EP3914279A1 - Hauterneuernde und heilende mischung aus peptidbestandteilen und deren verwendung - Google Patents

Hauterneuernde und heilende mischung aus peptidbestandteilen und deren verwendung

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Publication number
EP3914279A1
EP3914279A1 EP20709701.5A EP20709701A EP3914279A1 EP 3914279 A1 EP3914279 A1 EP 3914279A1 EP 20709701 A EP20709701 A EP 20709701A EP 3914279 A1 EP3914279 A1 EP 3914279A1
Authority
EP
European Patent Office
Prior art keywords
peptide
healing
mixture
skin
fact
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP20709701.5A
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English (en)
French (fr)
Inventor
Vladimir Kral
Pavel Martasek
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Globetech Innovation SRO
Original Assignee
Globetech Innovation SRO
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Filing date
Publication date
Application filed by Globetech Innovation SRO filed Critical Globetech Innovation SRO
Publication of EP3914279A1 publication Critical patent/EP3914279A1/de
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A61K8/65—Collagen; Gelatin; Keratin; Derivatives or degradation products thereof
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/58—Metal complex; Coordination compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/59—Mixtures
    • A61K2800/592—Mixtures of compounds complementing their respective functions
    • A61K2800/5922—At least two compounds being classified in the same subclass of A61K8/18

Definitions

  • compositions, formulations, and methods for topical or transdermal administration and treatment of wounds and/or for wound healing improvement are provided.
  • the process of acute wound healing is divided into three (3) phases.
  • the initial inflammatory phase followed by powerful remodelling and proliferation of tissues (proliferation phase) is further followed by the“mature phase” with re-epithelization, skin angiogenesis and the wound closure.
  • Re-epithelization includes migration and proliferation of epithelial tissues, above all keratinocytes.
  • Angiogenesis is the formation of new blood vessels from the already existing ducts that is regulated by a panoply of soluble cytokines, including growth factor polypeptides, as well as interactions of cellular cells and cellular matrices.
  • Chronic wounds have a different treatment profile compared to standard acute wounds as they usually stay in the inflamed condition for a longer period.
  • Non-healing wounds are most often found in patients with diabetes, venous stasis and in immobilised patients. Considering the aforementioned facts, it would be desirable to provide new biomolecules that safely and effectively facilitate the healing mechanism of epithelial and vascular wounds accompanying acute as well as chronic situations related to wound healing.
  • Chronic wounds have a different treatment profile compared to standard acute wounds as they usually stay in the inflamed condition for a longer period. Difficult-to-heal wounds are most often found in patients with diabetes, venous thrombosis and in immobilised patients. Considering the aforementioned facts, it would be desirable to provide new biomolecules that would specifically, safely and effectively facilitate the healing mechanism of epithelial and vascular wounds accompanying acute as well as chronic situations related to wound healing.
  • Persons with diabetes have a very low skin regeneration capacity. Skin-related complications of diabetes result in the skin that is dry, prone to cracking and slow healing. Persons with diabetes often suffer from slow and insufficient skin healing.
  • the primary reason for amputation is infections related to the formation of ulcers and damage to skin that is incurable at the present time.
  • the average risk of extremity amputation in persons with diabetes is 15 times higher compared to that in persons who do not have diabetes.
  • GHK glycosyl-L-histidyl-L-lysine
  • the GHK as a natural modulator of several cellular pathways for skin regeneration, is present in human plasma, saliva and urine, but its concentration decreases with age. GHK facilitates the intake of trace elements necessary for the regeneration of skin, such as copper.
  • the peptide acts in complex with Cu 2+ , facilitates the healing of wounds and skin and participates in enzymatic processes ( Gorouhi F, Mai bach HI Role of topical peptides in preventing or treating aged skin. Int J Cosmet Sci. 2009; 31: 327-345).
  • GHK stimulates both synthesis and decomposition of collagen and glycosaminoglycans and modulates the activity of metalloproteases and their inhibitors. It stimulates collagen, dermatan sulphate, chondroitin sulphate, low-molecular proteoglycan or decorin. It also facilitates the regeneration of the replication vitality of fibroblasts after radiotherapy. The molecule attracts immune and endothelial cells to the site of the wound.
