WO2024236533A1 - Rutin, also named oxerutin, for the treatment of epidermolysis bullosa - Google Patents

Rutin, also named oxerutin, for the treatment of epidermolysis bullosa Download PDF

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Publication number
WO2024236533A1
WO2024236533A1 PCT/IB2024/054788 IB2024054788W WO2024236533A1 WO 2024236533 A1 WO2024236533 A1 WO 2024236533A1 IB 2024054788 W IB2024054788 W IB 2024054788W WO 2024236533 A1 WO2024236533 A1 WO 2024236533A1
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Prior art keywords
rutin
oxerutin
doxycycline
treatment
epidermolysis bullosa
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PCT/IB2024/054788
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French (fr)
Inventor
Giuseppina ANNICCHIARICO
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LOSPALLUTI, Lucia
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Application filed by LOSPALLUTI, Lucia filed Critical LOSPALLUTI, Lucia
Publication of WO2024236533A1 publication Critical patent/WO2024236533A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

Definitions

  • EB Epidermolysis bullosa
  • EB Epidermolysis bullosa
  • blisters may also occur in the internal mucous membranes. It usually occurs in the neonatal period or during early childhood.
  • epidermolysis bullosa affects one child per 17,000 births, or about 500,000 people, compared with an Italian figure of one patient per 82,000 births, for a total of about 1,500 people with EB expected in the country.
  • Epidermolysis bullosa occurs in different forms of severity and can thus be divided into three main types: simplex, dystrophic, and junctional.
  • simplex the simplex form
  • dystrophic the less severe variant, in which blister formation is often limited to the hand and foot districts.
  • the dystrophic form is related to the damage or absence of anchoring fibrils in the basement membrane, where epidermis and dermis meet, and has been found in recent years to also have an autoimmune component.
  • the formation of blisters/vesicles is generalized to all body districts and is constant, leaving evident and complex scars.
  • the junctional form occurs in about 1% of cases and can be fatal from the early childhood.
  • the scarring lesions can go so far as to produce synechiae, the adherence/welding between two membranous structures or two normally distinct body portions, and thus reduce, for example, the size of the mouth, limit the opening of the eyes or even join the fingers or toes, thus limiting patients' mobility and autonomy in daily life.
  • Internal lesions such as at the level of the esophagus, can also prevent the patient from feeding properly, leading to a subsequent malnutrition problem.
  • Diagnosis is based on clinical observation followed by histological analysis performed on skin biopsy, and confirmatory genetic testing. To date, there are no ways to prevent the disease nor the occurrence of blisters/vesicles, other than some practical steps for a meticulous protection of the skin (use soft clothing, keep the skin moist, avoid scratching..) and the adoption of appropriate lifestyles that limit trauma to prevent as much as possible the formation of blisters and the subsequent possible infection. Additionally, the wound care, through dressings and bandages that can take up to many hours daily, turns out to be essential.
  • An object of the present invention is to provide a compound that can be used, alone or in combination, in the treatment of epidermolysis bullosa (EB), particularly dystrophic and junctional EB.
  • EB epidermolysis bullosa
  • Another object of the present invention is to provide a compound that is capable, alone or in combination, of reducing the extent and severity of EB-driven skin and/or mucosal lesions and/or preventing their occurrence.
  • An object of the present invention is rutin, also known as oxerutin, for use, alone or in combination, in the treatment of epidermolysis bullosa (EB).
  • EB epidermolysis bullosa
  • Rutin also commonly known as rutoside, oxerutin or vitamin P
  • Rutin is a flavonoid glycoside found in various types of plants, formed from the flavonol quercetin bound to the disaccharide rutinose. It is a compound whose both antioxidant and capillary wall-strengthening activities (through its action on platelet aggregates and subsequent release of cytokines) are known, thanks to which it is able to reduce the symptoms of venous insufficiency in the lower limbs and hemorrhoid plexus. It is currently marketed in Italy in the drug form under the trade name Venoruton®, targeted for the treatment of venous insufficiency in the lower limbs and hemorrhoids.
  • rutin also known as oxerutin
  • oxerutin for use in the treatment of EB is administered orally in daily doses of 1,000 mg to 8,000 mg, preferably from 3,000 mg to 5,000 mg, in single or multiple doses preferably divided into 3-5 doses per day.
  • rutin also known as oxerutin
