WO2021259471A1 - IMPLANT DERMIQUE À MODULATEURS DE L'ACTIVITÉ DE HIF-1α - Google Patents

IMPLANT DERMIQUE À MODULATEURS DE L'ACTIVITÉ DE HIF-1α Download PDF

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WO2021259471A1
WO2021259471A1 PCT/EP2020/067733 EP2020067733W WO2021259471A1 WO 2021259471 A1 WO2021259471 A1 WO 2021259471A1 EP 2020067733 W EP2020067733 W EP 2020067733W WO 2021259471 A1 WO2021259471 A1 WO 2021259471A1
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composition
hydroxy
carbonyl
acetic acid
amino
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PCT/EP2020/067733
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Dominik THOR
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Thor Dominik
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    • 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
    • A61K8/41—Amines
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
    • 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
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • 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
    • 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
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/91—Injection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/04—Drugs for disorders of the respiratory system for throat disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers

Definitions

  • the invention relates to dermal filler compositions for aesthetic and reconstructive purposes.
  • the invention relates to a composition comprising hyaluronic acid and a HIF-la activity potentiating agent.
  • Progressive aging results in progressive gradual loss of firmness and elasticity of the skin, along with a change in the volumes of muscles and bones in the facial area.
  • tissue atrophy occurs, the skin becomes thinner and the connective tissue changes.
  • the result is fine wrinkles and folds, as well as excess skin that creates the appearance of drooping eyelids or cheeks.
  • the signs of skin aging on the face include fine lines, nasolabial folds, puppet wrinkles, lip wrinkles, forehead wrinkles, crow's feet and glabellar folds.
  • Experts differentiate between chronological (intrinsic) and extrinsic skin aging.
  • the personal lifestyle can also accelerate the aging process.
  • Chronological skin aging is determined by endogenous, genetically determined factors, while harmful exogenous factors, such as UV light and chemical noxae, that have an accelerated effect on the endogenous aging process, are referred to extrinsic skin aging.
  • Dermal fillers are used to fill fine lines and wrinkles, augment decreased tissue volume in the lip area, reduce folds in the nasolabial area and to correct facial atrophy as well as asymmetry associated with age, trauma or congenital defects.
  • synthetic fillers are used in the field of plastic-reconstructive surgery. Injectable materials for tissue augmentation are an integral part of the treatment of sunken scars as well as tissue defects after trauma, surgical interventions and radiation.
  • Ideal injectable dermal filler materials should have a number of key properties. These include, biocompatibility, safety, the ability to stably reside at the site of implantation, the ability to maintain volume, the ability to remain adaptable and pliable, trigger minimal foreign body reactions, and not cause foreign body granulomas.
  • the ideal filler should be easy to inject, well mouldable, stay in the body for as long as possible, be non-allergenic, non-carcinogenic, not susceptible to infection or biofilm, yet be potentially reversible, temperature stable and cheap.
  • Various dermal fillers have been used in the past. These include bovine collagen, paraffin, liquid silicone, polytetrafluoroethylene, as well as polymer and silicone particles and autologous fat.
  • Biodegradable agents can be further subdivided into two categories: (1) non-permanent fillers, also referred to as replacement fillers (hyaluronic acid, collagen, and biological fillers), which have a short retention time in the body of typically several months to one year and eventually get resorbed by macrophage activation; (2) semi-permanent fillers or biostimulating fillers (polylactic acid, calcium hydroxyapatite and polycaprolactone) which can provide a longer lasting aesthetic improvement of up to a few years.
  • Semi-permanent fillers characteristically lead to a foreign body reaction associated with fibroblast activation and collagen synthesis. Permanent implants (polymethyl methacrylate, silicone) can achieve long-lasting results but with a higher potential risk of complications.
  • Non-permanent, biodegradable dermal fillers are usually based on hyaluronic acid (HA).
  • HA fillers Hyaluronic acid-based fillers
  • the application of last-generation HA fillers has been significantly reduced in pain by the addition of lidocaine, a local anaesthetic that has no effect on retention time, and in addition contributes to the continued high popularity of HA.
  • HA is a hydrophilic glycosaminoglycan with multiple polymer chains linked together by cross-linkers. HA naturally occurs in the body, but industrial production mostly takes place through bacterial cultures ( Streptococcus equi). In the human body, it is mostly used to build up the extracellular matrix of the skin and as a lubricant in joints. Approximately 50% of endogenous HA occurs in various layers of the skin and has a variety of tasks, with protection against dehydration, organization and enhancement of the extracellular matrix and involvement in endogenous tissue repair as the most important. Exogenous influences such as UV light or heat lead to destruction of the HA composition. Together with the decomposition of collagen, elastin and reticulin, this results in a degeneration of the body's own filling material of soft tissues and leads to increased wrinkling in old age.
  • HA fillers While endogenous HA has a half-life of only three days, for synthetically produced hyaluronic acid, the more crosslinks exist and the higher the concentration of HA chains, the higher the viscosity and, in general, the half-life. In long-lasting HA preparations a combination of short and long chains results in greater cross-linking. This potentially complicates the applicability, but causes a longer lasting filling effect, because the filler is less easily degraded by the body's own HA degrading enzyme hyaluronidase. Compared to other materials, most HA fillers can only provide a short augmentation effect. Unlike other synthetically produced biomaterials, HA fillers also result in low endogenous collagen formation.
