WO2016079766A1 - Composition thérapeutique - Google Patents

Composition thérapeutique Download PDF

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Publication number
WO2016079766A1
WO2016079766A1 PCT/IT2015/000279 IT2015000279W WO2016079766A1 WO 2016079766 A1 WO2016079766 A1 WO 2016079766A1 IT 2015000279 W IT2015000279 W IT 2015000279W WO 2016079766 A1 WO2016079766 A1 WO 2016079766A1
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Prior art keywords
medical composition
weight
skin
treatment
active ingredient
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PCT/IT2015/000279
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English (en)
Inventor
Maria Alessandra DI STEFANO
Stefano Manfredini
Silvia Vertuani
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Kethema Group Di Di Stefano Maria Alessandra
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Priority to EP15832702.3A priority Critical patent/EP3221011A1/fr
Publication of WO2016079766A1 publication Critical patent/WO2016079766A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L7/00—Cereal-derived products; Malt products; Preparation or treatment thereof
    • A23L7/10—Cereal-derived products
    • A23L7/152—Cereal germ products
    • 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

Definitions

  • the present invention relates to a medical product or a pharmaceutical product, overall defined a medical composition, for topical, oral, intra-vaginal or intra-bladder use, in particular as wound-healing agent and anti-inflammatory agent for broad use, for example for the treatment and the quick resolution of inflamed zones, of skin lesions, such as sores, ulcers, burns, scars, radiodermatitis, etcetera, or for the treatment of both the outer and inner mucous membrane of the human body.
  • a medical composition for topical, oral, intra-vaginal or intra-bladder use, in particular as wound-healing agent and anti-inflammatory agent for broad use, for example for the treatment and the quick resolution of inflamed zones, of skin lesions, such as sores, ulcers, burns, scars, radiodermatitis, etcetera, or for the treatment of both the outer and inner mucous membrane of the human body.
  • the medical product or the pharmaceutical product according to the present invention can therefore be applied in numerous diseases, for example those present in adults, in elderly people and in children.
  • the present invention therefore relates to the use of such medical composition as wound-healing agent and anti-inflammatory agent, having regenerating properties for the skin or mucous membranes and wound-healing agents for the aforesaid lesions or diseases and a method for the attainment thereof.
  • Skin constitutes the most outer border between man and the environment, the main protection member of the human body and acts both as barrier and as connection between the outside world and the internal organs.
  • Adult skin has a surface area of about 2 m 2 and a weight equal to 16% of the total weight of the human body; it also possesses high mechanical strength.
  • Skin has many functions that vary from the protection from pathogenic microorganism penetration to the barrier effect against harmful outside influences (e.g. mechanical, chemical or thermal) and protection from solar rays; in addition, due to its perspiration and evaporation (sweat) properties, it provides an important contribution to the maintenance of the body temperature necessary for the vital functions of the organism. Finally, skin has a considerable substance absorption capacity (transdermal administration of drugs); it is able to store such substances throughout its entire subcutaneous layer constituted by adipose tissue.
  • Skin is constituted by three tissue layers, i.e. epidermis, dermis and subcutaneous tissue, listed from the outermost to the innermost layer.
  • skin appendages (hair, nails, glands) constitute part of the skin, which are situated in the dermis but which are strictly connected with the epidermis.
  • the epidermis which is the outermost layer of the skin, is a stratified pavement epithelium tissue constituted by five differentiated layers; it has a thickness that can vary from 0.1 to 3 mm approximately according to the cutaneous territories. Regeneration occurs at the deepest layers, from where the cells are pushed towards the skin surface and, during the course of this migration, the complete keratinization of the cells occurs along with the loss of their nucleus.
  • the epidermis lacks vessels and is fed by means of the diffusion of nutritional substances from the bed of the dermis capillaries.
  • the dermis of mesodermal origin, is situated below the epidermis and is a connective tissue rich with vessels and nerves subdivided into two layers not delimited from each other, but which are differentiated from each other due to the thickness and the order of the connective tissue fibers.
  • the intercellular space of the outermost layer of the dermis is filled with an essential gelatinous fluid substance (extracellular matrix) in which the blood and tissue cells can freely move.
  • the deepest and thickest layer of the dermis is constituted by a weave of robust fiber bands, which are oriented parallel to the cutaneous surface, between which numerous meshes of elastic fibers are intersected, conferring characteristics of greater or lesser extensibility to the skin.
  • This orientation of fibers is functionally translated outward in the Langer lines, which constitute the skin tension lines, parallel to which the surgical incisions on the skin should be made in order to obtain an improved tissue repair and an improved healing.
  • the subcutaneous represents the innermost layer of the skin and is constituted by connective tissue with loose weave which does not have a clear delimitation with the overlying dermis. Except for a few areas of the body, adipose tissue can be deposited over the entire subcutaneous, which has an insulating, deposit and modeling function. Some skin appendages can also intervene in cutaneous regeneration.
  • the vascular system of the dermis allows the nutrition of the skin by means of the substances transported by the arterial blood, the cutaneous metabolism and the cellular turnover, the thermoregulation through mechanisms of vasoconstriction or vasodilatation, and the elimination of endogenous toxins (both through the vascular system and transdermal ly).
