EP4110360A1 - Formulation à base d'ingrédients naturels destinée à être utilisée dans le traitement de troubles proctologiques - Google Patents

Formulation à base d'ingrédients naturels destinée à être utilisée dans le traitement de troubles proctologiques

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Publication number
EP4110360A1
EP4110360A1 EP21708576.0A EP21708576A EP4110360A1 EP 4110360 A1 EP4110360 A1 EP 4110360A1 EP 21708576 A EP21708576 A EP 21708576A EP 4110360 A1 EP4110360 A1 EP 4110360A1
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EP
European Patent Office
Prior art keywords
honey
formulation
use according
weight
hyaluronic acid
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EP21708576.0A
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German (de)
English (en)
Inventor
Marianna ALTIERI
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Giuliani SpA
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Giuliani SpA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/63—Arthropods
    • A61K35/64—Insects, e.g. bees, wasps or fleas
    • A61K35/644—Beeswax; Propolis; Royal jelly; Honey
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • 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
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present invention generally relates to the field of pharmaceutical industry.
  • the invention relates to a natural base formulation for topical application for use in treating proctological disorders.
  • proctology pertains the medical and surgical treatment of colorectal and anal disorders, including hemorrhoids, proctitis and anal fissures.
  • hemorrhoidal proctological disorders are disorders caused by a swelling and/or an inflammation of hemorrhoids, (i.e. cushions of vascular tissue and connective tissue, located in the anal canal) due to, for example, an abnormal dilation and distortion of vascular channels, vascular thromboses, degenerative processes of collagen fibers associated with supporting connective tissue alterations, loss of functionality of the anal subepithelial muscle.
  • Hemorrhoids may develop outside of or inside of the anal canal and, in the latter case, they may be classified according to appearance and prolapse level.
  • Typical symptoms of hemorrhoids comprise bleeding, itching and burning during defecation, constant and persistent pain in the most advanced stages.
  • anal fissures are small cuts which typically form in the posterior margin of the anus, due to an excessive dilation of the same generally caused by the passage of hard bulky feces, as it often occurs during chronic constipation.
  • fissures do not spontaneously heal, they may give rise to an ulcer, whose healing takes much longer and is more difficult.
  • Fissure symptoms comprise: proctalgia during and after defecation, post defecation proctorrhagia, feeling of perianal weight, perianal itching and abrasions (which represent indicative symptoms of chronicization) .
  • rectal mucosa may be also subject to inflammations, known as proctitis, which may have several causes, including bacterial, viral, parasitic infections, traumata, drug use or as a consequence of medical treatments or of other pathologies.
  • proctitis may have several causes, including bacterial, viral, parasitic infections, traumata, drug use or as a consequence of medical treatments or of other pathologies.
  • Clinical signs of proctitis are intense burning and pain during evacuation, lesion formation in the anal area, blood and pus discharge.
  • drugs used for the treatment of hemorrhoidal proctological disorders the following are known: a) drugs by general route, including micronized diosmin-hesperidin and vitamin P, which have an anti-edema, protective action on capillaries, also reducing the perianal itching; and b) locally-acting drugs formulated in suppositories and ointments, typically based on heparin or substances with heparinoid action, cortisonoids and local anesthetics.
  • Steroid drugs administered chronically, may lead to hypotrophy of perianal skin and may promote the onset of or aggravate a perianal itching.
  • Some local anesthetics may have an allergic sensitization as side effect. Therefore, it is recommended to use them for short periods, especially in inflammatory or thrombotic manifestations. Said products further exert a short-lasting action and it is generally difficult to document their actual clinical efficacy; moreover, they may affect the symptoms (bleeding, burning, itching), but not the prolapse.
  • primary treatments comprise, first of all, the optimization of the hygienic local conditions by using specific, non-irritating detergents, generally with a low pH, the daily practice of tepid hip baths (which contribute to reduce the tone of the sphincter and to improve lifestyle especially regarding physical activity).
  • Other factors are also important, such as the introduction of fiber (including adding mucilage to the diet), the increase of liquids taken mainly with emollient tepid beverages (mallow, chamomile, berries tisane) or fruit juices- pear, kiwi, apricot - which facilitate intestinal regulation.