  • Injected HA is completely broken down and eliminated via the liver.
  • Various vitamins have been shown to stimulate the stabilization and synthesis of endogenous collagen and angiogenesis. Because of these positive properties, they are increasingly being explored as co factors in filler development to allow for degradation inhibition of HA and improve the retention of HA in the tissue. However, these efforts so far have failed to produce a long-lasting HA filler.
  • HA fillers can elicit inflammatory, hypersensitive or allergic reactions. It would therefore be desirable to develop an injectable dermal filler composition based on HA, which has an improved safety profile, in particular does not cause inflammatory, hypersensitive or allergic reactions or formation of nodules and granulomas.
  • HA fillers comprising a HIF-Ia activity potentiating agent (HP A) show delayed degradation of HA, significantly reduced inflammatory reactions, and permit a long-lasting, safe correction of soft tissue defects.
  • HP A HIF-Ia activity potentiating agent
  • compositions of the present invention provide inter alia one or more of the following advantages: (i) reduced inflammatory, hypersensitive or allergic reactions, (ii) reduced formation of nodules and granulomas, (iii) better integration of the filler material into the surrounding tissue, (iv) improved biocompatibility, (v) delayed degradation of HA, (vi) longer lasting correction of soft tissue defects, (vii) increased volume retention, (viii) improved local stimulation of dermal soft-tissue and (ix) better predictability of volume augmentation reducing interindividual and batch variations.
  • the present invention relates to a composition
  • a composition comprising hyaluronic acid and a HIF-la activity potentiating agent (HP A), wherein the composition is in a form selected from the group consisting of a solution for injection, a suspension for injection, an emulsion for injection, and a gel for injection.
  • HP A HIF-la activity potentiating agent
  • the present invention relates to the composition of the first aspect for use in medicine.
  • the present invention relates to the composition of the first aspect for use in a method of treatment of a condition selected from the group consisting of stress urinary incontinence, vesicoureteral reflux, vocal fold insufficiency, and vocal fold medialization.
  • the present invention relates to a method for replacing a biological tissue or increasing the volume of a biological tissue for cosmetic or therapeutic purposes, comprising administration of an effective amount of the composition according to the first aspect of the invention to a subject in need thereof.
  • the present invention relates to a method of treatment of a condition selected from the group consisting of stress urinary incontinence, vesicoureteral reflux, vocal fold insufficiency, and vocal fold medicalization, comprising administration of an effective amount of the composition of the first aspect of the invention to a subject in need thereof.
  • the present invention relates to a method of cosmetic treatment comprising the administration of the composition of the first aspect of the invention.
  • the present invention relates to the use of the composition of the first aspect of the invention for cosmetic applications.
  • the present invention relates to the composition of the first aspect of the invention for use in the prevention of inflammatory, hypersensitive or allergic reactions, or formation of nodules and granulomas, caused by a. a method for replacing a biological tissue or increasing the volume of a biological tissue, in particular dermal soft-tissue ; b. a method of treatment of a condition selected from the group consisting of stress urinary incontinence, vesicoureteral reflux, vocal fold insufficiency, and vocal fold medicalization; or c.
  • a method of cosmetic treatment in particular cosmetic treatment of wrinkles and lines of the skin, glabellar lines, nasolabial folds, chin folds, marionette lines, jawlines, buccal commissures, perioral wrinkles, crow's feet, cutaneous depressions, scars, temples, subdermal support of the brows, malar and buccal fat pads, tear troughs, nose, lips, cheeks, chin, perioral region, infraorbital region, and/or facial asymmetries.
  • the present invention relates to a kit comprising HA and a HP A, in particular DFO.
  • the present invention relates to a method for preparing an injectable dermal filler, comprising the steps of: (a) providing a HA gel, (b) providing a HP A, in particular deferoxamine (DFO), (c) mixing the HA gel and the HP A.
  • a) providing a HA gel comprising the steps of: (a) providing a HA gel, (b) providing a HP A, in particular deferoxamine (DFO), (c) mixing the HA gel and the HP A.
  • DFO deferoxamine
  • the present invention relates to a composition
  • a composition comprising hyaluronic acid and a HIF-Ia activity potentiating agent (HP A), wherein the composition is in a form selected from the group consisting of a solution for injection, a suspension for injection, an emulsion for injection, and a gel for injection.
  • HP A HIF-Ia activity potentiating agent
  • HIF-la activity potentiating agent refers to a compound that increases HIF-Ia activity.
  • HIF-la activity potentiating agents that exert their function by stabilizing HIF-la are also called “HIF-la stabilizing compounds”.
  • hyperoxia mimetics generally refers to HIF-la activity potentiating agents.
  • HIF-la is a master transcription factor essential for neovascularization, tissue regeneration and wound healing.
  • HIF-la modulators such as deferoxamine (DFO) or deferiprone (DFP), are small molecules that increase HIF-la activity and stability.
  • deferoxamine refers to N'-[5-(Acetyl-hydroxy-amino)pentyl]-N-[5-[3-(5-aminopentyl-hydroxy-carbamoyl) propanoylamino]pentyl]-N-hydroxy -butane diamide.
  • HIF-1 activity -potentiating agents in the context of medical treatments has been documented with deferoxamine being a well-researched drug in particular.