  • the cells of the immune system circulate in the blood, along with the components of the coagulation system which, in the case of wound of the blood vessels, contribute to the rapid closure of the damaged points.
  • Cutaneous wounds can be classified as acute or chronic: by chronic lesion, it is generally intended an alteration of the tissue structure which does not evolve towards the normal repair processes and which does not show any tendency towards healing in the arc of 6-8 weeks.
  • the passage from an acute wound to a chronic wound can occur in any step of its healing: a classic example are the post-traumatic ulcers of the lower limbs of an elderly person, of a diabetic, in the patient with vascular and autoimmune diseases (both due to vasculitis and corticosteroid therapy).
  • Normal acute wounds can be due to a surgical procedure or to a traumatic event, whether mechanical, thermal or chemical, and they progress towards a series of events that lead to the final healing of the lesion.
  • chronic wounds differ from the preceding due to the underlying disease and the type of tissue repair: generally they originate following a local alteration of cutaneous trophism due to a decreased supply of oxygen, whether this is due to a primitive disease of the arterial or venous vessels, to the age of the patient, to malnutrition, to metabolic diseases like diabetes, to local or systemic infections, to neurological diseases, renal diseases, immunological diseases or to the effects of a local and persistent pressure or to repeated and frequent trauma.
  • wounds include vascular ulcers (mainly of the lower limbs), the ulcers of the diabetic foot, the pressure, the ulcers from chronic inflammatory diseases, those from infectious diseases, the neoplastic ulcers and those from hematological diseases.
  • the chronic lesion can affect all the layers of the skin and can be extended to the muscles and bones.
  • Closed wounds characterized by damage to the staictures of the tissues and bones, of the blood vessels and nerves below the skin, without cutaneous laceration (closed fractures, dislocations, contusions, hematomas, cerebral commotion).
  • Tissue repair is a dynamic and interactive process that normally occurs in our organism and which involves soluble mediators, extracellular matrix, blood cells and parenchyma cells.
  • the healing of the cutaneous wounds is determined by a complex biological process which leads to the formation of new tissue of connective nature, the scar, which has the function of filling the loss of substance, represented by the wound itself.
  • the phases of the repair process which are distinct but can be overlapped in some moments, are the following.
  • the first, said inflammatory phase has a duration that can vary from 0 to 3 days and can be subdivided into the coagulation or hemostatic phase and the actual inflammatory phase.
  • the second, said proliferation phase has a duration that can vary from 3 to 24 days and finally the third, said maturation or epithelialization phase, has a duration that can vary from 6-10 days to 12-24 months.
  • the first phase is characterized by local bleeding due to the lesion of the vessels of the affected zone (of brief duration in most of the light wounds, while in the surgical wounds a suture of the affected zone follows).
  • the initial coagulation phase (which lasts about 10 minutes) provides for vasoconstriction caused by vaso-active substances liberated by the damaged cells, hematic infiltration (hemorrhage) and the subsequent plate aggregation.
  • Inflammation represents the complex defense reaction of the organism: defending from the action of many different types of pathogenic agents of mechanical, physical, chemical or bacterial origin.
  • the proliferation phase follows: here, cellular proliferation prevails that is aimed for the neotormation of vessels and for filling the loss of substance by means of granulation tissue.
  • the granulation tissue is a transitory and primitive entity that serves as a "bed" for the subsequent epithelialization phase.
  • the maturation of the collagen fibers begins.
  • the wound contracts and passes from a highly cellular tissue (granulation tissue) to a nearly non-cellular tissue.
  • the cutaneous covering completes the healing of the lesion.
  • the maturation phase can last several months, even years.
  • the general factors include the following: the age of the subject (the healing of the wounds is slower in elderly subjects), the nutritional state or vitamin deficiencies (individuals with serious nutritional deficiencies, above all protein deficiencies, have a significant slowing of the cicatricial process), systemic diseases or particular treatments (some diseases, for example diabetes, or some treatments, such as cytostatic and cortisone treatments, negatively affect the healing of the wounds).
  • each scar due to the maturation phase, improves its appearance over time until it becomes nearly invisible - even if it often continues to be regarded as a more or less serious unaesthetic item.
  • the outcomes can be objectively disfiguring.
  • tissue repair process following various factors (scars, lesions, burns, surgical operation outcomes, bedsores, excoriations, etc.), has always represented a considerable problem in the medical and dermatological field.
  • the mucous membrane instead, is the tissue portion in direct contact with the lumen of the hollow animal organs, which are in communication with the outside environment, like the digestive channel and the respiratory tract (excluding therefore the organs of the cardio-circulatory apparatus).
  • the mucous membrane is formed by the superimposition of four layers: a covering epithelium, which faces towards the lumen; a basal lamina, which constitutes the connection between the epithelial layer and the connective layer, constituted by lamina densa and lamina rara (in accordance with the protein composition) and by a fibroreticular lamina of connective origin; an intermediate lamina or tunica muscular intestinal with interwoven bands; and finally a muscularis mucosae, exclusively present in the organs of the digestive apparatus, starting from the esophagus, and composed of a layer of smooth muscular fibrocells, which is continuous with the tunica submucosa.