  • oxerutin is administered orally in combination with at least one other compound, specifically it is administered in combination with doxycycline.
  • Doxycycline is an antibiotic with broad-spectrum antibacterial activity belonging to the tetracycline class. In addition to being able to interfere at the level of the bacterial protein synthesis, doxycycline also has anti-inflammatory action, due to the activity at the level of interleukin 17, and inhibition of the metal-proteinases.
  • doxycycline is administered orally in combination with rutin, also known as oxerutin, in daily doses of 100 mg to 300 mg, preferably 200 mg.
  • rutin also known as oxerutin
  • rutin also known as oxerutin
  • for use in the treatment of EB can be formulated for oral administration according to any techniques known to the person skilled in the art.
  • said rutin can be in the form of capsules, tablets, powders, granules or others, in immediate- or controlled-release formulations.
  • said rutin, also known as oxerutin is administered in the commercial form currently sold under the trade name Venoruton®, preferably in the dosage form of powder for oral solution in sachets containing 1,000 mg rutin, also known as oxerutin.
  • doxycycline for use in the treatment of EB can be formulated for oral administration according to any techniques known to the person skilled in the art.
  • said doxycycline can be in the form of capsules, tablets, granules or others, in immediate- or controlled-release formulations.
  • this is doxycycline formulated in immediate-release tablets containing 100 mg doxycycline.
  • rutin also known as oxerutin
  • doxycycline can be formulated within a single pharmaceutical form for oral use that comprises both, according to all techniques known to the person skilled in the art.
  • Preferred pharmaceutical forms may be, for example, granules, capsules or tablets, for immediate or modified release.
  • doxycycline is administered orally after meals.
  • the object of the present invention represented by rutin, also known as oxerutin, for use, either alone or in combination with doxycycline, in the treatment of EB thus turns out to be a very interesting and effective response to the need for new and effective treatments for this rare disease particularly debilitating for patients, which, to date, has no treatment and care protocols capable of counteracting and/or preventing its effects.
  • the trial was initially carried out on three adult subjects suffering from dystrophic epidermolysis bullosa with severe phenotype, whose characteristics and treatment protocol are summarized in Table 1.
  • Subjects 1 and 2 were also previously treated with an experimental gene therapy involving a direct treatment of the lesions, which ended in January 2022 for both subjects. Said therapy is able to cause a recession/healing of the lesions, which, however, has a limited time duration due to natural regeneration of the epidermal tissues, which completely renew themselves according to physiological mechanisms. Indeed, there is a recurrence of the disease and the formation of new lesions about 3- 4 months after the treatment is stopped.
  • Subject 1 started the treatment according to the present invention 4 months after the discontinuation of the gene therapy, subject 2 started 9 months after the discontinuation.
  • rutin also known as oxerutin
  • rutin also known as oxerutin
  • + doxycycline treatment there was a measurable reduction in wound surface area of about 75%. This reduction turns out to be particularly attractive both from the point of view of decreasing pain and the possibility of infection but also because the presence of wide areas of skin without lesions allows easier skin care treatment than the prevention of the creation of new blisters (moisturizing, cleansing, application of emollient creams, etc.).
  • Subject 3 treated with rutin alone, also known as oxerutin, and for a shorter time than the other patients involved, as previously mentioned is also showing very encouraging signs with respect to the decrease in total lesion area and inflammation.
  • Venoruton® alone (rutin, also known as oxerutin, also referred to as oxerutin). The same benefit on the skin was observed for these patients. One of them, already suffering from squamous cell carcinoma before the initiation of therapy, showed recurrence.
  • the beneficial effects of treatment set forth above according to the present invention are evident.
  • the 3 patients treated with rutin, also known as oxerutin, and doxycycline showed 80% reduction in the extent of body surface area affected by wounds. They also showed a reduction in edema and pain from venous insufficiency of the lower limbs.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to the use of rutin, also known as oxerutin, alone or in combination with other compounds, in the treatment of severe forms of epidermolysis bullosa, a rare disease that carries with it the formation of blisters and subsequent lesions on the skin of patients suffering from it, following minor trauma.