  • the medical products most suitable for treating anal fissures involve formulations containing calcium antagonists or nitroglycerin, in the form of a cream, to be cyclically applied by topical route.
  • nifedipine which however may cause various undesired side effects, including headache and flushing.
  • WO 2011/ 154418 describes a preparation for vaginal and rectal use, said preparation comprising micronized hyaluronic acid, with a particle size comprised between 50gm and 200gm and a molecular weight comprised between 1,000,000 Da and 1,800,000 Da.
  • the preparation may also comprise a natural active substance selected from Aloe Vera, Centella Asiatica, Calendula, Tea tree essential oil and sweet almond oil.
  • CELEVIS GEL a product produced and sold by Nathura S.p.a, is a formulation for topical application including, as active ingredients, hyaluronic acid, Centella asiatica extract, Hamamelis virginiana extract and bovine colostrum. Said formulation is particularly suitable for treating proctological disorders.
  • the technical problem underlying the present invention is to provide a formulation for treating proctological disorders, including hemorrhoids, proctitis and anal fissures, said formulation containing natural active ingredients, having an excellent tolerability, and being substantially free of the side effects of the prior art formulations, and having an improved action compared thereto.
  • the present invention solves the above-mentioned technical problem by providing a composition for topical application, comprising hyaluronic acid or a pharmaceutically acceptable salt thereof, honey, Centella asiatica and Hamamelis virginiana, for use in treating proctological disorders.
  • the hyaluronic acid has a molecular weight comprised between 1300 kDa and 2200 kDa, conveniently comprised between 1500 kDa and 2000 kDa.
  • the Hamamelis virginiana is in the form of a hydroglyceric extract containing 1-5% Hamamelis virginiana dry extract by weight of the total weight of the hydroglyceric extract.
  • the Centella asiatica is in the form of a dry extract.
  • the honey is selected from the group comprising acacia honey, citrus honey, orange honey, wildflower honey, more preferably acacia honey.
  • the present invention also relates to a pharmaceutical formulation for topical application, comprising a composition for the use as defined above and at least one pharmaceutically acceptable excipient, for use in treating proctological disorders.
  • the hyaluronic acid or a pharmaceutically acceptable salt thereof, more preferably sodium hyaluronate is present in a quantity comprised between 0.1% and 2%, more preferably between 0.2% and 0.5%, by weight of the total weight of the formulation.
  • the dry extract of Centella asiatica is present in a quantity comprised between 0.1% and 2%, more preferably between 0.2 % and 0.5%, by weight of the total weight of the formulation.
  • the honey is present in a quantity comprised between 0.5% and 5%, more preferably between 1% and 3%, by weight of the total weight of the formulation.
  • the Hamamelis virginiana hydroglyceric extract is present in a quantity comprised between 0.01% and 5%, conveniently between 0.5% and 3%, by weight of the total weight of the formulation.
  • the at least one pharmaceutically acceptable excipient is selected from the group comprising sweet almond oil, glycerine, decyl oleate, hydroxyethyl acrylate/ sodium acryloyldimethyl taurate copolymer, capiylic glycol, hexane- 1,2-diol, cross-linked polyacrylic acid, ethylhexyl glycerol, sorbitan isostearate, polysorbate 60, lecithin, lactic acid, phytic acid, sodium hydroxide, tocopherol, ascorbyl palmitate, citric acid, trisodium disuccinate of ethylenediamine 37%.
  • sweet almond oil glycerine
  • decyl oleate hydroxyethyl acrylate/ sodium acryloyldimethyl taurate copolymer
  • capiylic glycol hexane- 1,2-diol
  • cross-linked polyacrylic acid ethylhexyl
  • the at least one pharmaceutically acceptable excipient is present in a quantity comprised between 2% and 10%, more preferably between 5% and 8%, by weight of the total weight of the formulation.
  • the above-mentioned pharmaceutical formulation is in the form of a gel or a O/W emulsion, more preferably a hydrophilic gel.