  • Some diseases can affect the mucous membranes, such as gastritis.
  • Gastritis is an inflammation of the gastric mucous membrane and various causes lead to this manifestation; innumerable types of gastritis exist, subdivided in the classic manner: acute and chronic gastritis.
  • duodenitis is an inflammation of the duodenum, and generally there are many different inflammatory diseases, e.g. intestinal, buccal or vaginal-bladder.
  • cosmetic products are known of various type, also of natural origin or with varied composition, e.g. with emollient or exfoliating activity. Nevertheless, cosmetic products are unable to treat and heal the damaged skin, facilitating the wound-healing thereof; moreover it is not even possible to apply a cosmetic product on the wounds.
  • the present invention therefore proposes solving such problems.
  • One object of the present invention is to improve the state of the art.
  • Another object of the present invention is to develop a medical composition for application on damaged skin or skin appendages or on the mucous membranes which has simple and practical application.
  • Another object of the present invention is to develop a medical composition having regenerating and/or wound-healing and/or anti-inflammatory properties for the skin, for skin appendages or for mucous membranes and having kinetics with quick and effective action.
  • Another object of the present invention is to develop a medical composition that is biologically active and at the same time safe from the microbiological standpoint.
  • a medical composition having the applications indicated according to independent claim 1 .
  • a still further object of the present invention is to develop a method for obtaining a medical composition which is quick and practical to attain, and which also makes the obtained product microbiologically stable.
  • a method for obtaining a medical composition according to independent claim 1 1.
  • figure 1 is a graph which illustrates the logarithmic variation of the microbial load with respect to the inoculated load for one version of the medical composition according to the present invention
  • ST Staphylococcus aureus
  • PS Pseudomonas aeruginosa
  • EC EC
  • figure 2 illustrates the results of the in vitro test, with the control present in column A, the sample with irritation present in column B while in column C the sample is treated with the present invention, for example with the first version thereof;
  • FIGS 3a to 10b illustrate several cases treated with the composition according to the present invention, in which the letter “a” indicates the case before the treatment and the letter “b" of each pair of figures indicates the final results.
  • the present invention relates to a medical product or a pharmaceutical product for a topical, oral, intra-vaginal or intra-bladder use.
  • the intra-vaginal or intra-bladder use according to one version of the invention is a topical use.
  • the use according to the present invention can also occur by means of injections, for example intra-dermal.
  • medical product any substance or product, usable on its own or in combination, intended to be used in man for the purpose of diagnosis, prevention, control, treatment or attenuation of a disease, a wound or a handicap or for the study, substitution of modification of anatomy or a physiological process.
  • the medical products preferably act in the human body or on the same through physical, mechanical, thermal means etcetera.
  • the medical product or pharmaceutical product according to the present invention will hereinbelow be defined overall as the medical composition.
  • the medical composition according to the present invention comprises an active ingredient of plant origin.
  • the plant active ingredient is derived from or comprises sprouted grains.
  • the plant active ingredient is derived from or comprises sprouted cereal grains (whole grains so to be able to sprout) such as rice, e.g. Oryza Sativa, oat, e.g. Avena sativa, barley, e.g. Hordeum vulgare, spelt or wheat, e.g. Triticum, corn, e.g. Zea mays, or mixtures thereof.
  • sprouted cereal grains such as rice, e.g. Oryza Sativa, oat, e.g. Avena sativa, barley, e.g. Hordeum vulgare, spelt or wheat, e.g. Triticum, corn, e.g. Zea mays, or mixtures thereof.
  • Such active ingredient is in the form of a powder which, in a first version of the invention, constitutes an aqueous suspension containing water and the powder of the aforesaid seeds.
  • the powder is obtained via exsiccation and triturating of the sprouted grains.
  • Such aqueous suspension comprises from 5 to 50% (weight/weight) of the powder of the indicated cereal grains, or 10-40%, or 20-30%.
  • the medical composition comprises 100% of such aqueous suspension containing the active ingredient of plant origin.
  • Such plant active ingredient especially when suspended in water, can be easily perishable at ambient temperature in about two days, due to the bacterial contamination and degradation to which the suspension can be subjected.
  • the packaging form of such medical composition is the single-dose, e.g. 5 ml or 10 ml, to be used for example, if the product is integral, within three years after the packaging or a day after the opening of the single-dose.
  • the plant active ingredient comprising or being derived from sprouted whole grains, has a great bioavailability of the bio-active nutrients and compounds present in the seed, because of an activated and intense enzymatic activity due in fact to the sprouting.
  • the cells present in the sprouted grains can be considered actual totipotent plant cells, rich with vitality and nutritional power, due for example to the high enzymatic, polyphenol, protein and sugar content (as described for example in Plant Foods Hum Nutr. 2012 Mar;67(l ):71 -5. doi: 10.1007/sl 1 130-01 1-0273-x.vTotal polyphenols, antioxidant and antiproliferative activities of different extracts in mungbean seeds and sprouts. Kim DK 1 , Jeong SC, Gorinstein S, Chon SU).
  • the plant active ingredient according to the present invention in fact, comprises a substantially protein or amino acid formulation, in which a high concentration of sugars is furthermore present (in particular mainly glucose, fructose, sucrose and maltose in smaller percentages).