  • peptides used for therapy or cosmetic treatment of complexion and/or skin are signal peptides Syn®-Coll (Palmitoyl Tripeptide-5) with the Pal-Lys-Val-Lys-OH structure that bind directly to the receptor ( Brzoska T, Bohm M, Liigering A, Loser K, Luger TA. Terminal signal: anti-inflammatory effects of melanocyte-stimulating hormone related peptides beyond the pharmacophore. Adv Exp Med Biol. 2010; 681: 107-116).
  • DecorinylTM tetrapeptide; Lupo MB, Cole AL. Cosmeceutical peptides. Dermatol Ther.
  • Argireline® with the following structure N-Acetyl-L-a-glutamyl-L-a-glutamyl-L-methionyl-L-glutaminyl- L-arginyl-L-argininamide
  • Vialox® with the following structure H-Gly-Pro-Arg-Pro-Ala- NH2
  • Syn®-ake Lupo MP, Cole AL Cosmeceutical peptides. Dermatol Ther. 2007; 20: 343- 349) reduce the contraction of face muscles and consequently the formation wrinkles by increasing the minimal threshold for muscular activity.
  • Glycine soya protein Preregen®; Siidel KM, Venzke K, Mielke H, Schunbach U, Mundt C, Jaspers S, et al. Novel aspects of intrinsic and extrinsic aging of human skin: beneficial effects of soy extract. Photochem Photobiol. 2005; 81: 581-587. Andre-Frei V, Perrier E, Augustin C, Damour O, Bordat P, Schumann K, et al. A comparison of biological activities of a new soya biopeptide studied in an in vitro skin equivalent model and human volunteers. Int J Cosmet Sci. 1999; 21: 299-311) and sericin (Lupo ALP, Cole AL.
  • Cosmeceutical peptides directly or indirectly inhibit the enzyme involved in the process ageing to the receptor (Brzoska T, Bohm M, Liigering A, Loser K, Luger TA. Terminal signal: anti inflammatory effects of a ⁇ -melanocyte-stimulating hormone related peptides beyond the pharmacophore. Adv Exp Med Biol. 2010; 681: 107-116). They stimulate fibrioblasts to produce collagen, the proliferation of elastin, glycosaminoglycans, proteoglycan and fibronectin.
  • MIF melanocytes
  • the use of the MIF hormone itself as a therapeutic agent is limited by its easy enzymatic hydrolysis.
  • a series of the MIF spiroderivatives has been prepared in particular with a view to eliminating this disadvantage ⁇ Kasafirek E.
  • Alaptid has been selected as the best analog both from the point of view of enzymatic stability and considering its pharmacodynamic profile. In addition to other effects, Alaptid has been proven as a substance with a significant curative effect in experimental animal models ⁇ Kasafirek E. et al. Cs. pat. 276270, 1992).
  • Alaptid is likely to have a negative impact on the inhibition of the release of the melanocyte stimulating hormone thus increasing the concentration of melanocytes in epidermis.
  • Melanocytes influence the formation and function of keratocytes via organelles known as melanosomes to a great extent. ⁇ McGrath J.A., EadyRA., Pope F.M. Rook's textbook of dermatology, 7th ed. Blackwell Publishing, 2004, pp.3-7; James W., Berger T. Elston D. Andrews' diseases of the skin: Clinical dermatology, 10th ed. Saunders, 2005, pp. 5-6).
  • Keratinocytes migrate from stratum basale via stratum spinosum and stratum granulosum into stratum corneum where they facilitate the recovery of eidermis. ⁇ Watt F.M. The epidermal keratinocyte. BioEssays 1988, 8, 163- 167).
  • Alaptid is a compound (log P equals -0.67) accompanied by a low value of solubility in water and other protic solvents. This fact results in certain disadvantages such as a partial separation of Alaptid during processing in the form of a white cover on the treated wounds. A lower concentration of Alaptid dissolved in formulation can result in a lower quantity of the active substance absorbed via stratum corneum. Results of the use of Alaptid nanoparticles have been published recently, e.g. PV 2011-232. The limited solubility of Alaptid in the physiological environment does not allow it curative potential to be utilized to the full extent.
  • the low solubility of Alaptid in a hydrophilic medium represents a significant disadvantage that may lead up to partial separation of Alaptid in the site subject to healing.