  • Deferoxamine is a drug with chelating properties, which is used in Europe and the US as a parenteral drug for iron overload (e.g., hemochromatosis and acute iron intoxication). The effect is based on the higher molecular structure of deferoxamine with its three hydroxamic acid groups. It binds the iron released during hemoglobin degradation and causes its renal excretion. Deferoxamine is also credited in the literature with a not yet fully explored role in collagen synthesis by acting as a cofactor in enzymatic reactions and affecting local collagen formation. Deferoxamine inhibits collagen cleavage by collagenase. Fibroblast cultures exposed to Deferoxamine demonstrated increased collagen synthesis.
  • the present invention relates to the use of HIF-la activity potentiating agents such as deferoxamine and deferiprone as part of a novel composition of a long-lasting, therapeutic, injectable dermal hyaluronic acid filler for aesthetic and reconstructive purposes.
  • a mini-pig model has been chosen as injectables have a longstanding history of preclinical evaluation in pigs - it has unexpectedly been discovered that by incorporating HIF-la activity potentiating agents into a synthetically prepared cross-linked hyaluronic acid, significantly reduced inflammatory reactions, significantly increased volume retention and better integration of the filler material can be achieved (Tab. 1 and 2, Fig. 1-4).
  • the term “dermal filler” as used within the context of the present specification refers to a gel or gel-like substance that can be injected beneath the skin to restore volume loss of the intradermal soft-tissue associated with aging or trauma.
  • HA filler a HA-based dermal filler, i.e. a dermal filler comprising HA as main component, is referred to as “HA filler”.
  • HPA filler a HA-based dermal filler further comprising a HIF-la activity potentiating agent (HP A) is referred to as “HPA filler”.
  • the HIF-Ia activity potentiating agent is an inhibitor of HIF hydroxylase.
  • inhibitor of HIF hydroxylase refers to a HIF-la activity potentiating agent that inhibits the activity of the HIF-la degrading enzyme prolylhydroxylase (PHD).
  • the HIF-la activity potentiating agent is an iron chelator.
  • PHD uses Fe 2+ ions as a cofactor, and one way to inhibit PHD is by reducing the availability of Fe 2+ using iron chelators or by introducing metal ions like Ni 2+ , Mn 2+ or Co 2+ that will compete with Fe 2+ .
  • iron chelator refers to a compound that binds Fe 2+ and thus reduces the amount of free Fe 2+ available for PHD mediated HIF hydroxylation reaction.
  • iron chelators are deferiprone (DFP), deferoxamine (DFO), 2, 2’-dipyridyl, deferasirox (DFR), and 3-hydroxy-4-oxo-l (4H)-pyridinealanine (mimosine).
  • the HIF-la activity potentiating agent is selected from the group consisting of deferoxamine (DFO), cobaltchloride (CoCl 2 ), 3-hydroxy-4-oxo-l (4H)- pyridinealanine, deferiprone (DFP), 2,2'-dipyridyl ciclopirox, dimethyloxalylglycine (DMOG), L- Mimosine (Mim), 3-hydroxy-l,2 dimethyl-4(lH)-pyridone (OH-pyridone), [(3-hydroxy-6- isopropoxy-quinoline-2-carbonyl aminoj-acetic acid, [3 -hydroxy -pyridine-2-carbonyl aminoj- acetic acid, [N-(l-chloro-4-hydroxy-isoquinoline 3-carbonyl)-amino]-acetic acid, [(7-bromo-4- hydroxy isoquinoline-3-carbonyl)-amino]-acetic acid, [(7-chloro-3
  • the HIF-la activity potentiating agent is selected from the group consisting of deferoxamine (DFO), cobaltchloride (CoCl 2 ), 3-hydroxy-4-oxo-l (4H)- pyridinealanine, deferiprone (DFP), 2,2'-dipyridyl, ciclopirox, dimethyloxalyl glycine (DMOG), L-Mimosine (Mim), 3-hydroxy-l,2 dimethyl-4(lH)-pyridone (OH-pyridone), oxoglutarates, heterocyclic carboxamides, phenanthrolines, hydroxamates, heterocyclic carbonyl glycines (including, but not limited to, pyridine carboxamides, quinoline carboxamides, isoquinoline carboxamides, cinnoline carboxamides, beta-carboline carboxamides, including substituted quinoline-2-carboxamides and esters thereof; substituted isoquinoline-3
  • DFO
  • [1,10]phenanthroline-3 -carboxylic acid 4-hydroxy-5-methoxy-[ 1 , 10]phenanthroline-3 - carboxylicacidethylester, [(7-benzyloxy-l-chloro-4-hydroxy isoquinoline-3-carbonyl)-amino]- acetic acid methyl ester, and 3- ⁇ [4-(3,3-dibenzyl-ureido)-benzenesulfonyl]-[2-(4 methoxy- phenyl)-ethyl]-l-amino ⁇ -N-hydroxy-propionamide.
  • the HIF-la activity potentiating agent is selected from the group consisting of deferiprone, deferoxamine, 2, 2’-dipyridyl, deferasirox, and 3-hydroxy-4-oxo- 1 (4H)-pyridinealanine.
  • the HIF-la activity potentiating agent is selected from deferiprone and deferoxamine.
  • the HIF-la activity potentiating agent is deferiprone.
  • the HIF-la activity potentiating agent is deferoxamine. It is preferred that the composition further comprises a local anaesthetic. The addition of an anaesthetic reduces the sensation of pain during the application of the composition.
  • the anaesthetic is lidocaine.
  • the lidocaine is present at a concentration of 0.1% to 5%.