  • the composition of the present invention contains natural ingredients with protective, hydrating, lenitive and lubricating action, which make it particularly suitable, in conjunction with conventional pharmacological therapies, for treating the most frequent proctological disorders, such as for example hemorrhoids, proctitis and anal fissures, alleviating symptoms of burning, itching and rubbing- induced pain related to said disorders.
  • proctological disorders such as for example hemorrhoids, proctitis and anal fissures
  • the present composition comprises high-molecular- weight hyaluronic acid (preferably 1500-2000 kDa), a highly hygroscopic molecule which promotes re-epithelialization and lubricates the anal epithelium. Moreover, thanks to its anti-inflammatory properties, hyaluronic acid also contributes to wound scarring, as well as to the reduction of pain and burning associated with anal disorders.
  • high-molecular-weight hyaluronic acid preferably 1500-2000 kDa
  • hyaluronic acid also contributes to wound scarring, as well as to the reduction of pain and burning associated with anal disorders.
  • the Centella asiatica extract promotes the maintenance of the integrity of the venous wall and microcirculation in compensation conditions.
  • Said properties counteract phenomena of localized weakness of the venous wall and of organization of the mucosa in cushions of highly vascularized tissue, which are typical of hemorrhoidal proctological disorders (in fact, mechanical stresses by hardened fecal masses play certainly a role in stressing the hemorrhoidal vascular plexus).
  • the present composition also comprises Hamamelis virginiana, in particular in the form of a hydroglyceric extract, whose properties, within the scope of treating proctological disorders, comprise the impermeabilization action of the most superficial layers of the skin and the mucosae, promoting regeneration of the damaged tissues, as well as the vasoconstrictor action on the superficial vessels of the skin.
  • the Hamamelis virginiana extract has also a strong antioxidative action, protects cellular hyaluronic acid from depolymerization by hyaluronidases, and protects endothelial cells and hyaluronic acid from free radicals. Moreover, topical application of said extract allows to considerably reduce irritating and inflammatory processes of the skin.
  • composition of the present invention advantageously comprises also acacia honey.
  • honey promotes a rapid formation of a moist interface on the wound, protecting it from the external environment.
  • honey advantageously has antibacterial, antifungal, antiviral and antioxidant properties, and it is also able to enhance production of nitric oxide, which promotes scarring and capillary circulation.
  • composition disclosed herein has an excellent tolerability on the skin and does not elicit side effects, so it is possible to use it when required or for a prolonged time without adverse effects, till normalization of the symptoms associated with proctological disorders.
  • composition according to the invention may be applied by topical route both externally, in the perianal and/or anal area, with a light massage directly in the affected area, or internally (rectum), by using a rectal applicator.
  • the present invention also relates to a formulation for topical application comprising the above-mentioned composition and at least one pharmaceutically acceptable excipient, for use in treating proctological disorders.
  • Figure 1A shows a bar graph concerning HaCaT-cell viability in the presence of Formulation A (1.5% honey and 0.2% hyaluronic acid) and of Formulation B (1.5% bovine colostrum and 0.2% hyaluronic acid), tested at concentrations of 10 mg/ml, 100 mg/ml and 1000 mg/ml, under basal conditions.
  • Figure IB shows a bar graph concerning HaCaT-cell viability in the presence of Formulation A (1.5% honey and 0.2% hyaluronic acid) and Formulation B (1.5% bovine colostrum and 0.2% hyaluronic acid), tested at concentrations of 10 mg/ml, 100 mg/ml and 1000 mg/ml, after treatment with 3mM methylprednisolone.
  • Figure 2 shows a bar graph concerning aquaporin 3 (AQP3) concentration in the homogenate of intestinal epithelium (colon) of the positive control sample (Ctr +, epithelium not treated with honey and subjected to dehydration), the negative control (Ctr-, epithelium not treated with honey and not subjected to dehydration) and the sample subjected to dehydration and treated with 1.5% acacia honey.
  • AQP3 aquaporin 3
  • Figure 3 shows a bar graph concerning cell viability of cells from the intestinal epithelium (colon) reconstructed in vitro in the presence of 1% SDS.
  • the present invention relates to a composition for topical application which comprises, as active ingredients, hyaluronic acid, acacia honey, Hamamelis virginiana and Centella asiatica, for use in treating proctological disorders.