  • the low solubility of Alaptid may also be the cause of its reduced absorption in the lower layer of epidermis.
  • Alaptid The effects of Alaptid are known from many publications, such as, for example, from the document Sklendf, Zbynek, et al. “Formulation and release of alaptide from cellulose-based hydrogels.”, Acta Veterinaria Brno 81.3 (2013): 301-306 describing the release of Alaptid from cellulosic hydrogels.
  • amino acids and peptides for the regeneration of tissues is well known.
  • amino acids are combined with peptides to regenerate muscles, for example, for oral administration.
  • Amino acids and peptides are also comprised in a number of cosmetic formulations preventing skin ageing. Such cosmetic products reduce complexion/skin dryness, protect and hydrate skin, improve its flexibility and youthful appearance and fill in superficial as well as deeper wrinkles.
  • cosmetic products reduce complexion/skin dryness, protect and hydrate skin, improve its flexibility and youthful appearance and fill in superficial as well as deeper wrinkles.
  • the properties of amino acids and peptides facilitating the regeneration of tissues are known, but in relation to complexion/skin they are accentuated predominantly by cosmetic and aesthetic medicine.
  • the document EP 1640041 discloses a cosmetic composition for topical treatment of especially wrinkled skin or skin exposed to intense photodamage.
  • the cosmetic composition includes an agent stimulating collagen synthesis being tri- up to hexapeptides and an agent increasing interaction between the extracellular matrix and fibroblasts.
  • the cosmetic composition may also comprise other cosmetically active substances, such as extracts, UV filters, moisturizing substances or amino acids.
  • the document US20050209131 discloses a cosmetic composition comprising amino acids and peptide complex with copper. This composition is employed in cosmetic preparations such as body lotion or cosmetic pre-moistened wipes preventing skin from drying and ensuring its protection.
  • the document W003030926 discloses an aqueous solution of a peptide complex with copper comprising at least one amino acid with allegedly curative effects.
  • the aqueous solutions are not tested in the aforementioned document, which fact raises suspicions as to the efficacy of such solutions.
  • the document US20130108700 discloses a composition of a gelatine matrix comprising a peptide and an amino acid. Such a formulation is applied by injection in the proximity of fresh wounds to prevent scar formation. Testing of the composition was performed after gynaecological surgeries where the patients were applied the composition into mucous membranes surrounding the site of incision. This procedure really reduced the scarring of the mucous membranes in the tested patients and increased the patients’ chances of successful pregnancy.
  • the document W02005042048 discloses a similar composition as the document US20130108700. However, in this case the composition is employed to heal bones, cartilages, ligaments, and tendons. The composition is also applied by injection.
  • the invention discloses a skin renewing and healing mixture of peptide components that shows surprising efficacy in quick healing of wounds, including difficult-to-heal diabetic wounds and that is based on a combination of peptide with at least one of the following components: a peptide (2-40 amino acids); an amino acid (arginine and/or cysteine in L-, D- or racemic form). It has been proven that a mixture of the aforementioned components has up to 100% higher in vivo efficacy in healing wounds in animal models and humans than the components applied individually.
  • amino acids in a mixture of topically curative peptide components act as donors of nitrous oxide (NO) or sulfane (H2S).
  • the skin renewing and healing mixture of peptide components comprises at least one peptide in concentration ranging from 0.001 to 50 mg/ml or g of the matrix or formulation. It has been proven based on in vivo tests that any increase in the concentration of peptide(s) above 0.001 mg/ml or g of the matrix results in therapeutic effect while an increase in the concentration of peptide(s) above 50 mg/ml or g of the matrix results in no desired therapeutic effect.
  • the pH value of the formulation ranges between 3.0 and 9.0.
  • the formulation has ionic strength at least 20 mM, more preferably 50 mM up to 100 mM, and the most preferably at least 120 mM prior to the formulation application.
  • the skin renewing and healing mixture of peptide components can be dissolved in one cosmetically or pharmaceutically acceptable solvent or in a mixture of cosmetically or pharmaceutically acceptable solvents such as water, ethanol, propanol, isopropanol, propylene glycol, butylene glycol, dipropylene glycol, ethoxylate or propoxylated diglycols, cyclic polyols.