  • composition further comprises one or more compounds selected from the group consisting of polyols, vitamins, amino acids, metals, antioxidants, and mineral salts.
  • the HIF-Ia activity potentiating agent is present at a concentration of 0.1% to 50.0% v/v. In more preferred embodiments, the HIF-Ia activity potentiating agent is present at a concentration of 0.1% to 30.0% v/v. In more preferred embodiments, the HIF-Ia activity potentiating agent is present at a concentration of 0.1% to 10.0% v/v. In even more preferred embodiments, the HIF-Ia activity potentiating agent is present at a concentration of 0.5% to 5.0% v/v. In even more preferred embodiments, the HIF-la activity potentiating agent is present at a concentration of 0.5% to 1.0% v/v. In most preferred embodiments, the HIF-la activity potentiating agent is present at a concentration of approximately 0.5% v/v.
  • DFO is present at a concentration of 0.1% to 50.0% v/v. In more preferred embodiments, DFO is present at a concentration of 0.1% to 30.0% v/v. In more preferred embodiments, DFO is present at a concentration of 0.1% to 10.0% v/v. In even more preferred embodiments, DFO is present at a concentration of 0.5% to 5.0% v/v. In even more preferred embodiments, DFO is present at a concentration of 0.5% to 1.0% v/v. In most preferred embodiments, DFO is present at a concentration of approximately 0.5% v/v.
  • the HA is present at a concentration of 10 mg/ml to 40 mg/ml, in particular 20 mg/ml to 30 mg/ml.
  • the HA is cross-linked, in particular the HA is characterized by a crosslinking degree of 2% to 20%, more particularly 5% to 10 %, even more particularly 6% to 8%.
  • cross-linking of HA refers to the formation of covalent bonds between HA molecules via hydroxyl groups.
  • Crosslinking agents that induce such formation of covalent bonds are known to the skilled person.
  • Examples are 1,4-butanediol diglycidyl ether (BDDE), 1, 4-bis (2,3-epoxypropoxy) butane, 1,4-bisglycidyloxybutane, 1,2-bis (2,3-epoxypropoxy) ethylene and 1- (2,3-epoxypropyl) -2,3 -epoxy cyclohexane and 1,4-butanediol diglycidyl ether.
  • the degree of crosslinking can be controlled by the size of the HA molecules. Longer HA chains result in less cross-linking. A combination of short and long HA chains results in greater cross-linking.
  • the composition is provided in a pharmaceutical dosage form suitable for injection into the skin, preferably for injection into the epidermis, dermis or subcutis, more preferably for injection into the dermis, and most preferably for injection into the stratum reticulare of the subject.
  • dosage forms are preferably selected from a solution for injection, a suspension for injection, an emulsion for injection, and a gel for injection.
  • the composition is in the form of a gel for injection.
  • a gel for injection to which the invention is not limited.
  • the composition according to the first aspect is a pharmaceutical composition.
  • the present invention relates to the composition of the first aspect for use in medicine.
  • the present invention relates to the composition of the first aspect for use in a method of treatment of a condition selected from the group consisting of stress urinary incontinence, vesicoureteral reflux, vocal fold insufficiency, and vocal fold medialization.
  • the treatment comprises administration of an effective amount of the composition according to the first aspect of the invention to a subject in need thereof.
  • the administration comprises injection of the composition into a tissue, in particular a soft tissue.
  • the increased volume of the injected tissue leads to an improvement of the respective condition.
  • Which tissue is injected with the composition according to the first aspect of the invention depends on the condition. In the case of vesicoureteral reflux, the composition is injected into the bladder wall near the opening of the ureter.
  • the injection of the composition is periurethral, e.g. at the level of the mid-urethra or the bladder neck (Kasyan and Pushkar, Cent European J Urol. 2015; 68(3): 339).
  • the composition is injected into the superficial layer of the vocal fold as lamina intestinal replacement or into the medial aspect of the paraglottic space (lateral aspect of the thyroartyenoid/lateral cricoarytenoid muscle complex) (Mallur and Rosen, Clin Exp Otorhinolaryngol. 2010 Dec; 3(4): 177-182).
  • the use comprises injection of the composition into the epidermis, dermis or subcutis, of a subject in need thereof, more preferably injection into the dermis, and most preferably injection into the stratum reticulare.
  • the present invention relates to a method for replacing a biological tissue or increasing the volume of a biological tissue for cosmetic or therapeutic purposes, comprising administration of an effective amount of the composition according to the first aspect of the invention to a subject in need thereof.
  • the term “subject” is understood to include a mammal such as an animal and, more preferably, a human that is receiving or intended to receive treatment, as it is herein defined. While the term “subject” is often used herein to refer to a human, the invention is not so limited. Accordingly, the term “subject” refers to any animal, mammal or human having or at risk for a medical condition that can benefit from the treatment.
  • the present invention relates to a method of treatment of a condition selected from the group consisting of stress urinary incontinence, vesicoureteral reflux, vocal fold insufficiency, and vocal fold medicalization, comprising administration of an effective amount of the composition of the first aspect of the invention to a subject in need thereof.
  • the terms “treats”, “treating”, “treatment” and “to treat” include both prophylactic or preventive treatment (that prevent and/or slow the development of a targeted pathologic condition or disorder) and curative, therapeutic or disease-modifying treatment, including therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic condition or disorder; and treatment of subjects at risk of contracting a disease or suspected to have contracted a disease, as well as subjects who are ill or have been diagnosed as suffering from a disease or medical condition.