  • the active ingredient according to the present invention comprises natural ingredients such as proteins, carbohydrates, fibers, vitamins, essential amino acids, GABA (gamma-aminobutyric acid or 4-aminobutanoic acid), mineral salts (such as phosphonis, magnesium, potassium, zinc, selenium, calcium, iron), phenolic antioxidant compounds such as ferulic acid esters and phytosterols like gamma oryzanol, etcetera.
  • GABA gamma-aminobutyric acid or 4-aminobutanoic acid
  • mineral salts such as phosphonis, magnesium, potassium, zinc, selenium, calcium, iron
  • phenolic antioxidant compounds such as ferulic acid esters and phytosterols like gamma oryzanol, etcetera.
  • phenolic compounds are antioxidant and anti-mutagenic and perform an important role in numerous processes that maintain the health of the human body.
  • sprouted rice with respect to white rise, has a content of GABA that is ten times greater, a content of fibers, vitamin E, niacin and lysine about 4 times greater and a content of vitamins B l and B6 and of magnesium greater than about 3 times.
  • the high fiber content assists the medical composition according to the present invention in carrying out a barrier effect, due to the medical product in question, on the wounds or on the damaged skin or also on the inflamed mucous membranes, in such a manner stimulating a quick healing.
  • Such mix of natural ingredients determines the high biological activity of the medical composition according to the present invention, capable of reactivating and stimulating the repair processes of the skin or skin appendages or mucous membranes in an entirely natural manner.
  • the amino acids comprise cystine in a particularly high concentration; this is a particular constituent of keratin.
  • lipids present in the medical composition according to the present invention in particular in its plant active ingredient, those present in greater quantity are lauric acid, palmitic acid, oleic acid (which can constitute more than half of the lipid fraction), linoleic acid and linolenic acid.
  • the content of GAB A increases to 25-45 mg over 100 g of plant active ingredient.
  • GABA GABA
  • the medical composition according to the present invention is microbiologically sterile and, in a first version thereof of the invention, it can be directly applied on injured or damaged skin.
  • such first version of the invention can be applied on injured or damaged skin appendages or on injured or damaged mucous membranes.
  • the medical composition is in the form of an aqueous suspension.
  • the medical composition according to the present invention is in emulsion form, e.g. dermatological cutaneous emulsion.
  • the medical composition in this second version is an emulsion composed of three phases: a first fatty or oily phase (phase I), a second aqueous phase (phase II) and a third phase (phase III) comprising the above-described plant active ingredient and possible further active compounds of interest.
  • such oil-in-water emulsion comprises:
  • the active ingredient comprises sprouted whole grains of rice or of Oryza sativa.
  • Such medical composition in its second version, can be used topically on non-damaged skin for the treatment of all the inflammatory diseases of the skin (without damaged skin) or of skin appendages or of mucous membranes.
  • the second version of the invention can be used in the continuation treatment, after having applied the first version of the medical composition in question.
  • the emulsion in question can for example be contained in containers, such as 50 ml polyethylene or polypropylene tubes, sealed with screw cap.
  • the medical composition comprises from 5 to 50% (weight/weight) of the powder of the indicated cereal grains, or 10-40%, or 20-30%, i.e. of active ingredient based on the total weight of the composition, and the remaining percentage of water.
  • the second version of the invention in which the medical composition is in oil-in-water emulsion form, 10-20% by weight of active ingredient based on the total weight of the composition is present.
  • the second version of the invention comprises 10- 20% by weight of aqueous suspension containing the plant active ingredient based on the total weight of the emulsion.
  • the fiber contained in the medical composition according to the present invention has difficulty in dissolving in water. Also for this reason, the first version is in suspension form while the second version is in emulsion form (in which the fiber must be well- resuspended).
  • the plant active ingredient according to the present invention particularly when suspended in water, has enhanced biological activity, with respect to active ingredients, for example obtained from the same plant material, but without the same having sprouted.
  • the regenerating capacity of the active ingredient was evaluated in vitro, in order to characterize the activity of the same.
  • Phase ⁇ of the test an irritant stimulus was applied on an in vitro experimental skin insert, thus reducing the vitality of the keratinocytes by 75%.
  • Phase 11 of the test the medical composition according to the invention was applied on the damaged skin insert.
  • the tested medical composition is in aqueous suspension form (first version of the invention).
  • Case 1 woman, 68 years old, thyroidectomy and drain scars (figure 3a). In only two weeks of treatment, there is the clear remission of the scars, with no keloid formation (figure 3b).
  • Case 2 woman, 72 years old, evident post-operation scarring, from removal of facial melanoma, with clear facial disfiguring (figure 4a); the patient manifested a great psychological disturbance due to this situation. In only three weeks of treatment, there was a clear remission of the scars, and no keloid formation; the patient observed a clear anti-aging effect with respect to the non-treated side (figure 4b).
  • Case 3 woman, 75 years old, deep post -trauma lesion on the right leg, presence of post suture cord (figure 5a). After about two months in home treatment with different known medical products, actual healing was not attained, so that the only solution seemed to be plastic surgery. Considerable improvement was achieved after only three days of treatment with the medical composition according to the present invention, with total elimination of all the post-suture cords; complete healing after three weeks of home treatment (figure 5b).