  • proctological disorders means the set of diseases and disorders affecting the last segment of the digestive system, namely rectum and anus, and said expression comprises: hemorrhoids, anal fissures, anal and perianal fistulae, abscesses and proctitis.
  • composition as a scarring, lubricating and anti-inflammatory agent, thus counteracting the main symptoms associated with said disorders, including itching, inflammation, burning and rubbing-induced pain, and promoting the restoration of a physiological, hydrated, elastic and intact environment.
  • the present composition is suitable for topical application since it may be formulated so as to allow its application on the skin, for example in the form of a gel or of a cream, thereby allowing local application in a simple and functional way.
  • topical application refers to an administration of the present composition by direct contact with the action site to which it is intended, typically the skin and/or the mucosae, thereby performing a local action.
  • composition of the invention allows to obtain a combined and synergistic action of the ingredients constituting the same, performing, in particular, scarring function and immunomodulatory function, which are increased and effective even at low concentrations.
  • the composition of the invention comprises hyaluronic acid, or a pharmaceutically acceptable salt thereof, preferably having high molecular weight, i.e. having a molecular weight of at least 1300 kDa, preferably between 1500 kDa and 2000 kDa.
  • Hyaluronic acid is able to bind different types of biological molecules, including water, lipid substances such as membrane phospholipids, positively charged substances (tertiary ammonium), proteins with which form proteoglycans are formed, as well as components of the extracellular matrix.
  • the high hygroscopicity of high-molecular-weight hyaluronic acid is essential for carrying out its action of tissue hydration and maintenance of the extracellular space, thereby facilitating the transport of nutrients and ions in solution.
  • hyaluronic acid plays an important role as free-radical scavenger and as an antioxidant; in particular, high-molecular-weight hyaluronic acid advantageously forms a viscous layer around the cells in a dose-dependent manner, slowing down the movement of reactive oxygen species (ROS).
  • ROS reactive oxygen species
  • hyaluronic acid is involved in various cellular responses activated by receptor binding: in the first inflammatory stage, it is accumulated in the damaged tissue, inducing the release of inflammatory cytokines thanks to the interaction with CD44, and improves the infiltration of cells which migrate to the damage site; during the granulation stage, the high hyaluronic acid levels promote cell proliferation and migration of, for example, keratinocytes, and angiogenesis.
  • hyaluronic acid is able to attract fibroblasts to the wound site, facilitating the synthesis of new collagen, carrying out the so-called gap- filler function.
  • Hyaluronic acid is also directly involved in scar formation and in tissue remodeling itself; in particular, high-molecular-weight hyaluronic acid carries out a structural function.
  • hyaluronic acid is particularly suitable for treating the symptoms related to proctological disorders.
  • Centella asiatica used in the form of a dry extract, which contains different active substances, the most important among them being asiaticoside, madecassoside and centelloside, which belong to the chemical class of the triterpene compounds.
  • the extract should contain at least 6% of total triterpene derivatives, expressed as asiaticoside; advantageously, the dry extract of Centella asiatica used in the composition according to the present invention is titrated to 10% triterpenes.
  • Centella asiatica stimulates collagen production by human fibroblasts, improving the connective structure of the vessel wall.
  • the triterpene fraction of Centella induces an increase of production of fibronectin, a structural protein important for supporting the wall of venous vessels, in human fibroblast cultures.
  • a further effect of the Centella asiatica extract is the improvement of scarring processes, which is fundamental to alleviate the symptoms associated with anal fissures.
  • Asiaticoside promotes fibroblast proliferation and synthesis of new extracellular matrix, playing a role in cell-cycle progression, in extracellular-matrix synthesis and in cell proliferation, with increase of the proteins involved in the synthesis of new extracellular matrix in fibroblasts.
  • asiaticoside has an anti-inflammatory property, probably due to the inhibition of nitric oxide (NO) synthesis, thereby facilitating scarring of ulcers, as well as an anti-itching and anti-inflammatory activity.
  • NO nitric oxide
  • the present composition also comprises Hamamelis virginiana, in particular in the form of a hydroglyceric extract.