  • the skin renewing and healing mixture of peptide components can be preferably dissolved with a pharmaceutical or cosmetic vector, such as liposomes, or the mixture of topically curative peptide components can be adsorbed onto powder organic polymers or powder minerals - such as talc or bentonites.
  • the mixture of topically curative peptide components can be fixed in any cosmetically or pharmaceutically acceptable vector.
  • the skin renewing and healing mixture of peptide components can be used in combination with other active substances, cosmetically or pharmaceutically active ones.
  • the final formulation is then used either for cosmetic purposes focused on care for complexion/skin, or as a medicament.
  • the formulation has rejuvenating and revitalizing properties.
  • the skin renewing and healing mixture of peptide components may comprise peptides with other groups, such as signal or protective ones (tBoc, tags).
  • the peptides may also be associated with nanoparticles and/or liposomes, such as those carrying other active substance.
  • Peptides may also be modified by glycosylation, pegylation, acetylation, methylation, ubiquitination, hydroxylation, palmitoylation, phosphorylation or otherwise, provided that such modification does not affect the curative properties of the peptide.
  • the presence of Cu or Zn in the peptide metalocomplex can increase the efficacy by 5 to 10 more percent compared to treatment by peptides without the presence of metal;
  • the mixture of topically curative peptide components preferably includes both a basic peptide and its metalocomplex.
  • the curative efficacy of such a preparation is increased by 8 to 12% compared to that of preparations comprising either peptide or peptide metalocomplex.
  • the mixture of topically curative peptides preferably includes the Cu-GHK peptide metalocomplex, where Cu-GHK is a natural, autologous substance, the quantity of which, however, decreases with age.
  • the skin renewing and healing mixtures of peptide components that comprise peptide metalocomplex(es) show enhanced efficacy in particular in the case of non-healing wounds.
  • the metalocomplexes are prepared in the laboratory environment by a simple synthesis where the peptide is dissolved or suspended in anhydrous methanol (MeOH) or acetonitrile, a concentrated solution of the metal, preferably Cu 2+ or Zn 2+ , is added to the mixture along with two base equivalents, preferably sodium methoxide (MeONa) or another strong base. The mixture is stirred at ambient temperature for a period of 40 to 120 minutes. Then the respective peptide metalocomplex is extracted and dried. The dried peptide metalocomplex is used in a number of embodiments of the skin renewing and healing mixture of peptide components.
  • the skin renewing and healing mixture of peptide components stimulates the proliferative growth of fibroblasts and epithelial cells, such as keratinocytes, has positive effects on the entire wound healing process in laboratory animals as well as human volunteers.
  • the skin renewing and healing mixture of peptide components efficaciously fills in wrinkles and rejuvenates complexion, lightens dark spots and birth marks, and prevents a formation of scars after cosmetic surgeries, such as a removal of freckles and birth marks.
  • the skin renewing and healing mixture of peptide components has also been used for the treatment of burns, after surgeries and microsurgeries, with common injuries or for larger regions of injured skin, such as grazed sites.
  • the diketopiperazine spirocyclic peptide such as Alaptid in the aforementioned combinations, has properties that considerably improve the growth of dermal cells in concentrations that also have antimicrobial effects. This enormous advantage can be utilized in particular in difficult-to-heal, flamed or diabetic wounds where sepsis and infection are major obstacles preventing the wound from healing.
  • the skin renewing and healing mixture of peptide components also influences the function of metalloproteases that play a role in healing of both acute and chronic wounds due to the control of the degradation and deposition of intercellular substance in the wound.
  • the skin renewing and healing mixture of peptide components increases the level of metalloproteases in the site of the wound, by which the degradation of intercellular substance in the wound is accelerated and healing of the wound enabled.
  • diketopiperazine spirocyclic peptides For the skin renewing and healing mixture of peptide components, 2 main groups of curative proteins, namely diketopiperazine spirocyclic peptides and linear peptides, were used. Both the groups can also be divided into natural and synthetic.
  • the natural peptides such as the GHK peptide (Gly-His-Lys) or DAHK peptide (Asp-Ala-His-Lys) and other, play a vital role in skin regeneration. They influence the proliferation of skin cells, their regeneration and longevity. It has been proven that a combination of natural peptides with synthetic ones is preferable.
