due to chemical and physical causes.

The treatment of the wound must allow restitutio ad integrum , that is, it must ensure a complete restoration of the functions of the skin, it must reduce the risk of infection and it must make the wound acceptable from an aesthetic point of view, thus avoiding the formation of keloids. This objective is achieved both by adopting some solutions in the preoperative period and through the correct treatment of the wound. In particular, it is necessary to remove any necrotic material from the wound bed, reduce the bacterial load, the excess exudate, while simultaneously protecting the edges and using advanced dressing technologies. The choice of one treatment rather than another depends on the type of surgical wound which in turn depends on the type of surgical procedure performed which may affect the risk of wound infections. Surgical procedures can therefore be classified according to the risk of wound infection as follows:

Table 3.

In the case of a“clean” wound, it is assumed that the wound environment, whose edges are normally closed using stitches, is clean and with low bacterial contamination. There arises the need to keep the wound in good cleaning conditions, avoiding bacterial over contamination. and protect the suture from contact with clothing and with dirt.

Thus:

• Unless otherwise prescribed, disinfect the wound regularly using a specific antiseptic;

• Apply a sterile prepared dressing with high absorbency of exudates;

• Change the dressing whenever necessary (e.g. when it is dirty, soaked with exudate or when it has lost adhesiveness);

• If you have to wet the skin (for example, for a shower), use suitable waterproof dressings.

In the case of skin lesion due to a sharp object, in the specific case due to surgical scalpel, skin healing occurs faster than when fortuitous events cause skin injuries, they do not require external applications to facilitate the two edges of the wound to fit perfectly.

Healing of surgical wounds is facilitated by the use of stitches that fill the cut portion and allow healing within weeks.

It is also true that there are considerations to be made in this case: the physician will instruct the patient on several measures to be taken so that the wounds heal in the best possible way without further complications for the subject in question. In order to avoid nagging and sometimes serious adverse effects, the patient must avoid:

• lifting weights;

• practising sports;

• carrying out heavy work in the immediate weeks close to surgery,

Wound healing may also depend on the presence of any infectious symptoms : if for any reason the wound appears infected, recovery times will certainly be longer and it may also be necessary to use drugs against infections and pain killers, if the wound causes the person physical pain that is stronger and more persistent than usual. This possibility may occur due to the presence of pathogenic agents which have altered the condition of the wound; bacterial infection can occur when applying the stitches with the presence of some bacteria either inside the human body or present on the equipment used or in subsequent dressings due to failure to comply with good hygiene practice. An accurate and perfect hand cleansing, use of sterile material (gloves, gauzes, etc.) are good bacterial infection prevention standards in the post-surgical period.

Daily measures that can be taken in order not to risk irritating the scars and to improve their healing are:

• Gentle cleansing;

• Comfortable clothing, avoid rubbing;

• Avoid exposure to the sun;

• Repair oil and ointments;

• It is important to choose an extremely delicate cleansing of the part by choosing washing ointments or cleansing oils that do not dry or dehydrate the area, but, guarantee nourishment and strengthen the hydrolipidic mantle;

• Hot and cold can infect scars: the heat, such as the temperatures of the sauna, can damage the scars, likewise it is good to pay attention to the temperatures that are too low, protecting the scars from the strong frost which, just like the heat, can damage them further, making the treatment even more difficult;

• The clothing used is of remarkable importance: it is good not to use clothes that are too elastic and restrictive in the vicinity of the scar, the fibres can irritate the epidermal tissue of the scar.

• Exposure to sunlight in summer should be more cautious if there are scars on the skin. High protection against the harmful rays of the sun must always be used and, in the presence of scars, the attention must be greater, if possible, to prevent the sun from hitting scars;

• Specific repair oils act reducing the reddening of the scar and making the skin softer, more elastic and smoother. It should be borne in mind that the treatments suitable to eliminate scars should start as soon as possible. After an operation, as soon as the scar can be treated, that is, immediately after eliminating the stitches, it is advisable to start the treatment immediately. Some basic rules must be followed in order to achieve the desired effects: the scar must be completely healed, it must be massaged carefully starting from the centre of the scar to reach the outside until it is completely absorbed. The treatment of scars requires daily constancy;

• The duration of treatment depending on the nature and“age” of the scar. Generally, the first treatment period is eight weeks, after which the first positive effects of the application should be visible.