  • the main chemical constituents of the dry extract of Hamamelis virginiana are tannins, gallotannins and hamamelis tannins (2% to 10%), and triterpenes, diterpenes and flavonoids (quercetin and kaempferol) are also present.
  • the properties are mainly astringent, but also flebotonic and analgesic, which makes said extract particularly suited for treating hemorrhoids.
  • tannins are connected to their ability to form complexes with macromolecules, in particular proteins, thanks to the affinity of tannins for proline amino acid residues.
  • tannins contained in the Hamamelis virginiana extract impermeabilize the most superficial layers of the skin and mucosae, thereby promoting regeneration of the damaged tissues, and have an important vasoconstrictor action on the superficial vessels of the skin.
  • the astringent and anti-inflammatory properties of the Hamamelis virginiana extract are due to the inhibition of the enzymes responsible for the degradation of connective tissue; in fact, vascular integrity is impaired by the increase of the activity of these enzymes.
  • the anti inflammatory action in particular, is due to proanthocyanidins, such as catechin and epicatechin.
  • the active compounds of said extract inhibit self- association of ascorbic acid, increase capillary resistance, reduce capillary permeability, increase venous-lymphatic tone and stabilize collagen.
  • the present composition also comprise honey, preferably acacia honey.
  • This ingredient has a number of biological activities which are extremely useful for treating proctological disorders, including for example an important action of tissue hydration, as well as an action as a barrier for protecting a superficial wound (for example, fissures), as shown in detail in the Examples.
  • honey is able to adjust pH, increase nitric oxide production, exert an antioxidant action, as well as counteract the establishment and diffusion of foreign microorganisms (for example, bacteria, fungi, molds and viruses), thereby promoting and accelerating the process of scarring.
  • foreign microorganisms for example, bacteria, fungi, molds and viruses
  • the present invention also relates to a formulation for topical application, said formulation comprising the above-mentioned composition and one pharmaceutically acceptable excipient, for treating proctological disorders as defined above.
  • the formulation of the invention comprises, in percentage by weight of the weight of the total composition, the following active ingredients:
  • the formulation of the invention comprises, in percentage by weight of the weight of the total composition, the following active ingredients:
  • the pharmaceutically acceptable excipients which can be used in the formulation according to the present invention comprise: sweet almond oil (prunus dulcis), glycerine, decyl oleate, hydroxyethyl acrylate/ sodium acryloyldimethyl taurate copolymer, caprylic glycol, hexane- 1,2-diol, cross-linked polyacrylic acid, ethylhexyl glycerol, sorbitan isostearate, polysorbate 60, lecithin, lactic acid, phytic acid, sodium hydroxide, tocopherol, ascorbyl palmitate, citric acid, trisodium disuccinate of ethylenediamine 37%.
  • excipients are present in the formulation in an overall amount comprised between about 2% and 10% w/w, preferably between 5% and 8% by weight of the formulation, the rest consisting of water.
  • the present formulation for topical application is in the form of a gel or of an O/W emulsion, more preferably in the form of a hydrophilic gel, even more preferably having a pH between 7 and 8.
  • the formulation in the form of hydrophilic gel not only allows to have an easily applicable on the skin product, as it is rapidly absorbed, but also it allows an application that is not greasy, since it is a water-based formulation.
  • the present formulation may also be advantageously formulated as a cream for topical application.
  • the formulation of the invention is able to assist the treatment of the symptoms associated with proctological disorders, including hemorrhoids, proctitis and anal fissures, significantly reducing burning, dryness, rubbing-induced pain, improving the elasticity and tone of the tissues and promoting the restoration of a balanced and lubricated environment.
  • the formulation of the invention also allows to exert an improved lenitive and anti-inflammatory action, associated with a very low cytotoxicity, thanks to the combination of the natural active ingredients, as described above in detail and as reported in the experimental section herein.
  • the formulation of the invention also allows to exert an improved lenitive and anti-inflammatory action, associated with a low cytotoxicity, thanks to the combination of its natural active ingredients, as described above.
  • the present composition is also convenient due to the ease of preparation.
  • EXAMPLE 2 Comparative test on the effect of human fibroblast migration ("scratch test”) between a composition according to the present invention and the product “CELEVIS GEL”.