  • the term does not necessarily imply that a subject is treated until total recovery.
  • treats also refer to the maintenance and/or promotion of health in an individual not suffering from a disease but who may be susceptible to the development of an unhealthy condition.
  • treatment also intended to include the enhancement of one or more primary prophylactic or therapeutic measures.
  • the present invention relates to a method of cosmetic treatment comprising the administration of the composition of the first aspect of the invention.
  • a "cosmetic treatment” in contrast to a therapeutic treatment, has the effect of preventing, mitigating and/or correcting a cosmetically undesirable condition such as signs of skin ageing, and in particular of wrinkles, loss of elasticity, firmness and/or tonicity of the skin.
  • the cosmetic treatment is treatment of wrinkles and lines of the skin, glabellar lines, nasolabial folds, chin folds, marionette lines, jawlines, buccal commissures, perioral wrinkles, crow's feet, cutaneous depressions, scars, temples, subdermal support of the brows, malar and buccal fat pads, tear troughs, nose, lips, cheeks, chin, perioral region, infraorbital region, and/or facial asymmetries.
  • the administration comprises injection into the skin, preferably into the epidermis, dermis or subcutis, more preferably into the dermis, most preferably into the stratum reticulare.
  • the present invention relates to the use of the composition of the first aspect of the invention for cosmetic applications.
  • the cosmetic application is treatment of wrinkles and lines of the skin, glabellar lines, nasolabial folds, chin folds, marionette lines, jawlines, buccal commissures, perioral wrinkles, crow's feet, cutaneous depressions, scars, temples, subdermal support of the brows, malar and buccal fat pads, tear troughs, nose, lips, cheeks, chin, perioral region, infraorbital region, and/or facial asymmetries.
  • cosmetic treatment and “cosmetic application” relate to the treatment of a healthy area of skin.
  • healthy area of skin refers to a skin area which is not afflicted with any disease, disorder or pathological condition which commonly requires therapeutic treatment (e.g. infections, papulose-squamous skin diseases, urticaria, erythema, dermatitis Solaris acuta, rosacea, purpura actinica, and pigmentation disorders such as melasma of a certain severity that commonly requires therapeutic treatment).
  • Healthy skin is preferably intact, unwounded, has no haemorrhages and/or haematomas, and is dermatologically unremarkable. Healthy skin can also be called “physiologically normal skin”. The loss of elasticity, firmness and/or tonicity of the skin and/or the formation of wrinkles associated with normal ageing is not to be considered as a disease, disorder or pathological condition.
  • the present invention relates to the composition of the first aspect of the invention for use in the prevention of inflammatory, hypersensitive or allergic reactions, or formation of nodules and granulomas, caused by a. a method for replacing a biological tissue or increasing the volume of a biological tissue, in particular dermal soft-tissue ; b. a method of treatment of a condition selected from the group consisting of stress urinary incontinence, vesicoureteral reflux, vocal fold insufficiency, and vocal fold medicalization; or c.
  • the present invention relates to a kit comprising HA and a HIF-la activity potentiating agent, in particular DFO.
  • the present invention relates to a kit comprising the composition according to the first aspect of the invention.
  • the present invention relates to a method for preparing an injectable dermal filler, comprising the steps of: (a) providing a cross-linked hyaluronic acid gel, (b) providing a HIF-Ia activity potentiating agent, in particular DFO, (c) mixing the cross-linked hyaluronic acid gel and the HIF-Ia activity potentiating agent.
  • Fig. 1 shows injection of the composition comprising a HIF-Ia activity potentiating agent.
  • Fig. 2 shows the evaluation of volume retention after 90 days using an MRI scan.
  • Fig. 3 shows CD4 and CD45 negative histology of the injected site, indicating the absence of allergic reactions or inflammation.
  • Fig. 4 shows that volume retention after 90 days that was 67% higher with the composition comprising HIF-Ia activity potentiating agent Deferoxamin (DFO) than with the unsupplemented HA composition.
  • Miniature swine are the animal model of choice for the preclinical assessment of drugs targeting the endocrine, ocular, and dermal system. Swine have been used extensively in dermal research because of the comparability of their integument to that of humans. During the past half century, they have been used in preclinical dermal toxicology, dermal pharmacokinetics, dermal photo- toxicity, dermal wound healing studies, and a broad array of other biomedical research applications. The value of miniature swine dermal models for preclinical safety is confirmed by medical studies. Overall, the predictive value of miniature swine safety and efficacy studies to human outcomes of all reviewed drugs were 89% and 100%, respectively.
  • HA DFO supplementation an off-the-shelf dermal filler product has been used.
  • the DFO molecule has been integrated into the dermal fillers using a technique called “shuffling” by experienced plastic surgeons.
  • This technique is similarly used to add local lidocaine anesthesia to HA dermal fillers.
  • a syringe with 0.1 ml of aqueous solution gets added to a standard 1 ml HA syringe using female-to-female adaptors. Due to HA filler’s structural and rheological properties they make for an ideal carrier for slow release drug delivery applications.
  • HA acts as a depot matrix, which slowly releases the DFO into the surrounding tissue over the course of the HA’s natural degradation.
  • the overall material characteristics of HA have remained largely unchanged due to this supplementation, with an improvement of the filler’s rheological properties reported by the doctors, who mentioned an easier application made possible by the additional aqueous solution added to the HA syringe.