  • the synthetic proteins the CAR protein or diketopiperazine peptides (e.g.
  • Alaptid can be taken.
  • a combination of diketopiperazine peptides with the GHK peptide/Cu- GHK peptide in the ratio of 1 : 1 has been proven as beneficial to a great extent.
  • the performance of the GHK peptide/Cu-GHK peptide mixture in combination with arginine has been proven and seems to preferable to the same extent and the treatment with such a mixture takes longer by approximately 1/10 compared to treatment with a mixture of diketopiperazine + GHK/Cu-GHK.
  • a mixture of at least two types of diketopiperazine peptides is also preferable for the treatment.
  • a combination of two diketopiperazines is by up to 70% more efficacious than the application of one diketopiperazine applied individually.
  • a combination of the GHK protein / Cu-GHK protein with arginine in the presence of a protein, preferably collagen, fibrinogen or elastin has proven to be beneficial.
  • a protein preferably collagen, fibrinogen or elastin
  • its is preferable to add to the mixtures of peptides an amino acid, such as arginine, as a donor of NO, and/or the amino acid cysteine, as a donor of TkS. Addition of the amino acids results in efficacy improvement.
  • diketopiperazine peptides used for the skin renewing and healing mixture of peptide components can be described by the following general formulas:
  • Alaptid-CD complex 6-methyl-MeAlaptid; 6,9-di-MeAlaptid, 6-EtAlaptid; 6-hexylAlaptid; 9-ethylAlaptid; 6-Pal alaptide 6-palmitoyl 8-methyl-6,9-diazaspiro[4.5]decane-7,10-dione; 8-methyl-6,9-diazaspiro[5.5]undecane-7,10-dione;
  • the skin renewing and healing mixture of peptide components may preferably be in the form of solution, suspension, emulsion, ointment, balm, tincture, elixir, patch, bandage, dressing material, alginate dressing or compress, topical solution, infusion or surgical wash.
  • the matrix of the aforementioned forms preferably includes proteins.
  • the skin renewing and healing mixture of peptide components is preferably applied onto wounds in formulation with a gel matrix.
  • the gel matrix comprises a protein and saccharide components in the ratio of 1 : 1 by weight and an aqueous buffer solution containing Ca 2+ , Mg 2+ , and Zn 2+ , preferably in the form of calcium acetate, zinc acetate or magnesium acetate.
  • the pH value of the gel preferably ranges between 3 and 9. Thanks to the presence of cations, the gel is formed either by complexation with collagen and/or by cation-controlled gelation.
  • the protein component is preferably collagen, split collagen, fibrinogen, split fibrinogen, elastin, split elastin, gelatine, hydrolysed gelatine, BSA, etc.
  • the saccharide component is preferably hyaluronic acid, pectin, alginate, carrageenan, alginic acid, oxidized and non- oxidized forms of cellulose, cellulose derivatives - for example carboxymethyl cellulose and its salts, other carboxylated saccharides, chitosan, sorbitan caprylate, flaxseed gum, pectate and other oligo- and polysaccharides, etc.
  • the matrix may also be formed by synthetic polymers, such as polyacryl amides, poly(lactic-co-glycolic acid) (PLGA) and polylactic acid (PLA).
  • the gel matrix provides skin hydration, nourishment and toning, is preferable for use in combination with the skin renewing and healing mixture of peptide components for the treatment of chronic wounds, decubitus ulcers, diabetic complications, and treatment following laser and cosmetic surgeries.
  • the skin renewing and healing mixture of peptide components it smooths wrinkles, decelerates the formation of new ones and efficaciously decelerates the process of complexion ageing, stimulates skin cells to produce collagen and elastin, brightens and equalizes the colour of the complexion.
  • the gel applied to wounds in formulation with the skin renewing and healing mixture of peptide components is preferably sterile.
  • the matrix may also be oil in water or water in oil, and the peptide and/or amino acid and/or protein is preferably present in the fat phase.
  • the fat phase preferably comprises also phosphatidylcholine or other lecithin.
  • Lecithin is preferably present in the composition in the form of liposomes or micelles or other structures containing nitrous oxide, peptides or both.