  • the test was performed in vitro, using a dermal human fibroblasts primary culture, cultured in DMEM medium (supplemented with 10% fetal bovine serum (FBS), 2mM glutamine, penicillin (100 IU/ml) and streptomycin (100 pg/ml)) in an incubator at 37°C and in 5% CO2 atmosphere.
  • FBS fetal bovine serum
  • 2mM glutamine penicillin
  • streptomycin 100 pg/ml
  • LI commercial product “CELEVIS GEL” containing, as active ingredients, hyaluronic acid (0.2%), colostrum (1.5%), Centella asiatica extract (0.5%), Hamamelis virginiana extract (2%).
  • L2 composition according to the invention, consisting of hyaluronic acid (0.2%), acacia honey (1.5%), witch hazel extract (2%), and Centella asiatica dry extract (0.5%);
  • L3 composition consisting of the following excipients, as defined in Example 1: SEPINOV EMTIO (3 %), glycerine 99.8% PF (2%), SENSIVA (0.3%), SYMDIOL68 (1%), NATRLQUEST E30 (0.4%), lactic acid (0.01%), purified water (q.s. to 100).
  • Control growth medium DMEM as defined above.
  • samples are the starting samples from which the dilutions used for the present test were obtained.
  • the thus-obtained solutions of LI, L2 and L4 contained a final concentration of 1 mg/ml hyaluronic acid.
  • control sample was thus considered as an ideal reference parameter, because, consisting only of culture medium and 10% fetal serum, it stimulated cell growth (and thus promoted the scratch scarring), without ever causing inhibition of the cells.
  • Sample L2 did not show any cytotoxic behavior in vitro at both tested dosages (10 mg/ well and 100 mg/ well) in the two series of experiments.
  • sample LI and sample L3 showed an inhibitory action on cell migration with the increase in dose; in particular, this behavior is more evident for sample LI, probably because of the hyper- stimulating action of colostrum, very rich in growth factors, which action becomes a cytotoxic-like effect on the cells.
  • This result shows that the composition of the present invention, which contains the same active ingredients in the same quantities as sample L2, has a scarring effect considerably higher than that of the composition contained in the known commercial product “CELEVIS GEL”.
  • sample L4 was greater than that of sample LI, meaning that the combination of hyaluronic acid and honey is more stable and more effective than the combination of hyaluronic acid and colostrum contained in sample LI.
  • EXAMPLE 3 Comparative tests between the combination of hyaluronic acid and honey, and the combination of hyaluronic acid and colostrum.
  • HaCaT human keratinocytes
  • MET 3mM methylprednisolone
  • Methylprednisolone is able to inhibit cell proliferation and can thus create a condition where cell turnover is impaired, mimicking a difficult- to-heal wound condition.
  • the test was performed at three different times (3 hours, 6 hours and 24 hours), using different concentrations of the studied samples in the range comprised between 0.1 mg/ml and 100 mg/ml.
  • Cell Counting Kit-8 (Sigma Aldrich) was used for cell viability evaluation.
  • Formulation A based on honey and hyaluronic acid, such as the composition of the present invention, showed the ability to improve cell viability in a time period of 24 hours, and also showed to be able to counteract the anti-proliferative effects induced by methylprednisolone, demonstrating an immunomodulatory capacity even at low concentration better than that showed by Formulation B, based on colostrum and hyaluronic acid, such as the product “CELEVIS GEL”.
  • the antioxidant-activity test using the DPPH radical is one of the fastest techniques for evaluating the antioxidant activity of a substance, and allows to measure the reducing activity of antioxidant molecules against DPPH, which is characterized by a purple red color and decolourises in the presence of an antioxidant agent.
  • Formulation A and formulation B were tested in seven 1:2 serial dilutions in water, using ascorbic acid (gradual concentrations between 25 and 0.78 pg/ml), a known antioxidant agent, as a positive control.
  • % inhibition [(Abs c -Abs e )/Abs c ] x 100 wherein: - Abs c is the absorbance of the positive control determined at 517 nm
  • Both formulations A and B showed maximum antioxidant activity at the concentration of 10 mg/ ml, according to the values showed in the Table below.