  • this method of using off-the-shelf fillers has the additional advantage of underlining the technology’s suitability for being used by leading players as an easy supplement for their existing HA filler product lines.
  • the DFO could also be integrated into the filler during manufacturing and before cross-linking to increase shelf-life.
  • lidocaine may be included to ensure a low-pain application.
  • the use of the present invention is for the purpose of treating soft tissue defects and increasing soft tissue volume, thereby mitigating or correcting signs of aging of the skin consisting of wrinkles, wrinkles, thinner lips, drooping skin and sagging skin, especially fine lines, nasolabial folds, puppet wrinkles, lip wrinkles, forehead wrinkles, crow's feet and glabella folds.
  • the skin site to which the present invention is applied is preferably in the face, neck, trunk or limbs of the individual.
  • HPA filler showed a volume retention after 90 days that was 67% higher than the unsupplemented HA product (figure 4). Volume retention was significantly better than that of pure HA, continuous over time and lacking the differences between different test subjects linked to changes in individual hyaluronidase, which is similar to the difference in effect reported in human patients.
  • the preclinical study further confirmed the excellent biocompatibility and tolerability of the DFO containing HA filler.
  • the injected material showed an improved adaptation and improved integration into the surrounding tissue, which stimulates soft tissues locally without inflammatory foreign body reactions, capsule or granuloma formation. Over the test period of 90 days neither the formation of fibrotic capsules nor granulomas could be detected on MRI.
  • the DFO containing filler material resulted in no allergic reactions or inflammation.
  • the better integration of the implant by local soft tissue modulation unexpectedly achieved in the preclinical studies is triggered by HIF upregulation via the HA DFO supplementation.
  • the intracellular presence of DFO and its HIF modulating effect has been proven to activate over 100 downstream genes, chiefly responsible for cell processes like angiogenesis, cell proliferation, migration and glucose metabolism.
  • Studies demonstrated that the activation of fibroblasts via HPA in vitro enhances cell metabolism, proliferation, survival and viability while reducing cellular stress. This activation leads to production of new collagen strains, extracellular matrix, glycosaminoglycans and nutritive blood vessels.
  • the volume retention effect is supported by this HIF- la activity mediated local collagen modification.
  • DFO inhibits collagen cleavage by collagenase and enhances collagen synthesis.
  • HPA filler stimulates soft tissues locally without an inflammatory foreign body reactions or granuloma formation. Additionally, the improved adaptation and improved integration into the surrounding tissue of the injected material due to the addition of DFO ensures the effective prevention of dermal filler complications and provides the HPA filler with a superior safety profile compared to pure HA products.
  • the majority of the increased volume retention effect of the HPA filler is directly linked to the improved protection of hyaluronic acid from degradation via the effective downregulation of hyaluronidase activity as a direct consequence of HIF upregulation caused by local DFO released by the supplemented filler.
  • the degradation of hyaluronic acid is catalysed by hyaluronidases, a family of enzymes, which are produced by bacteria, such as staphylococcus aureus, and in the human body are predominantly found in the lysosome of skin fibroblasts. Fibroblasts are the most common cells of connective tissue in animals and synthesize the extracellular matrix and collagen.
  • Hyal-1 hyaluronidase is usually the enzyme used by a doctor who wants to break down hyaluronic acid.
  • Hyal-1 is first synthesized in the body as a 52 kDa protein that is transported to the Golgi apparatus and then targeted to dense lysosomes and subjected to a proteolytic processing during transport or upon arrival in these compartments which leads to different Hyal-1 forms other than the 52 kDa variant and thus to inactivation and subsequently to a much reduced HA degradation.
  • HIF upregulation via DFO achieves this effect in the local tissue surrounding the implant. This can be shown by in-vitro tests using differential centrifugation western blotting followed by analysis of their HA degrading ability via an in-gel degradation assay using the zymography technique.
  • DFO can further reduce degradation of the HA via reactive molecules, which attack the HA upon injection and thereby contribute to volume retention. This is linked to the inflammatory response triggered when a needle is inserted into the skin tissue, which activation of free radical-generating enzymes on the injection site. Those reactive molecules attack the injected HA and try to break down its overall structure. DFO as a strong antioxidant and free radical scavenger reduces and prevents damage from such free radical reactions and provides better resistance to the gel’s degradation. DFO further helps stabilize physico-chemical properties of the product in the syringe during its storage at room temperature. Combined with HA it can exert protection from degradation of the HA via several mechanisms and thereby contribute to volume retention.
  • HIF-Ia activity potentiating agents include iron chelators such as deferoxamine (DFO), the hypoxia mimetic cobaltchloride (CoCl 2 ), and mimosine, 3-Hydroxy-4-oxo-l (4H)-pyridinealanine, or other factors that may mimic hypoxia.
  • iron chelators such as deferoxamine (DFO), the hypoxia mimetic cobaltchloride (CoCl 2 ), and mimosine, 3-Hydroxy-4-oxo-l (4H)-pyridinealanine, or other factors that may mimic hypoxia.
  • hydroxylase inhibitors including deferiprone (DFP), 2,2'-dipyridyl, ciclopirox, dimethyloxallyl glycine (DMOG), L-Mimosine (Mim) and 3-Hydroxy-l,2 dimethyl-4(lH)- Pyridone (OH-pyridone).