  • Case 4 man, 80 years old, affected by vasculitis, has a post-trauma lesion on the left leg (figure 6a), in home treatment, for about a month, with different known medical products and without any actual improvement or healing.
  • the lesion initially required a pre-treatment with an occlusive bandage soaked with the medical composition according to the present invention, in order to remove all the exudates that had by then solidified.
  • Case 5 man, 48 years old, who has been affected by psoriasis at the upper limbs for about 10 years, with exfoliation, inflammation and considerably itchy manifestation (figure 8a).
  • corticosteroids for controlling the inflammatory and exfoliation state of the disease.
  • the man is treated with the medical composition according to the present invention and after three weeks of treatment there is a considerable improvement of the inflammatory and exfoliation state, with complete resolution of the itchy manifestation (figure 8b).
  • Case 6 woman, 64 years old, affected by hives of food origin, following an excessive intake of dried fruit, with itchy manifestation (figure 9a). Total remission of the eczema and of the itchy symptoms after three weeks of home treatment with the medical composition according to the present invention (figure 9b).
  • Case 7 woman, 55 years old, affected by eczema for about a year, with lesions and total compromising of normal functionality and use of her hands. In treatment with corticosteroids without attaining any actual benefit (figure 10a). After three weeks of treatment with the medical composition according to the present invention, there is a total remission of the disease and total recovery of functionality of the patient's hands (figure 10b).
  • Case 8 woman, 75 years old, affected by first-degree burn on the right foot due to an accidental pouring of boiling water: with the formation of serous membrane and the presence of bacterial infection at the outer ends. Treated with a known product, such as that known with the commercial name Fitostimoline cream, but without showing improvements (figure 7a). The patient is treated with the present invention and reports an immediate sensation of relief and wellbeing. Resolution of the inflammatory process, complete regeneration of the skin after two weeks, complete resolution of the burn with the elimination of the damaged tissue and perfect healing of the injured skin after three weeks (figure 7b).
  • the medical composition according to the present invention also acts as anti-aging agent for the skin. Such action reduces the inflammation, fills the damaged skin and normalizes the sensitivity of the skin itself.
  • the use applications as medication or wound-healing agent and/or anti-inflammatory agent of the medical composition according to the present invention are, generally, mainly the following:
  • the first version of the invention is mainly used, which is microbiologically sterile and in which the plant active ingredient is more concentrated than in the second version,
  • adjuvant in cosmetic surgery treatments for example as filler (e.g. hence in injectable form), or anti-aging agent,
  • the medical composition according to the present invention performs a barrier action, i.e. protective and filmogenic, on the wounds of the skin or dermis or skin appendages or mucous membranes, with restoration of the cutaneous or tissue integrity. As said, such action is also performed due to the fiber content of the composition itself.
  • the medical composition according to the present invention assists the natural skin repair and regeneration processes for injured skin or damaged dermis or skin appendages or inflamed mucous membranes and it is also used for the treatment of scarring processes of the dermis.
  • the medical composition stimulates and indicates the natural tissue repair, in order to prevent the onset of the keloid.
  • the medical composition according to the present invention is indicated in all the inflammatory cutaneous or mucous membrane diseases, even possibly without injured skin or wounds.
  • the medical composition according to the present invention improves cutaneous elasticity.
  • Such plant active ingredient is provided with a considerable regenerative capacity for the tissue of the skin and of the mucous membranes, quick and effective for the treatment of cutaneous lesions or lesions present in the mucous membranes, in the current case in dermatological field, in gynecology, and in cosmetic surgery or medicine.
  • the medical composition according to the present invention has proven to be particularly useful and indicated for treating and bringing relief to skin, to skin appendages or to mucous membranes that are damaged and/or inflamed, affected by lesions, scars, bedsores, cosmetic or superficial surgery outcomes, superficial chemical- physical burns, ulcers, radiodermatitis in oncology, fissures, e.g. anal or breast, psoriasis, erythema, acute or chronic vulvovaginal dermatoses; due to the strong emollient action and anti-inflammatory activity of the aforesaid medical composition, moreover, the same is indicated for the treatment of itchy conditions, such as eczema of various type, contact dermatitis (e.g. ICD or "Irritant Contact Dermatitis" or ACD "Allergic Contact Dermatitis").
  • itchy conditions such as eczema of various type, contact dermatitis (e.g. ICD or "Irritant Contact
  • the medical composition according to the present invention therefore has a very important biological activity but, due to the plant active ingredient that it contains and the consequent enzymatic and microbial activity present in the same, it could be subjected to microbial attack and quick degradation.
  • the technological problem to overcome consists of stabilizing the medical composition - which is biologically active - according to a "soft" mode that blocks the degradation activity, leaving the biological activity of interest unaltered.
  • a stabilization method which provides for the use of a stabilizing mixture (which is mixed with the aqueous suspension according to the present invention) adapted to allow the process of packaging the medical composition, particularly of its first version.
  • the medical composition or its plant active ingredient is treated, possibly within 24 hours after its production, with a stabilizing mixture.