Description

“Rutin, also named oxerutin, for the treatment of epidermolysis bullosa”
Technical background
Epidermolysis bullosa (EB), also referred to as "butterfly children syndrome", is a group of rare and disabling inherited genetic diseases that make the skin fragile and prone to the formation of blisters/vesicles, in response to even minor lesion, for example, caused by simple friction, a scratch and/or heat, or even spontaneously. In severe cases, blisters may also occur in the internal mucous membranes. It usually occurs in the neonatal period or during early childhood.
Worldwide, epidermolysis bullosa affects one child per 17,000 births, or about 500,000 people, compared with an Italian figure of one patient per 82,000 births, for a total of about 1,500 people with EB expected in the country.
Epidermolysis bullosa occurs in different forms of severity and can thus be divided into three main types: simplex, dystrophic, and junctional. In more than half of cases, EB arises in the simplex form, the less severe variant, in which blister formation is often limited to the hand and foot districts. The dystrophic form, on the other hand, is related to the damage or absence of anchoring fibrils in the basement membrane, where epidermis and dermis meet, and has been found in recent years to also have an autoimmune component. In this case, the formation of blisters/vesicles is generalized to all body districts and is constant, leaving evident and complex scars. Finally, the junctional form occurs in about 1% of cases and can be fatal from the early childhood.
In the most severe forms of the disease, in fact, the scarring lesions can go so far as to produce synechiae, the adherence/welding between two membranous structures or two normally distinct body portions, and thus reduce, for example, the size of the mouth, limit the opening of the eyes or even join the fingers or toes, thus limiting patients' mobility and autonomy in daily life. Internal lesions, such as at the level of the esophagus, can also prevent the patient from feeding properly, leading to a subsequent malnutrition problem.
Diagnosis is based on clinical observation followed by histological analysis performed on skin biopsy, and confirmatory genetic testing. To date, there are no ways to prevent the disease nor the occurrence of blisters/vesicles, other than some practical steps for a meticulous protection of the skin (use soft clothing, keep the skin moist, avoid scratching..) and the adoption of appropriate lifestyles that limit trauma to prevent as much as possible the formation of blisters and the subsequent possible infection. Additionally, the wound care, through dressings and bandages that can take up to many hours daily, turns out to be essential.
Currently, for epidermolysis bullosa there is no decisive cure, although several treatments, including gene therapy, are being investigated.
The first drug in Europe for the treatment of dystrophic and junctional epidermolysis bullosa, called Filsuvez®, with a gel formulation for topical use, containing a birch bark extract derivative as the active ingredient, has recently been approved thanks to the data from a Phase III study. However, it is a topical treatment of lesions, acting on the level of the symptoms, increasing the speed of wound healing, and not on the causes.
Thus, there is still a great need for a compound, or a combination of compounds, for the treatment of EB, particularly in its more severe forms, that allows the size of preexisting lesions to be reduced and possibly the formation of new blisters/vesicles in the various body districts to be prevented.
Objects of the invention
An object of the present invention is to provide a compound that can be used, alone or in combination, in the treatment of epidermolysis bullosa (EB), particularly dystrophic and junctional EB.
Another object of the present invention is to provide a compound that is capable, alone or in combination, of reducing the extent and severity of EB-driven skin and/or mucosal lesions and/or preventing their occurrence.
These and other objects are achieved by the subject matter of the present invention, which relates to a compound for use, alone or in combination, in the treatment of epidermolysis bullosa.
Description of the invention
An object of the present invention is rutin, also known as oxerutin, for use, alone or in combination, in the treatment of epidermolysis bullosa (EB).
Rutin, also commonly known as rutoside, oxerutin or vitamin P, is a flavonoid glycoside found in various types of plants, formed from the flavonol quercetin bound to the disaccharide rutinose. It is a compound whose both antioxidant and capillary wall-strengthening activities (through its action on platelet aggregates and subsequent release of cytokines) are known, thanks to which it is able to reduce the symptoms of venous insufficiency in the lower limbs and hemorrhoid plexus. It is currently marketed in Italy in the drug form under the trade name Venoruton®, targeted for the treatment of venous insufficiency in the lower limbs and hemorrhoids.