  • the matrix for the skin renewing and healing mixture of peptide components is in the form of gel, cream, lotion, ointment, solution, solid“stick”, etc. that can be applied or sprayed onto the skin, e.g. injured.
  • the prepared skin renewing and healing mixture of peptide components attains high efficacy in accelerated wound healing. This result is based on shortened peptide chains used for healing and also by adding donors of NO and ELS.
  • the skin renewing and healing mixture of peptide components reduces time required for healing in healthy patients nearly to one third compared to standard treatment (from 8 weeks to 3 weeks) and in ill patients with chronic dermal defects, the time required for healing is reduced up to 7 times (from 20 weeks to 3 weeks); in some patients with chronically inflamed wounds the skin renewing and healing mixture of peptide components allows treatment in otherwise unmaintainable cases intended for amputation.
  • preparations comprising a mixture of peptide components - peptide + Arg + Cys as per Example 1
  • the wounds and/or dermal defects healed with such formulations were healed in murine models on average in 3 weeks, in healthy patients in 3 weeks, and in diabetics, healing was attained in 3 to 7 weeks.
  • control groups with the application of a gel matrix itself the wounds in murine models were healed on average in 8 weeks, in healthy patients in 8 weeks and the healing of difficult-to-heal wounds took 8 to 20 weeks; however, only one patient was healed completely.
  • preparations as per Example 8C i.e. control groups with no treatment, the wounds in murine models were healed on average in 8 weeks, in healthy patients in 8 weeks and the healing of difficult-to-heal wounds was completed only in one patient out of five, namely in 31 weeks with red spots remaining present in all tested subjects.
  • Fig. 1 Comparison of the selected preparations used in murine models
  • Fig. 2 A histological image, day 21 of experimental wound healing in a mouse by the preparation mentioned in Example IB, enlarged 40 times
  • Fig. 3 A histological image, day 28 of experimental wound healing in a mouse by the preparation mentioned in Example 2, enlarged 40 times
  • Fig. 4 A histological image, day 28 of experimental wound healing in a mouse by the preparation mentioned in Example 7, enlarged 40 times
  • Fig. 5 A histological image, day 50 of experimental wound healing in a mouse by the preparation mentioned in Example 8B, enlarged 40 times
  • Fig. 7 Table of wound healing with the use of the selected preparations
  • Fig. 8 Chart of wound healing with the use of the selected preparations
  • the mixture was stirred at 5,000 revolutions for 2 hours.
  • the two immiscible liquids were mixed.
  • the acquired poly disperse emulsion was mixed with 2 g of powder racemic arginine and 0.5 g of powder racemic cysteine and was additionally homogenized in a homogenizer at ambient temperature at 3,000 rpm. Homogenization improved the stability of the prepared emulsion.
  • Emulsion with 5% content of Alaptid was prepared.
  • 1 g of powder DAHK peptide and 0.2 g of powder L-arginine was mixed in the gel matrix consisting of 2 g of gelatine, 1 g of chitosan, 1 g of hyaluronic acid and 3 g of collagen, 7 g of carrageenan, and 86 g of phosphate buffer at pH 7 with 5% magnesium acetate.
  • the ingredients of the gel matrix were mixed together and stirred for 5 minutes using a magnetic stirrer at 300 rpm and then for 25 more minutes at 130 rpm. Then the DAHK peptide and L-Arg were added to the gel matrix and the mixture was stirred at 2,000 rpm for 5 more minutes.
  • 3 g of powder Alaptid were mixed in the gel matrix consisting of 4 g of collagen, 3 g of split collagen, 1 g of hyaluronic acid, 3 g of alginate, 3 g of carrageenan, and a 86 g of acetate buffer at pH 6.5 with 3% magnesium acetate.
  • the ingredients of the gel matrix were mixed together and stirred for 15 minutes using a magnetic stirrer at 400 rpm and then for 25 more minutes at 130 rpm. Then Alaptid was added to the gel matrix and the mixture was stirred at 5,000 rpm for 5 more minutes.
  • the control gel matrix was prepared from 7 g of collagen, 7 g of pectin, and 86 g of phosphate buffer at pH 7 with 5% calcium acetate. The ingredients of the gel matrix were mixed together and stirred for 5 minutes using a magnetic stirrer at 300 rpm and then for 25 more minutes at 130 rpm. Then the gel matrix was stirred at 2,000 rpm for 1 more minute.