  • Formulation A showed to have a higher antioxidant activity than Formulation B; this is probably due to the fact that the honey contained in Formulation A contains polyphenols and other secondary antioxidant metabolites.
  • the comparative tests illustrated in this Example show that the combination of honey and hyaluronic acid, on which the composition of the present invention is based, is more effective than the composition of colostrum and hyaluronic acid, on which the product “CELEVIS GEL” is based, in promoting cell viability over time, also more effectively counteracting the reduction of cell viability in keratinocytes treated with methylprednisolone .
  • the combination of hyaluronic acid and honey showed better antioxidant properties than the combination of colostrum and hyaluronic acid.
  • the combination of hyaluronic acid and honey, on which the composition according to the present invention is based proves to be highly effective in the treatment of difficult-to-heal wounds, where cell turnover and local immunity are impaired, which are typical conditions of proctological disorders.
  • EXAMPLE 4 Hydrating properties of honey The study described below evaluated the ability of acacia honey to facilitate and preserve tissue hydration.
  • the acacia honey tested was purchased from Apicoltura Vangelisti s.r.l. (Miele Vangelisti).
  • the experimental model was an intestinal epithelium (colon) reconstructed in mtro, starting from human cells, which were experimentally subjected to a dehydration condition by exposing the cells to laminar air flow (under hood) for 6 hours.
  • the marker relating to the hydration state was the Aquaporin 3 protein (AQP3), a channel protein which facilitates the rapid flow of water molecules in tissues. Under the experimental conditions, the expression of this protein was induced by a stressful condition of dehydration to facilitate the flow of water between the intra- and extracellular compartments and counteract tissue hydration.
  • AQP3 Aquaporin 3 protein
  • CTR- tissues of negative control
  • Example 4 evaluated the “barrier effect” of the honey used in Example 4 by evaluating its ability to protect the intestinal epithelium reconstructed in tro from the action of an irritating agent, in particular a solution of 1% SDS (sodium dodecyl sulphate).
  • an irritating agent in particular a solution of 1% SDS (sodium dodecyl sulphate).
  • this solution is able to induce a significant damage to the tissue, inducing a high cell mortality.
  • CTR- tissue of negative control
  • CTR+ tissue of positive control
  • tissue treated with 1% SDS and previously treated with 1.5% acacia honey i.e. tissue treated with 1% SDS and previously treated with 1.5% acacia honey.
  • the tissue on which a homogeneous layer of honey was applied showed a better cell viability compared to the positive control, meaning that honey has an important tissue protection activity against irritating agents, highlighting a significant “barrier effect”.
  • the internal blades After activating the external blades at a speed of 20 rpm, the internal blades at a speed of 40 rpm, setting up a mixing speed at 1400 rpm, 2 g vegetable glycerin, 1.5 g acacia honey, 10 g Sepinov EMTIO and 0.2 g hyaluronic acid sodic salt were added.
  • the internal blades After activating the external blades of the turboemulsifier at a speed of 20 rpm, the internal blades at a speed of 40 rpm, setting up a mixing speed at 1400 rpm, 0.5 g Centella asiatica dry extract were added. After 40 minutes mixing, once homogeneity was reached, the aqueous phase so obtained was cooled to 25°C.
  • the aqueous phase containing the Centella asiatica extract was added to the above-mentioned aqueous phase containing hyaluronic acid and acacia honey, mixing for 30 minutes till homogeneity. Subsequently, 1 g SYMDIOL, 0.3 g SENSIVA SC 50, 0.4 g NATRLQUEST E30 and 2 g Hamamelis virginiana hydroglyceric extract were added.

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Abstract

L'invention concerne une composition pour application topique, comprenant de l'acide hyaluronique ou un sel pharmaceutiquement acceptable de celui-ci, du miel, Centella asiatica et Hamamelis virginiana, destinée à être utilisée dans le traitement de troubles proctologiques ; l'invention concerne également une formulation pharmaceutique pour application topique, comprenant la composition mentionnée ci-dessus et au moins un excipient pharmaceutiquement acceptable, destinée à être utilisée dans le traitement de troubles proctologiques.