According to a preferred aspect of the invention, rutin, also known as oxerutin, for use in the treatment of EB is administered orally in daily doses of 1,000 mg to 8,000 mg, preferably from 3,000 mg to 5,000 mg, in single or multiple doses preferably divided into 3-5 doses per day.
According to an aspect of the present invention, rutin, also known as oxerutin, is administered orally in combination with at least one other compound, specifically it is administered in combination with doxycycline.
Doxycycline is an antibiotic with broad-spectrum antibacterial activity belonging to the tetracycline class. In addition to being able to interfere at the level of the bacterial protein synthesis, doxycycline also has anti-inflammatory action, due to the activity at the level of interleukin 17, and inhibition of the metal-proteinases.
According to a particularly preferred aspect of the invention, doxycycline is administered orally in combination with rutin, also known as oxerutin, in daily doses of 100 mg to 300 mg, preferably 200 mg.
According to the present invention, rutin, also known as oxerutin, for use in the treatment of EB can be formulated for oral administration according to any techniques known to the person skilled in the art. For example, said rutin can be in the form of capsules, tablets, powders, granules or others, in immediate- or controlled-release formulations. According to a preferred aspect of the invention said rutin, also known as oxerutin, is administered in the commercial form currently sold under the trade name Venoruton®, preferably in the dosage form of powder for oral solution in sachets containing 1,000 mg rutin, also known as oxerutin.
According to the present invention, doxycycline for use in the treatment of EB can be formulated for oral administration according to any techniques known to the person skilled in the art. For example, said doxycycline can be in the form of capsules, tablets, granules or others, in immediate- or controlled-release formulations. Preferably this is doxycycline formulated in immediate-release tablets containing 100 mg doxycycline.
According to an aspect of the present invention, if desired, rutin, also known as oxerutin, and doxycycline can be formulated within a single pharmaceutical form for oral use that comprises both, according to all techniques known to the person skilled in the art. Preferred pharmaceutical forms may be, for example, granules, capsules or tablets, for immediate or modified release.
According to a preferred aspect of the invention, rutin, also known as oxerutin, is administered orally on an empty stomach.
According to a preferred aspect of the invention, doxycycline is administered orally after meals.
If desired or necessary, rutin, also known as oxerutin, for use alone or in combination with doxycycline in the treatment of EB according to the present invention, may be administered along with other therapies.
Object of the present invention is also a kit comprising a pharmaceutical formulation for oral use, containing rutin, also known as oxerutin, and a pharmaceutical formulation for oral use of doxycycline.
Unexpectedly, as will be demonstrated in the experimental part that follows, the administration of rutin, alone or in combination with doxycycline, to patients with epidermolysis bullosa, particularly dystrophic EB, resulted in a significant reduction, up to 70-80%, in the amplitude of lesions and their severity, a reduction in the liquid contained in the vesicular lesions, as well as a slowing of the tendency for synechia formation/progression.
The object of the present invention represented by rutin, also known as oxerutin, for use, either alone or in combination with doxycycline, in the treatment of EB thus turns out to be a very interesting and effective response to the need for new and effective treatments for this rare disease particularly debilitating for patients, which, to date, has no treatment and care protocols capable of counteracting and/or preventing its effects.
Experimental section
Clinical trial protocol
The trial was initially carried out on three adult subjects suffering from dystrophic epidermolysis bullosa with severe phenotype, whose characteristics and treatment protocol are summarized in Table 1.
The small size of the sample tested is determined in that, speaking of a rare disease, all studies devoted to it suffer, due to contingent reasons, from a paucity of subjects who can be involved in the trial.
Table 1 : Characteristics and treatment protocol of the subjects of the clinical study
Figure imgf000006_0001
Subjects 1 and 2 were also previously treated with an experimental gene therapy involving a direct treatment of the lesions, which ended in January 2022 for both subjects. Said therapy is able to cause a recession/healing of the lesions, which, however, has a limited time duration due to natural regeneration of the epidermal tissues, which completely renew themselves according to physiological mechanisms. Indeed, there is a recurrence of the disease and the formation of new lesions about 3- 4 months after the treatment is stopped.