  • the stabilizing mixture can comprise benzyl alcohol, benzoic acid and dehydroacetic acid in a 80:8: 12 ratio at a concentration comprised between 0.1 - 1.5% (weight/weight, this is the final concentration, after having also mixed the aqueous suspension with the active ingredient), preferably 0.3-1%.
  • the stabilizing mixture alternatively can comprise benzyl alcohol, glycerol, benzoic acid and sorbic acid in a 1 : 1 : 1 : 1 ratio at a concentration comprised between 0.1 -1 .5% (weight/weight, this is the final concentration, after having also mixed the aqueous suspension with the active ingredient), preferably 0.3- 1 %.
  • the stabilizing mixture can alternatively comprise water, sodium benzoate, potassium sorbate in a 55:35 : 1 5 ratio at a concentration comprised between 0. 1 - 1 .5% (weight/weight, this is the final concentration, after having also mixed the aqueous suspension with the active ingredient), preferably 0.3-1%.
  • the resulting mixture is treated by means of a thermal process, for example pasteurization or UHT, or radiating process in order to eliminate the microbial activity.
  • a thermal process for example pasteurization or UHT, or radiating process in order to eliminate the microbial activity.
  • the product thus obtained does not have microbial activity, but preserves the entire nutritional component suitable for supporting the natural cellular trophism and hence for facilitating and accelerating the cutaneous healing processes, or the healing processes of the skin appendages or the mucous membranes.
  • the resulting medical composition to be applied on the damaged skin (as well as on the further described zones), is therefore microbiologicaliy inactive but functionally active.
  • the process for making the medical composition according to the present invention therefore comprises the following steps: providing an aqueous suspension comprising the plant active ingredient, bringing the mixture to a pH value comprised between 8-4, preferably between 4.5-6.5, mixing such aqueous suspension with a stabilizing mixture, sterilizing the resulting mixture by means of a thermal treatment or possibly by means of radiation.
  • the live and perishable cellular activity of the medical composition cannot generally be treated by means of some forms of sterilization (gamma rays, beta rays, ethylene oxide or microfiltration).
  • the preferred form of sterilization is therefore pasteurization.
  • This sterilization phase occurs in a manner such that the components of the medical composition or of the active ingredient contained therein are not degraded or damaged, so as to preserve unaltered the biological activity of the medical composition.
  • the medical composition or the resulting plant active ingredient are adapted to be used for the formulation of sterile dermatological products for the treatment in wound-healing and post-operation wound-healing phase for the quickest resolution without formation of keloids.
  • the presence of preservative agents is avoided in the first version of the medical composition according to the present invention (which is packaged in single-doses immediately after such treatment).
  • the second version of the invention being packaged in greater quantities with respect to the single dose, and being adapted to come into contact with non-damaged tissues, can comprise preservative agents.
  • the step of providing an aqueous suspension comprising the plant active ingredient comprises the steps of drying the plant material that constitutes and comprises the active ingredient in question, and triturating and reducing such exsiccated material into powder.
  • the process according to the present invention also comprises a step of packaging the medical composition in microbiologically controlled atmosphere.
  • Such evaluation was conducted by means of HPLC analysis. Such method was further implemented in order to characterize the mixture with a marker suitable for monitoring the possible degradation of the active compounds during the various stabilization processes.
  • a marker suitable for monitoring the possible degradation of the active compounds during the various stabilization processes For such purpose, the most representative and known polyphenol component was selected, Gamma-oryzanol. Such molecule is known for its high instability at even moderately harsh environmental conditions, such as 70°C heat.
  • a qualitative- quantitative method was developed based on a HPLC analysis. Such method was developed so to be suitable as method for the quality control of the product during the various processing steps.
  • the test provides for the contamination of the product with microorganisms of different species and the subsequent evaluation of the reduction of microbe load by means of the plate count of the number of live germs at regular time intervals for a period of 28 days, according to acceptability criteria of the ISO 1 1930:2012 norm.
  • the procedural steps consist of: preliminary microbe count on the samples to be examined; preparation of the microorganisms for the inoculation; inoculation of the samples; controls at pre-established intervals of microorganism survival; evaluation of the results.
  • the ISO (International Organization for Standardization) 1 1930:2012 norm describes how to execute the microbiological tests for the evaluation of the microbicidal effectiveness of the preservative system of a product subjected to an "in vitro" microbe contamination.
  • microorganisms used are: Staphylococcus aureus (Gram+), Pseudomonas aeruginosa (Gram-), Escherichia coli (Gram-), Candida albicans (Yeast), Aspergillus brasiliensis (Mold).
  • the concentration of the inoculation (time zero: tO) must be comprised between 10 3 and I 0 6 Colony-Forming Units [CFU (vital microorganisms)] / g of product.
  • the diluent used is physiological solution and the neutralizer appropriate for the anti- microbe test (present in the agar of the plate in order to facilitate the bacteria growth) is Eugon L T 100 liquid broth.
  • the culture media used are the following: Tryptic Soy Broth (TSB) for the preparation of the microbe suspensions of the standard used strains, Tryptic Soy Agar (TSA) for the bacteria, Sabouraud Dextrose Agar (SDA) + CFL for Candida albicans and for Aspergillus brasiliensis.