• For more severe situations with older scars, treatment and application should be extended several months from approximately three to six months.

Skin wounds are lesions that result from the loss of epidermis, parts of the superficial dermis and, sometimes, even deeper layers of the skin. These deep lesions are particularly painful and do not demonstrate a normal tendency to spontaneous healing. In fact, skin ulcers are often a symptom of an underlying pathological condition, which also causes a slowing down of wound healing and resolution processes.

Skin ulcers may occur as a result of physical trauma, with or without vascular damage, resulting in tissue loss. Other causes include infections, venous stasis, vasculitis, neoplasms, neurological problems and autoimmune diseases with vascular involvement. The most severe and painful skin lesions are chronic, i.e. those lesions that do not heal and progress through normal healing phases such as inflammation, proliferation, remodelling.

The most common chronic ulcers include lower limb ulcers, diabetic ulcers and pressure ulcers. Unlike acute ulcers that can heal within days or weeks, chronic ulcers can last for months or years. Besides affecting the individual physically and psychologically, this condition also represents a management problem for the health system.

In chronic ulcer, excessive capillary proliferation may be observed with enlarged fibroblasts and cells characteristic of the chronic inflammatory process, including lymphocytes and macrophages (granulation tissue).

Several causes of deep lesions can be identified: prolonged mechanical pressure can cause so-called decubitus ulcers , i.e. skin lesions that develop in areas of the body where blood perfusion is reduced; this condition can occur in patients who are bedridden for long periods or in persons who are forced to wear corrective appliances or orthopaedic busts.

Peripheral vasculopathy (PVD) can also lead to very painful ischemic foot ulcers. PVD and neuropathy are often present simultaneously in the same patient. As a matter of fact, it is likely that the reduction of the cutaneous blood flow, due to macrovascular disorders, will make the vascular system more susceptible to occlusions during periods of high biomechanical pressure on the skin.

Diabetic ulcers are of neuropathic origin and they are usually found on the sole of the foot or where there are bone malformations which create conflict with the footwear; they can be of the vascular type and they are usually found on the tips of the toes of the foot or on the heel, but there are also those with mixed aetiology which, however, always recognise this type of localisation. In this condition a thickening of the basal membrane and an endothelial swelling of the capillaries are often observed. The terminal arteries are responsible for supplying blood (and oxygen) to the toes. Relative oedema caused for example by trauma, septic thrombosis, or infection may result in total occlusion of the terminal arteries previously compromised and thus cause gangrene of the toe. However, it is unlikely for occlusive microvascular disorders to be the direct cause of ulceration. In the pathological condition called venous insufficiency , the valves are damaged and do not allow an amount of the blood present in the venous region to be properly expelled.

The ensuing slowing down of the circulation causes the fluid to be filtered through the vessel wall in the surrounding tissues, causing damage and the onset of the ulcer.

Strategies are therefore required to enable the identification of high-risk patients, as well as the prevention of potential dangerous interactions, which often result in the ulcer.

Recent research has emphasized the importance of psychological factors involved in the development of diabetic foot ulcer.

Studies have shown that the perception, based on symptoms, of the risks that can be taken and the intimate conviction of the effectiveness of personal care in diabetic patients were associated with preventive care-oriented behaviour.

A correct approach to the ulcer is to consider it as a continuous solution of the skin, that is, a wound, which must be put in the best conditions to heal. The repair occurs through the formation of connective tissue which is covered by multiplication of the epithelial cells and migration thereof from the edges of the lesion to the centre thereof. It is affected by both local factors (blood supply, the presence of oxygen, the presence of bacteria or the presence of tissue damage, the type of dressing) and systemic factors (malnutrition, diabetes, vitamin deficiency, drug use, hypoxia, hypovolemia, etc.).

There is no optimal method for the treatment of wounds in general, which can therefore vary depending on the patient’s condition, the type of lesion and the evolution thereof. The basic principle is to promote healing by taking care of the natural environment in which tissue repair processes occur, such as granulation and re-epithelisation, and by avoiding the conditions that slow it down, such as changes in moisture, pH and temperature.