Subject 1 started the treatment according to the present invention 4 months after the discontinuation of the gene therapy, subject 2 started 9 months after the discontinuation.
Results
Administration of rutin, also known as oxerutin, led to a general reduction in wound width in all three subjects and since the first weeks of treatment. In subjects 1 and 2, after about three months of combined rutin, also known as oxerutin, + doxycycline treatment, there was a measurable reduction in wound surface area of about 75%. This reduction turns out to be particularly attractive both from the point of view of decreasing pain and the possibility of infection but also because the presence of wide areas of skin without lesions allows easier skin care treatment than the prevention of the creation of new blisters (moisturizing, cleansing, application of emollient creams, etc.).
Experience with prolonged treatment, particularly on subject 1, has demonstrated that the improvement in health status remains measurable and progressive even after 10 months of therapy.
In particular, a reduction is found in the surface area of even the oldest lesions, even dating back to the subject's early life and never fully healed, with a marked decrease in the inflamed surface area. In addition, it was possible to measure a reduction in the number of liquid-containing blisters in the various body districts and the decrease in the amount of the liquid itself present in the blisters, which went from about 10 mL liquid per blister to less than 1 mL, down to even 0.3-0.5 mL liquid per blisters.
Another surprising result, and particularly interesting with respect to the quality of life of subjects suffering from EB, concerns the evolution of synechiae. In particular, subject 1, suffering from progressive adherence between two fingers of one hand, was able to observe the non-advanced extent of adherence throughout the treatment period.
Subject 3, treated with rutin alone, also known as oxerutin, and for a shorter time than the other patients involved, as previously mentioned is also showing very encouraging signs with respect to the decrease in total lesion area and inflammation. Continued experimentation will make it possible to determine with greater certainty the extent of the positive effects, which are certainly present, of the treatment according to the present invention and to evaluate the synergistic effect brought about by the combination of rutin, also known as oxerutin, and doxycycline.
Further experimental trials were carried out on 2 additional patients, for a total of 5 severe EB patients manifesting, in particular one, lower limb edema with pain from venous insufficiency demonstrated by Doppler ultrasound. 3 adult severe-phenotype patients use Venoruton® (rutin, also known as oxerutin) and doxycycline at a dosage of one 1000-mg sachet per 10 kg and one 100-mg tablet twice a day of doxycycline. They all had squamous cell carcinoma. 2 of these patients underwent surgical excision of the tumor in the summer of 2021 and after 36 months had no recurrence. The third patient has no recurrence six months after surgical excision of the carcinoma. All showed wound reduction of 80% to the total wounded skin surface area.
Another 2 patients take Venoruton® alone (rutin, also known as oxerutin, also referred to as oxerutin). The same benefit on the skin was observed for these patients. One of them, already suffering from squamous cell carcinoma before the initiation of therapy, showed recurrence.
From what set forth above, the beneficial effects of treatment set forth above according to the present invention are evident. In particular, the 3 patients treated with rutin, also known as oxerutin, and doxycycline showed 80% reduction in the extent of body surface area affected by wounds. They also showed a reduction in edema and pain from venous insufficiency of the lower limbs.
Out of the 4 patients affected by squamous cell carcinoma, 3 of them, also treated with doxycycline according to the present invention, showed no recurrence. In particular, 2 patients underwent surgical excision of the squamous cell carcinoma between July and August 2021. The same patients started the treatment with doxycycline at the same time. The first patient started the treatment with Venoruton® on May 25th, 2022, while the second patient started the treatment with Venoruton® in September 2022.
Both patients to date make continuous use of the Venoruton® and doxycycline combination therapy according to the present invention.
Both patients:
- 3 years after surgical excision of the squamous cell carcinoma
- 3 years after starting the doxycycline therapy
- 24 months after the introduction of Venoruton® therapy (the first patient)
- 20 months after the introduction of Venoruton® therapy (the second patient) have had no recurrences of squamous cell carcinoma.