EP21708576.0A 2020-02-26 2021-02-22 Formulation à base d'ingrédients naturels destinée à être utilisée dans le traitement de troubles proctologiques Withdrawn EP4110360A1 (fr)

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IT102020000003934A IT202000003934A1 (it) 2020-02-26 2020-02-26 Formulazione a base naturale per l’uso nel trattamento di disturbi proctologici
PCT/EP2021/054261 WO2021170516A1 (fr) 2020-02-26 2021-02-22 Formulation à base d'ingrédients naturels destinée à être utilisée dans le traitement de troubles proctologiques

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Citations (5)

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US5234914A (en) * 1991-06-11 1993-08-10 Patent Biopharmaceutics, Inc. Methods of treating hemorrhoids and anorecial disease
ITBO20010648A1 (it) * 2001-10-24 2002-01-24 Farma Derma S R L Uso di acido ialuronico per la produzione di un preparato ad uso rettale, in particolare per il trattamento dei processi riparativi tissutali del canale ano-rettale dopo chirurgia proctologica di emorroidi, proctiti, criptiti, ragadi anali, fissure,
WO2011154418A1 (fr) * 2010-06-09 2011-12-15 Farma-Derma Srl Préparation pour un usage vaginal et rectal et procédé de production afférent
CN104173232A (zh) * 2014-08-06 2014-12-03 金玲 一种提升肌肤抵抗力并修复微损肌肤的美容液制作方法
US20180236009A1 (en) * 2017-02-22 2018-08-23 San Melix Laboratories, Inc. Buckwheat honey and bacitracin wound-healing dressing

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JP2004059519A (ja) * 2002-07-30 2004-02-26 Noevir Co Ltd 痩身用皮膚化粧料
WO2015158841A1 (fr) * 2014-04-17 2015-10-22 Grasl Jürgen Timbre, jeu de timbres, procédé et utilisation pour un traitement médical ou cosmétique

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US5234914A (en) * 1991-06-11 1993-08-10 Patent Biopharmaceutics, Inc. Methods of treating hemorrhoids and anorecial disease
ITBO20010648A1 (it) * 2001-10-24 2002-01-24 Farma Derma S R L Uso di acido ialuronico per la produzione di un preparato ad uso rettale, in particolare per il trattamento dei processi riparativi tissutali del canale ano-rettale dopo chirurgia proctologica di emorroidi, proctiti, criptiti, ragadi anali, fissure,
WO2011154418A1 (fr) * 2010-06-09 2011-12-15 Farma-Derma Srl Préparation pour un usage vaginal et rectal et procédé de production afférent
CN104173232A (zh) * 2014-08-06 2014-12-03 金玲 一种提升肌肤抵抗力并修复微损肌肤的美容液制作方法
US20180236009A1 (en) * 2017-02-22 2018-08-23 San Melix Laboratories, Inc. Buckwheat honey and bacitracin wound-healing dressing

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Title
AL-WAILI NOORI S ET AL: "The safety and efficacy of a mixture of honey, olive oil, and beeswax for the management of hemorrhoids and anal fissure: A pilot study", THE SCIENTIFIC WORLD JOURNAL, THE SCIENTIFICWORLD LTD, GB, NL, vol. 6, 2 February 2006 (2006-02-02), pages 1998 - 2005, XP009116049, ISSN: 1537-744X *
ANONYMOUS: "Celevis Gel - Trattamento Emorroidi 30 mL + Applicatore | Farmasave.it", 11 June 2019 (2019-06-11), pages 1 - 5, XP093281694, Retrieved from the Internet <URL:https://www.farmasave.it/nathura-celevis-gel-trattamento-emorroidi-30-ml-applicatore.html> *
See also references of WO2021170516A1 *
WOLFF HELMUT H ET AL: "Hamamelis in children with skin disorders and skin injuries: results of an observational study", EUROPEAN JOURNAL OF PEDIATRICS, SPRINGER BERLIN HEIDELBERG, BERLIN/HEIDELBERG, vol. 166, no. 9, 20 December 2006 (2006-12-20), pages 943 - 948, XP037828622, ISSN: 0340-6199, [retrieved on 20061220], DOI: 10.1007/S00431-006-0363-1 *

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