  • TLB Tryptic Soy Broth
  • TSA Tryptic Soy Agar
  • SDA Sabouraud Dextrose Agar
  • CFL Candida albicans and for Aspergillus brasiliensis.
  • the method comprises the semination on the surface of a Petri plate.
  • Criterion A after 7 days, reduction of at least 3 logarithms for the bacteria and at least 1 logarithm for Candida albicans; after 14 days, reduction of at least 3 logarithms for the bacteria (without any increase with respect to the preceding), at least 1 logarithm for Candida albicans (without any increase with respect to the preceding) and no increase with respect to tO for Aspergillus brasiliensis; after 28 days, reduction of at least 3 logarithms for the bacteria (without any increase with respect to the preceding), at least 1 logarithm for Candida albicans (without any increase with respect to the preceding) and at least 1 logarithm for Aspergillus brasiliensis.
  • Criterion B after 14 days: reduction of at least 3 logarithms for the bacteria, at least 1 logarithm for Candida albicans and no increase with respect to tO for Aspergillus brasiliensis; after 28 days, reduction of at least 3 logarithms for the bacteria (without any increase with respect to the preceding), of at least 1 logarithm for Candida albicans (without any increase with respect to the preceding) and no increase for the Aspergillus brasiliensis.
  • Compliance with criterion A the microbiological risk is acceptable and the product is considered protected against the microbe proliferation, and it is not necessary to consider other factors that are independent from the formulation.
  • compliance with criterion B the microbiological risk is acceptable, but the evaluation of the microbiological risk must also take under consideration the control factors independent of the formulation, such as the characteristics of the packaging, in order to reduce the microbiological risk.
  • the anti- microbe evaluation of the product must be evaluated only in consideration of the estimated microbiological risk (product packaged in a single-dose, in compliance with the good manufacturing practice (GMP) norms, in order to ensure the microbiological quality of the finished product.
  • GMP good manufacturing practice
  • microbiological safety of a product is based on the combination of different factors, not only based on the results of the aforesaid test, but also on the formulation of the products, on the use conditions and on the type of package that contains them, on the production and packaging mode in accordance with the good manufacturing practice (GMP) norms.
  • GMP good manufacturing practice
  • the medical composition according to the invention is in compliance with criterion A: the microbiological risk is acceptable.
  • Gram+ reduction of the inoculation within 2 days
  • Gram- for EC
  • PA reduction of the inoculation within 14 days
  • mycete reduction for CA
  • ASP reduction of the inoculation within 7 days.
  • the medical composition is considered protected against microbial proliferation.
  • This study has the purpose of analyzing the effect of the composition according to the present invention on the healing of cutaneous wounds (wound healing), by comparing it to that obtained after treatment with two drugs known for their skin healing properties, the first drug containing as active ingredient hyaluronic acid and silver sulfadiazine (e.g. the cream known with the commercial name Connettivina plus®) and the second drug containing as active ingredient triticum vulgare and phenoxyethanol (e.g. the cream known with the commercial name Fitostimoline®).
  • the first drug containing as active ingredient hyaluronic acid and silver sulfadiazine e.g. the cream known with the commercial name Connettivina plus®
  • the second drug containing as active ingredient triticum vulgare and phenoxyethanol e.g. the cream known with the commercial name Fitostimoline®.
  • the primary keratinocytes were cultivated in 75cm 2 flasks in Dulbecco's modified Eagle's medium (DMEM Lonza®, Milan, Italy) enriched with glucose (4.5g/l), containing 10% fetal bovine serum (FBS), 1% (2mM) L-glutamine, (lOOU/ml) penicillin and streptomycin (lOOpg/ml).
  • DMEM Lonza® Dulbecco's modified Eagle's medium
  • FBS fetal bovine serum
  • 2mM 2mM L-glutamine
  • penicillin and streptomycin penicillin and streptomycin
  • the cells were treated w i t h different doses of the composition according to the present invention, of the above-indicated first daig and second drug for 24h.
  • the cells were seminated in a 6-well plate at a concentration of l x l 0 6 cel ls/ml .
  • the study of the cellular vitality was carried out 24 hours after the treatment wi t h the compounds by means of a cytofluorimetric test and through the determination of the released LDH levels.
  • the cytofluorimetric test was carried out by using the kit Muse Count&Viability (Millipore, Corporation, Billerica, MA, USA). The cells (l xl O 6 cells/ml) were resuspended in PBS. 10 ⁇ of this cellular suspension was added to 190 ⁇ of Muse Count&Viability working solution and incubated for 5 min at ambient temperature in the dark. Subsequently, the cells were analyzed at the Muse Cell Analyzer (Millipore). The release of LDH was measured by means of an enzymatic test: in the first step, NAD+ is reduced to NADH/H+ by the conversion of the LDH-catalyzed pyruvate lactate.
  • the catalyst (Diaphorasis) transfers H/H+ ions from NADH/H+ to tetrazole salt, which is reduced to formazan.
  • the cells were lysed with 2% (v/v) of Triton X-100 in culture media for 30 min at 37 °C in order to obtain a maximum release of LDH with 100% toxicity (positive control).