Claims

1. Rutin, also known as oxerutin, for use in the treatment of epidermolysis bullosa.
2. The rutin, also known as oxerutin, for use according to claim 1, characterized in that said rutin, also known as oxerutin, is administered in combination with doxycycline.
3. The rutin, also known as oxerutin, for use according to claim 1 or 2, characterized in that said rutin, also known as oxerutin, is administered orally in an amount of 1,000 mg to 8,000 mg per day, preferably 3,000 mg to 5,000 mg per day.
4. The rutin, also known as oxerutin, for use according to claim 2 or 3, characterized in that said doxycycline is administered orally in an amount of 100 mg to 300 mg per day, preferably 200 mg per day.
5. The rutin, also known as oxerutin, for use according to any one of the preceding claims, characterized in that said epidermolysis bullosa is dystrophic epidermolysis bullosa.
6. The rutin, also known as oxerutin, for use according to any one of the preceding claims, characterized in that said rutin is administered in the form of a powder for oral solution containing 1,000 mg rutin 3 to 5 times per day.
7. The rutin, also known as oxerutin, for use according to any one of claims 2-6, characterized in that said doxycycline is administered twice per day in the form of immediate-release tablets containing 100 mg doxycycline.
8. A kit comprising a pharmaceutical formulation for oral use, containing rutin, also known as oxerutin, and a pharmaceutical formulation for oral use of doxycycline.
9. The kit according to claim 8 wherein said pharmaceutical formulation for oral use containing rutin, is in the form of a powder for oral solution containing 1,000 mg rutin.
10. The kit according to claim 8 or 9 wherein said pharmaceutical formulation for oral use containing doxycycline is in the form of immediate-release tablets containing 100 mg doxycycline.
PCT/IB2024/054788 2023-05-17 2024-05-17 Rutin, also named oxerutin, for the treatment of epidermolysis bullosa WO2024236533A1 (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017035665A1 (en) * 2015-09-03 2017-03-09 Delivra, Inc. Transdermal formulations for delivery of doxycycline, and their use in the treatment of doxycycline-responsive diseases and conditions

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017035665A1 (en) * 2015-09-03 2017-03-09 Delivra, Inc. Transdermal formulations for delivery of doxycycline, and their use in the treatment of doxycycline-responsive diseases and conditions

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Title
ALMEIDA J. S. ET AL: "Hydrogels containing rutin intended for cutaneous administration: efficacy in wound healing in rats", JOURNAL DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, vol. 38, no. 7, 8 November 2011 (2011-11-08), US, pages 792 - 799, XP093108660, ISSN: 0363-9045, DOI: 10.3109/03639045.2011.628676 *
BARDHAN AJOY ET AL: "Epidermolysis bullosa", NATURE REVIEWS DISEASE PRIMERS, NATURE PUBLISHING GROUP UK, LONDON, vol. 6, no. 1, 24 September 2020 (2020-09-24), XP037255119, DOI: 10.1038/S41572-020-0210-0 *
GULLÓN BEATRIZ ET AL: "Rutin: A review on extraction, identification and purification methods, biological activities and approaches to enhance its bioavailability", TRENDS IN FOOD SCIENCE & TECHNOLOGY, vol. 67, 1 September 2017 (2017-09-01), GB, pages 220 - 235, XP093201369, ISSN: 0924-2244, DOI: 10.1016/j.tifs.2017.07.008 *
HANNAH M SINGER ET AL: "Wound culture isolated antibiograms and caregiver-reported skin care practices in children with epidermolysis bullosa", PEDIATRIC DERMATOLOGY, 1 January 2018 (2018-01-01), pages 92 - 96, XP055465726, Retrieved from the Internet <URL:http://www.woundsinternational.com/media/issues/623/files/content_10609.pdf> DOI: 10.1111/pde.13331 *
LICHOTA ANNA ET AL: "Therapeutic potential of natural compounds in inflammation and chronic venous insufficiency", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 176, 15 August 2019 (2019-08-15), pages 68 - 91, XP085707318, ISSN: 0223-5234, DOI: 10.1016/J.EJMECH.2019.04.075 *
PLENERT W.: "Studie zur Blasenbildung bei der Epidermolysis bullosa", vol. 78, no. 3, 1 January 1956 (1956-01-01), Berlin/Heidelberg, pages 329 - 340, XP093108676, ISSN: 0340-6199, Retrieved from the Internet <URL:http://link.springer.com/article/10.1007/BF00436745/fulltext.html> DOI: 10.1007/BF00436745 *
TRAN NGOC QUYEN ET AL: "In Situ Forming and Rutin-Releasing Chitosan Hydrogels As Injectable Dressings for Dermal Wound Healing", BIOMACROMOLECULES, vol. 12, no. 8, 27 June 2011 (2011-06-27), US, pages 2872 - 2880, XP093088306, ISSN: 1525-7797, DOI: 10.1021/bm200326g *

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