  • mice and patients were tested for healthy injured patients and in diabetic injured patients and/or patients with non-healing wounds.
  • wounds resulting from microsurgeries in diabetics difficult-to-heal wounds, venous ulcers, decubitus ulcers and fistulas were concerned.
  • the tested group of mice and patients always included 5 tested subjects.
  • the wounds were applied 0.002 g of peptide on a daily basis, i.e. 0.2 g of 1% peptide formulation a day.
  • Tests on mice were assessed every 24 hours, tests on patients were recorded on a daily basis by the patients themselves - a photograph with a short description of the wound was taken every day. The records were assessed by the attending physician later on.
  • Example 4 With preparations as per Example 4, the wounds in murine models were healed on average in 5 weeks, in healthy patients in 5 weeks and the healing of difficult-to-heal wounds took 5 to 12 weeks. With preparations as per Examples 5 and 6, the wounds in murine models were healed on average in 4 weeks, in healthy patients in 4 weeks and difficult-to-heal wounds healing took 4 to 8 weeks. With preparations as per Example 8A, i.e. control groups with the application of a peptide itself in a gel matrix (Alaptid was used as a model), the wounds in murine models were healed on average in 7 weeks, in healthy patients in 7 weeks and difficult-to-heal wounds healing took 7 to 20 weeks. With preparations as per Example 8B, i.e.
  • control groups with the application of a gel matrix itself the wounds in murine models were healed on average in 8 weeks, in healthy patients in 8 weeks and the healing of difficult-to-heal wounds took 8 to 20 weeks; however, only one patient was healed completely.
  • preparations as per Example 8C i.e. control groups with no treatment, the wounds in murine models were healed on average in 8 weeks, in healthy patients in 8 weeks and the healing of difficult-to-heal wounds was completed only in one patient out of five, namely in 31 weeks with red spots remaining present in all tested subjects.
  • a group of 35 women at the age of 30 to 60 was tested. Prior to testing, photos of the faces of all the women were taken by the camera Canon 5D mark III (full frame) with the lens Canon EF 100 2,8L USM. The photographs were taken with the shutter 11, ISO 100 with the face exposed to three studio luminaires with the output of 500 W. The group was divided into a control and tested subjects. The control part of the group was applied a placebo preparation, while the tested subjects were applied the preparation as per Example IB. The placebo was the gel matrix without added peptide and amino acids.
  • Example IB The women applied the preparation as per Example IB twice a day for a period of 6 weeks. After testing completion, the faces of the women were documented again, i.e. photos of their faces were taken by the macro lens camera. The photo of each woman before and after testing were compared by image analysis. On average, 70% smoothing of wrinkles was attained with twice-a-day application for 6 weeks, while in the control group the smoothing of wrinkles amounted to 8% probably due to hydration provided by the gel matrix.
  • a group of 35 women at the age of 28 to 59 was tested. Prior to testing, photos of the faces of all the women were taken by the camera Canon 5D mark III (full frame) with the lens Canon EF 100 2,8L USM. The photographs were taken with the shutter 11, ISO 100 with the face exposed to three studio luminaires with the output of 500 W. The women applied the preparation as per Example 7 twice a day for 6 weeks. After testing completion, the faces of the women were documented again, i.e. photos of their faces were taken by the macro lens camera. The photo of each woman before and after testing were compared. On average, 62% smoothing of wrinkles was attained with application twice a day for 6 weeks.

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EP20709701.5A 2019-01-21 2020-01-20 Hauterneuernde und heilende mischung aus peptidbestandteilen und deren verwendung Pending EP3914279A1 (de)

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KR20240042649A (ko) * 2021-08-12 2024-04-02 쉔젠 윈키 테크놀로지 컴퍼니 리미티드 합성 펩티드, 화장료 조성물 또는 약학 조성물 및 그의 사용
CN113662877A (zh) * 2021-09-07 2021-11-19 肽领生物科技(上海)有限公司 一种蓝酮肽修护精华液的制备方法
CN114349823B (zh) * 2022-01-25 2023-07-18 杭州禾泰健宇生物科技有限公司 一种双靶向多功能类肽化合物及其制备方法和应用
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