  • the quantities of LDH in the supernatant were determined and calculated according to the instructions of the kit (Roche Italy, Milan).
  • the cells were seminated in a 6-well plate at a concentration of l xl O 6 cells/ml. At each single cell layer, a "scratch" was executed by means of the use of a 200ul metal point in order to generate a zone lacking cells (0.8- 1 mm in width). After washing in PBS, the cells were treated with the different compounds and photographed at different times: immediately after the scratch and at 2, 4, 6, 8, 12, 24 h after the scratch. The area was marked at the base of the plate and the same field was photographed at each time in order to evaluate the migration/proliferation of the cells in the area of the wound.
  • the BrdU test was carried out according to the original protocol by Roche (BrDU kit for the test, Roche, Milan, Italy). The cells were seminated in a 96-well plate at the concentration of 5x10 4 cells/ml. After the treatment, 10 ⁇ of BrdU solution was added to each well for 16- 18 h. Then the cells were fixed and the D A was denatured in order to allow the incorporation of BrdU. Subsequently, the cells were incubated with an anti-BrdU antibody conjugated with peroxidase for 90 min at ambient temperature. After three washing steps, the bonded peroxidase was detected by means of the use of a reaction substrate. Once this reaction was blocked by adding ( 1M) H2SO4, the optical density of the yellow-color reaction product was measured, at the wavelength of 450 nm, by means of an EL1SA reader.
  • the cells (I xl O 6 cells/ml), 24h after the treatment, were washed in 0.1M PBS. 200 ⁇ of this cellular suspension was centrifuged at 300xg for 5 minutes and the obtained pellet was resuspended in 200 ⁇ of 70% Ethanol in ice and incubated for 3 h at -20°C. At the end of this period, after centrifugation and washing, 200 ⁇ of MUSETM Cell Cycle Reagent were added to the obtained pellet and incubated for 30 minutes at ambient temperature, before measurement.
  • the cells were placed on ice and washed 2 times with phosphate buffer (PBS). Subsequently, they were lysed with a buffer containing 20mM Tris base, pH 7.4, 75mM NaCl, 20mM EGTA, I mM Na3V04, 2.5 raM NaF, 2.5 g/ml aprotinin, I mM PMSF (phenylmethylsulfonylfluoride), ⁇ tg/ml leupeptin, I mM sodium pyrophosphate and 1% Triton X-100 (Sigma; Milan, Italy) and centrifuged at 13500 rpm at 4°C for 15 minutes. The protein concentration was determined by means of the Bradford method (Biorad Protein assay, Milan, Italy).
  • the membrane was left for 1 hour and 30 min at ambient temperature in TBS (20mM Tris- base, 140mM NaCl, pH 7.4) containing 3% milk (Skim milk powder for microbiology; Merk, Florence, Italy). After two washings in TBS-Tween (TBS-T 20mM Tris-base, 140mM NaCl, 32 0.05% tween, pH 7.4), the membrane was incubated for the entire night with the primary antibody (Millipore rabbit anti-cyclin, diluted with a solution of TBS-T containing the 0.3% milk).
  • TBS Tris- base, 140mM NaCl, pH 7.4
  • the membrane was incubated for the entire night with the primary antibody (Millipore rabbit anti-cyclin, diluted with a solution of TBS-T containing the 0.3% milk).
  • the membrane was washed three times with TBS and subsequently incubated for 1 hour and 30 minutes with the secondary antibody conjugated with the enzyme "horseradish peroxidase". After a series of washings, the secondary antibody was highlighted by means of the chemiluminescence technique.
  • composition according to the present invention causes an improvement of the cell repair speed and/or an increase of the cellular vitality.
  • the cell repair speed and/or the cellular vitality are increased, for example by a percentage comprised between 30% and 60% with respect to the used controls and comparison references, e.g. with respect to the first and second drug listed above.
  • composition according to one version of the present invention for example, already occurs within 24 hours from the treatment or within 12 hours from the treatment or within 8 hours from the treatment or even within 4 or 2 hours from the treatment.
  • the composition according to the present invention Consequently, by means of the composition according to the present invention, one obtains a quicker and hence more effective closure of the wound or repair of the lesion present on the skin and/or on the mucous membranes and/or on the skin appendages.
  • the medical composition according to the present invention in particular its use as wound- healing agent and/or anti-inflammatory agent for the skin, skin appendages or mucous membranes and the method for the attainment thereof, solves the abovementioned technical problems and has the above-described advantages.

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Abstract

L'invention concerne une composition thérapeutique comprenant un ingrédient actif d'origine végétale dérivé de grains germés ou comprenant des grains germés, destinée à être utilisée sur la peau, les phanères ou les muqueuses, ainsi qu'un procédé d'obtention de cette composition thérapeutique.
PCT/IT2015/000279 2014-11-17 2015-11-17 Composition thérapeutique WO2016079766A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220249347A1 (en) * 2021-02-10 2022-08-11 TRI-K Industries, Inc. Composition and Method Containing Pea and Quinoa Natural Peptides And Niacinamide to Enhance Skin Glow, Radiance And Even Skin Tone

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