In the choice of the most suitable treatment, certain general principles concerning these processes must therefore be taken into account, in particular:

• Oxygen : it has been proven that the wound healing rate is directly proportional to the local oxygen tension; as a matter of fact, epithelial cells need oxygen to move and reproduce. Therefore, the lesion should be kept clean by the presence of fibrin, necrotic tissue or pressure ulcers that take away the necessary oxygen.

• Moisture : the concept of healing in a moist environment is a relatively recent acquisition of research on wound repair. In a moist environment, cell proliferation appears to start after 6 hours as opposed to the 18 hours required in a dry environment.

• Temperature : it greatly affects cell regeneration. The optimum temperature is 37° C. A decrease of even only two degrees is sufficient to inhibit leukocyte mobility. After a dressing, it takes approximately 40 minutes for the cleansed lesion to resume normal temperature and 3 hours to resume mitotic activity. Therefore, dressings which do not require frequent changes and the use of solutions at room temperature for cleaning are preferred.

• Cell repair : in the early stages of healing the epithelial cells migrating across the surface of the lesion have poor adhesion to the underlying dermis, hence they can be easily removed. Therefore, as part of the dressing operations, movements of the lesion margins and too frequent dressing changes are to be avoided, as they may hinder healing.

The burn is a lesion of the integumentary tissues caused by exposure of the tissue to thermal sources, to chemical substances (chemical burn), to electrical sources or to radiation. Despite the best prevention implemented worldwide, burns remain a major cause of traumatic injury affecting all ages. Nevertheless, survival after extensive bums has improved substantially over the past 30 years. This is due to many factors including:

• immediate pre-hospital therapy;

· early treatment of shock and potential post-burn lung dysfunction;

• the better understanding of the physiopathological mechanisms involved in the burn shock;

• appropriate antibiotic therapy;

• the progress achieved in the surgical approach.

It is therefore evident that the treatment of patients who have suffered burns is long-term and often requires large amounts of resources to obtain complete healing, both medical and psychological. To this end, prevention is a vital factor that can bring down the mortality and disability caused by burns. It is therefore important to implement training programs for the entire community, especially for the most vulnerable, such as children and the elderly.

To plan for the right treatment of the lesion, the depth of the burn that caused the lesion must be estimated. These can be divided into three categories:

Table 4

It is common to find all three types of burns within the same wound and depths can change over time especially if infection occurs.

When choosing the treatment to be used to effectively manage a bum, it is not only necessary to classify it, but it is also important to understand the pathophysiology of a burn. It is therefore important to understand what was the cause of the bum and what kind of physiological response it will induce. Burns result in both a local and systemic response. As regards the local response, relevant studies identified three areas:

1. Coagulation zone : located at the point of maximum damage. In this zone there is irreversible loss of tissue due to coagulation of the constituent proteins.

2. Stasis zone : it is characterised by reduced tissue perfusion. The tissue in this area is potentially recoverable. The main objective of the first management of the bum is to increase tissue perfusion in this zone and to prevent irreversible damage caused by hypopoperfusion, extensive oedema, hypoxia or infection.

3. Hyperemia zone : the outermost zone where there is greater tissue perfusion. Tissue in this zone can be recovered if there is no severe or prolonged hypoperfusion sepsis.

As far as the systemic response is concerned, the release of cytokines and other inflammatory mediators causes the increase of local capillary permeability, and when the burns are extensive, in the remote organs. The systemic inflammatory response is responsible for reducing the circulating volume due to loss of liquids both due to the release thereof through the injured skin surface and due to the pouring thereof to close and remote tissues. The main mechanism of this passage of liquids is the increase in permeability of the microcirculation. Hypovolemia is the initial mandatory consequence of the movements of liquids that occur after extensive burn damage. If the loss is copious, a hypovolemic shock occurs. These changes, coupled with the loss of fluids from the bum injury, result in systemic hypotension and therefore hypoperfusion.