  • HIF hydroxylase inhibitors are described herein, including but not limited to, oxoglutarates, heterocyclic carboxamides, phenanthrolines, hydroxamates, and heterocyclic carbonyl glycines (including, but not limited to, pyridine carboxamides, quinoline carboxamides, isoquinoline carboxamides, cinnoline carboxamides, beta-carboline carboxamides, including substituted quinoline-2-carboxamides and esters thereof; substituted isoquinoline-3 - carboxamides and substituted arylsulfonylaminohydroxamicacids and the like.
  • heterocyclic carbonyl glycines including, but not limited to, pyridine carboxamides, quinoline carboxamides, isoquinoline carboxamides, cinnoline carboxamides, beta-carboline carboxamides, including substituted quinoline-2-carboxamides and esters thereof; substituted isoquino
  • Compounds reported to stabilize HIF- la also include [(3-hydroxy-6-isopropoxy-quinoline-2-carbonyl amino]- acetic acid, [3-hydroxy-pyridine-2-carbonyl amino]-acetic acid, [N-( 1 -chloro-4-hydroxy- isoquinoline 3-carbonyl)-amino]-acetic acid, [(7-bromo-4-hydroxy isoquinoline-3-carbonyl)- amino]-acetic acid, [(7-chloro-3 hydroxy-quinoline-2-carbonyl)-amino]-acetic acid, [(1 bromo-4- hydroxy-7-chloromethyl-isoquinoline-3 carbonyl)-amino]-acetic acid, [(l-Bromo-4-hydroxy-7 phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid, [(1 Chloro-4-hydroxy-7-phenoxy- isoquinoline-3-carbonyl) aminoj-acetic acid, [(l-
  • the present invention is illustrated by the following preparation of a dermal filler; to which it is of course not limited.
  • the dermal filler is for the purpose of treating soft tissue defects and increasing soft tissue volume, thereby mitigating or correcting signs of aging of the skin consisting of wrinkles, wrinkles, thinner lips, drooping skin and sagging skin, especially fine lines, nasolabial folds, puppet wrinkles, lip wrinkles, forehead wrinkles, crow's feet and glabella folds.
  • the skin site to which the present invention is applied is preferably in the face, neck, trunk or limbs of the individual.
  • the preparation of the HA-based gel is done by hydrating the HA powder (hyaluronate salts such as sodium hyaluronate, potassium hyaluronate, magnesium hyaluronate, calcium hyaluronate and combinations thereof) using water and subsequent filtration to remove impurities.
  • hyaluronate salts such as sodium hyaluronate, potassium hyaluronate, magnesium hyaluronate, calcium hyaluronate and combinations thereof
  • Crosslinking of the gel is then carried out with a crosslinking agent known to the expert and suitable for the crosslinking of polysaccharides and their derivatives via their hydroxyl groups (for example selected from the group consisting of 1,4-butanediol diglycidyl ether (BDDE), 1, 4-bis (2,3-epoxypropoxy) butane, 1,4-bisglycidyloxybutane, 1,2-bis (2,3-epoxypropoxy) ethylene and 1- (2,3 -epoxypropyl) -2,3 -epoxy cyclohexane and 1,4-butanediol diglycidyl ether).
  • BDDE 1,4-butanediol diglycidyl ether
  • 1,4-bis (2,3-epoxypropoxy) butane 1,4-bisglycidyloxybutane
  • the degree of crosslinking of the HA component of the present compositions ranges from at least about 2% to up to about 20%.
  • the degree of crosslinking of HA in some of the compositions is greater than 5%, for example, about 6% to about 8%.
  • the concentration of HA in the compositions described herein is preferably at least 10 mg / ml and up to about 40 mg / ml.
  • the concentration of HA in some of the compositions ranges between about 20 mg / ml and about 30 mg / ml. Then, by methods known to those skilled in the art, the pH of the material is stabilized at about 7.5 to about 8.0 and unreacted crosslinking agents are removed.
  • lidocaine for this purpose, which is solubilized in a powder form using water for incorporation.
  • the HA-based injectable composition has a lidocaine concentration between at least about 0.1% and about 5%.
  • An HIF-Ia activity potentiating agent is then added in an effective concentration, which is a concentration at which delayed degradation of the injected hyaluronic acid is achieved.
  • Deferoxamine in its powdered form deferoxamine mesylate, is soluble in water at 50 mg / ml and is solubilized using water for incorporation.
  • the HA-based injectable composition has a deferoxamine concentration between 0.1% -50% v/v, preferably from 0.1% -30%, more preferably from 0.1% -10%, even more preferably from 0.5%. 5% or even 0.5% -1%, or substantially 0.5%.
  • the composition is homogenized to produce a highly homogeneous gel having the desired consistency and stability. After homogenization, the composition is introduced into syringes and sterilized.
  • An injectable dermal filler composition in the form of a gel comprising crosslinked hyaluronic acid and a suitable HIF-la activity potentiating agent, such as an iron chelator, a hypoxia mimetic, a HIF hydroxylase inhibitors or HIF-Ia stabilizing compound.
  • a suitable HIF-la activity potentiating agent such as an iron chelator, a hypoxia mimetic, a HIF hydroxylase inhibitors or HIF-Ia stabilizing compound.
  • a method for preparing an injectable dermal filler composition according to item 1, comprising: (a) providing a crosslinked hyaluronic acid gel, (b) providing a HIF-la activity potentiating agent, (c) mixing the crosslinked hyaluronic acid gel and the HIF-la activity potentiating agent.