Accurate assessment of the depth of bum at the time of admission is important for making decisions about dressings and surgery to be carried out. However, burn injury is a dynamic living environment that will change according intrinsic factors (such as release of inflammatory mediators, bacterial proliferation) and extrinsic factors (such as dehydration, systemic hypotension, cooling). It is therefore important to check the wound at regular intervals until healing. Optimal wound treatment reduces morbidity and, in larger lesions, mortality, and it should also be capable of reducing healing time and reducing the need for secondary recon struction. In brief, the main treatments used in a first burn wound management are as follows:

• Full-thickness or third-degree injuries : there are no regenerative elements. This type of bum should be subjected to surgery as soon as possible.

• Deep or second-degree skin lesions are difficult to heal in three weeks. The incidence of antiesthetic hypertrophic scars rises from 33% to 78% if healing is delayed from three to six weeks. Therefore, these lesions should be treated with removal surgery and grafts within the first 5-10 days.

· Superficial wounds or first-degree burns should heal by spontaneous regeneration within two weeks. They should be cleaned and dressed every other day to optimise the wound healing environment. Antimicrobial agents are added if there is a likelihood of infection (perineum, feet) or suspected invasive infection.

Several studies demonstrate the efficacy of creams and/or gels containing Aloe Vera in reducing burn wound healing times. Akhtar et al evaluated the efficacy of Aloe Vera by comparing it with a cream with framycetin, an antibiotic capable of interrupting bacterial protein synthesis, in patients with superficial burns and reported a reduction in the healing times of subjects treated using Aloe Vera. While Khorasani et al demonstrated the efficacy of Aloe Vera in reducing the healing times of subjects with second degree bums compared to treatment with a Silver sulfadiazine cream, a metal-organic compound obtained by reacting silver nitrate with sulfadiazine which acts as a local antimicrobial.

An object of the present industrial invention patent application is to provide a new medicinal composition alternative to prior art compositions and which is particularly effective in the healing processes during its use in the treatment of the aforementioned lesions.

Description of the invention

The present description regards a particular medical composition to be administered through topical route and in the form of an ointment, recommended for the treatment of cancer patients having:

• Severe radiation injuries;

• Exposed metastases;

• Deep sores and wounds, including those that reach the layers of tissue beneath the dermis;

• Deep surgical wounds;

• Bums.

The definition of the medicinal composition according to the present industrial patent application stems from the need to support chronic, and sometimes painful, diseases which arise following cancer treatments and which have the skin as their primary target. Whereas, on the one hand, the increased efficacy of cancer therapies is slowly transforming the interpretation of the evolution of neoplastic disease, from incurable disease to potentially curable disease, patient suffering still persists, both during and as a result of therapy. In particular, changes in the skin affected by ionising radiation may affect not only the activities of daily life but also the quality of life itself. As a matter of fact, it is possible to encounter difficulties in dressing as well as in the movement of a limb or of the area affected by the treatment while visible reactions can occur until the loss of independence and self- care, without forgetting the impact of costs in the health management of skin reactions. Radiotherapy is an absolute therapeutic tool in the treatment of tumours. Minimising X-Ray damage on healthy tissues is one of the goals of radiation therapists and medical physicists. Furthermore, chemotherapy, even when performed long after the end of radiotherapy, may lead to acute and sub-acute lesions in the previously treated areas.

Specifically, the medicinal composition according to the present invention comprises: polyethylene glycol 400; polyethylene glycol 4000; micronized allantoin; 18-b glycyrrhetinic acid or chlorhexidine gluconate.

Below is a detailed description of the quantities of said substances present in the composition in question and of the mechanism of action of each of said components.

Detailed description of the invention

As indicated in the table below, the medicinal composition in the form of an ointment according to the present invention comprises: Polyethylene glycol 400 at an amount of 67% by weight; Polyethylene Glycol 4000 at an amount of 26.3%; micronized allantoin at an amount of 5% by weight; 18-b glycyrrhetinic acid at an amount of 1% by weight; Chlorhexidine gluconate at an amount of 0.5% by weight; Vitamin A acetate at an amount of 0.2% by weight.

Table 5.

Of the aforementioned components, Allantoin is a natural substance, present both in the natural world and in the plant world, and it is naturally also found in the human organism where it essentially performs antioxidant functions.

The medicinal composition in the form of an ointment according to the present invention allows a higher concentration of Allantoin, a component known for its precious regenerating and protective properties.

As a matter of fact, it has been shown that the action of Allantoin is to actively participate in the wounds and grazes healing process thanks to its ability to promote cell proliferation, even quickly. In patients undergoing cancer treatment, there is a weakening in natural tissue repair processes: Allantoin therefore actively contributes towards the protection and healing of tissues even in cases of wounds and sores which are particularly resistant to therapies. All cancer treatments, but even surgical wounds or sores in general, causing tissue damage, require careful and safe dressing to avoid compromising the treatment itself, to accelerate the repair and to obtain the best aesthetic result possible. In these cases, the Allantoin ointment dressing may be performed in the open, i.e. by massaging the ointment on the treated part and not covering or by covering with a cotton gauze as it occurs with wounds.

Allantoin can also absorb exudates, it prevents bacterial colonisation and accelerates the repair process.

Historically, during the first World War, it was noted that the wounds infested by larvae of a common green bottle fly (Lucilia sericata) healed better than those not infested; the effect was attributed to allantoin produced by the larvae of the common green bottle fly. In traditional medicine it was customary to apply the secretion of fly larvae and worms which contained Allantoin.

In particular, the healing mechanism assisted by Allantoin occurs through the regulation of the inflammatory response, ensuring a stimulation of fibroblast proliferation and the synthesis of the extracellular matrix, which are fundamental components for the tissue regeneration of open wounds. Allantoin also participates in the formation of epithelial tissue, avoiding the formation of disfiguring scars, and can therefore also be used for the treatment of burns scars, as well as for the topical treatment of postoperative scars. Therefore, besides performing an important dermo-repair action, it also has moisturising properties, thus being suitable for the treatment of dry, dull and cracked skin.

In high concentrations, it has an excellent keratolytic activity, that is to say it loosens the junctions between cells in the stratum corneum, hence the superficial necrotic elements can be removed, with the advantage of softening and regenerating the skin.

It is one of the main constituents of the snail drool and its antioxidant, lenitive, moisturising and healing capacities make it one of the perfect molecules to promote physiological cellular regeneration.

In addition, safety tests and assessments were conducted on the use of Allantoin with concentrations up to 2% with positive outcomes.

It has already been widely discussed how the ideal skin ulcer dressing must be adsorbent, permeable, non-stick, non-toxic and easy to remove. Polyethylene glycol (PEG) ointment with 5% allantoin has been shown to have the ideal dressing characteristics with antiseptic and healing properties. PEG with 5% allantoin was applied directly to the injured skin or applied on a gauze. The results obtained in the Dermatology study of Istituto Clinico Humanitas were very satisfactory: a 40% average reduction in healing time with costs reduced by 60%. It is concluded that the PEG ointment with 5% allantoin is a good low-cost skin ulcer dressing. Polyethylene glycol (PEG) is a polymer prepared through the polymerisation of ethylene. There are different types of polyethylene glycol, classified according to the average length of the molecules, i.e. the number in the formula. Such change in the average length of the molecules corresponds to different physical properties (such as viscosity) and various practical applications of PEG, while the chemical properties are almost identical.

The PEG ointment, a mixture of solid and liquid phase PEG, appears from a visual and tactile point of view - as a vaseline ointment while having opposite properties. PEGs are hydrophilic, that is, they have an intrinsic capacity to absorb water in large quantities and they are also water soluble as such. Basically, creating a PEG ointment allows to obtain an exudate drainage effect. PEGs do not have cell toxicity, they are also used intravenously to draw liquids from interstices in particular pathologies, hence they do not interfere with growth and migration in the tissue repair process.

The PEG ointment confers anti-stick and gas permeability properties to the dressing.

The synergistic action of PEG and allantoin is demonstrated by the average decrease in healing time, with a consequent reduction in the length of convalescence and ultimately a reduction in the skin ulcer management costs for health care facilities.

Chlorhexidine is a chemical synthesis disinfectant with a wide range of antiseptic action. As a matter of fact, it has been used since 1954 for various purposes with excellent safety and efficacy results, such as hand washing by health care personnel, preoperative skin preparation and as a disinfectant prior to insertion of intravascular or arterial catheters. Chlorhexidine has a broad antibacterial spectrum particularly against Gram-positive and Gram-negative bacteria, anaerobes and aerobes and yeasts. Its bactericidal action is occurs drastically increasing the permeability of the bacterial cell membrane altering the protein structure thereof; this causes the precipitation of various cytoplasmic macromolecules and subsequent cell death due to the lysis of the bacterial cell or of the fungus.