  • a product comprising an injectable dermal filler composition according to item 1 or a kit comprising said composition for cosmetic applications, including cosmetic treatment of wrinkles and lines of the skin, glabellar lines, nasolabial folds, chin folds, marionette lines, jawlines, buccal commissures, perioral wrinkles, crow's feet, cutaneous depressions, scars, temples, subdermal support of the brows, malar and buccal fat pads, tear troughs, nose, lips, cheeks, chin, perioral region, infraorbital region, and/or facial asymmetries.
  • An injectable dermal filler composition according to item 1 or a kit comprising said composition for use in therapy 9.
  • a method for replacing or filling of a biological tissue or increasing the volume of a biological tissue for cosmetic or therapeutic purposes comprising administering to a subject in need thereof an effective amount of the injectable dermal filler composition according to item 1.

Abstract

La présente invention concerne une composition comprenant de l'acide hyaluronique (HA) et un agent de potentialisation de l'activité de HIF-1α (HPA), la composition étant sous une forme choisie dans le groupe constitué par une solution pour injection, une suspension pour injection, une émulsion pour injection et un gel pour injection. De plus, la présente invention concerne ladite composition destinée à être utilisée en médecine, en particulier dans une méthode de traitement d'une affection choisie dans le groupe constitué par l'incontinence urinaire d'effort, le reflux vésico-urétéral, l'insuffisance de cordes vocales et la médialisation de cordes vocales. L'invention concerne en outre une méthode de remplacement d'un tissu biologique ou d'augmentation du volume d'un tissu biologique à des fins cosmétiques ou thérapeutiques, une méthode de traitement et une méthode de traitement cosmétique comprenant l'administration de ladite composition. En outre, l'invention concerne l'utilisation de ladite composition pour des applications cosmétiques, un kit comprenant du HA et un HPA, en particulier de la DFO, et une méthode de préparation d'un implant dermique injectable, comprenant les étapes consistant à : (a) utiliser un gel de HA, (b) utiliser un HPA, en particulier de la DFO, (c) mélanger le gel de HA et le HPA.
PCT/EP2020/067733 2020-06-24 2020-06-24 IMPLANT DERMIQUE À MODULATEURS DE L'ACTIVITÉ DE HIF-1α WO2021259471A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5217998A (en) * 1985-07-02 1993-06-08 Biomedical Frontiers, Inc. Composition for the stabilization of deferoxamine to chelate free ions in physiological fluid
US20100092546A1 (en) * 2008-10-10 2010-04-15 Gurtner Geoffrey C Topical and Transdermal Delivery of HIF-1 Modulators to Prevent and Treat Chronic Wounds
US20110201571A1 (en) * 2008-11-07 2011-08-18 Anteis S.A. Heat sterilised injectable composition of hyaluronic acid or one of the salts thereof, polyols and lidocaine
EP2594274A1 (fr) * 2010-06-04 2013-05-22 Kao Corporation Nouveau facteur favorisant la décomposition de l'acide hyaluronique et son inhibiteur
US20190008984A1 (en) * 2015-12-17 2019-01-10 The Regents Of The University Of Michigan Devices, compositions and related methods for accelerating and enhancing bone repair

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5217998A (en) * 1985-07-02 1993-06-08 Biomedical Frontiers, Inc. Composition for the stabilization of deferoxamine to chelate free ions in physiological fluid
US20100092546A1 (en) * 2008-10-10 2010-04-15 Gurtner Geoffrey C Topical and Transdermal Delivery of HIF-1 Modulators to Prevent and Treat Chronic Wounds
US20110201571A1 (en) * 2008-11-07 2011-08-18 Anteis S.A. Heat sterilised injectable composition of hyaluronic acid or one of the salts thereof, polyols and lidocaine
EP2594274A1 (fr) * 2010-06-04 2013-05-22 Kao Corporation Nouveau facteur favorisant la décomposition de l'acide hyaluronique et son inhibiteur
US20190008984A1 (en) * 2015-12-17 2019-01-10 The Regents Of The University Of Michigan Devices, compositions and related methods for accelerating and enhancing bone repair

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DAS DIPANKAR ET AL: "Characterizations of hyaluronate-based terpolymeric hydrogel synthesized via free radical polymerization mechanism for biomedical applications", COLLOIDS AND SURFACES B: BIOINTERFACES, ELSEVIER AMSTERDAM, NL, vol. 170, 31 May 2018 (2018-05-31), pages 64 - 75, XP085458726, ISSN: 0927-7765, DOI: 10.1016/J.COLSURFB.2018.05.059 *
KASYANPUSHKAR, CENT EUROPEAN J UROL., vol. 68, no. 3, 2015, pages 339
LINDVALL S ET AL: "Influence of various compounds on the degradation of hyaluronic acid by a myeloperoxidase system", CHEMICO-BIOLOGICAL INTERACTIONS, ELSEVIER SCIENCE IRLAND, IR, vol. 90, no. 1, 1 January 1994 (1994-01-01), pages 1 - 12, XP023831689, ISSN: 0009-2797, [retrieved on 19940101], DOI: 10.1016/0009-2797(94)90106-6 *
MALLURROSEN, CLIN EXP OTORHINOLARYNGOL., vol. 3, no. 4, December 2010 (2010-12-01), pages 177 - 182

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