Hand washing with chlorhexidine has been shown to reduce the bacterial flora present by 86%-92%. In addition, chlorhexidine has a residual activity on the skin which helps prevent rapid regrowth of bacterial organisms by improving the skin’s antiseptic action.

In particular, the presence of Chlorhexidine in the medicinal composition according to the present invention confers said composition a great effectiveness not only for treating but also for preventing infections which can often occur on open wounds, bums and sores of any kind. In particular, clinical studies have shown a significant reduction in infections in wounds of patients treated with chlorhexidine in a preventive manner. However, even on already infected wounds, chlorhexidine has proved effective in the treatment thereof.

18-b glycyrrhetinic acid is extracted from liquorice roots and its essential anti-inflammatory as well as lenitive and adjuvant properties in skin repair processes have been pharmacologically demonstrated.

The anti-inflammatory effects of 18-b glycyrrhetinic acid can be attributed to its ability to enhance the effects of glucocorticoids on the one hand and to inhibit the generation of neutrophils, potential mediators of inflammation. A possible anti-tumour action of 18-b glycyrrhetinic acid has also been evaluated: it could be capable of triggering apoptosis of tumour cells thanks to the ability to induce a transition of mitochondrial permeability.

Vitamin A is an antioxidant and as such plays an important role in countering the negative effects of free radicals and therefore has a considerable anti-cancer property. Its main functions, as a component of the medicinal composition according to the present invention, are to support the repair and nutrition of the skin: as a matter of fact, vitamin A and its analogues, retinoids (they indicate the amount of usable vitamin A that has been broken down and takes its place in the blood, ready to perform its task), are in fact widely demonstrated to be essential to the health of epithelia, especially of the epidermis. As a matter of fact, the skin consisting of epithelial tissues, readily reacts to a deficiency of vitamin A. The cells of the surface, of the stratum corneum that is, and of some lower layers, wither and die. This dead tissue breaks the pores and sebaceous glands, preventing the sebum from reaching the surface of the skin. Clogged pores can cause itching over the entire body, also increasing the vulnerability to skin infections such as impetigo, vesicles, and pustules. It has also been shown that vitamin A, applied directly to wounds, hastened the healing process in cases where it was delayed by the use of cortisones. People suffering from diabetes or people who have undergone surgery and are slow to heal can be helped with vitamin A supplements. It also stimulates the production of mucus which, in turn, prevents the formation of evident scars.

Lastly, a description relating to the method for preparing the medical composition in the form of an ointment according to the present invention is outlined hereinafter. More in detail, in one of the preferred embodiments thereof, the composition according to the present invention was obtained by weighing PEGs and melting them together at a temperature of 65°C, letting them cool spontaneously and simultaneously weighing the other quantities in powder form separately and subsequently mixing them and adding them to the previously thickened PEG base. Lastly, the ointment thus obtained was mixed in a mixer until homogeneity.

Claims

1. Composition comprising polyethylene glycol 400; polyethylene glycol 4000;

Micronized allantoin; 18-b glycyrrhetic acid; Chi orhexi dine gluconate; Vitamin A acetate.

2 Composition according to the preceding claim, wherein polyethylene glycol 400 is at an amount of 67% by weight; polyethylene glycol 4000 is at an amount of 26.3%; micronized allantoin is at an amount of 5% by weight; 18-b glycyrrhetinic acid is at an amount of 1% by weight; Chlorhexidine gluconate at an amount of 0.5% by weight;

Vitamin A acetate is at an amount of 0.2% by weight, said components completing 100% by weight of said composition.

3. Composition according to any one of the preceding claims in the form of an ointment.

4. Composition according to any one of the preceding claims for medical use.

5. Composition for use according to the preceding claim in a method of treatment of radiation injuries, visible metastases, sores and deep wounds, deep surgical wounds and bums found in cancer patients.

6 Composition for use according to the preceding claim to be administered topically