WO2018182436A2 - Composition sous forme de gel - Google Patents

Composition sous forme de gel Download PDF

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Publication number
WO2018182436A2
WO2018182436A2 PCT/PL2018/000028 PL2018000028W WO2018182436A2 WO 2018182436 A2 WO2018182436 A2 WO 2018182436A2 PL 2018000028 W PL2018000028 W PL 2018000028W WO 2018182436 A2 WO2018182436 A2 WO 2018182436A2
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WO
WIPO (PCT)
Prior art keywords
composition
hyaluronic acid
lecithin
composition according
concentration
Prior art date
Application number
PCT/PL2018/000028
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English (en)
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WO2018182436A3 (fr
Inventor
Sp. Z O.O. Biovico
Artur WILANDT
Krzysztof Lemke
Jan PROCEK
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Biovico Sp Z O O
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Publication of WO2018182436A2 publication Critical patent/WO2018182436A2/fr
Publication of WO2018182436A3 publication Critical patent/WO2018182436A3/fr

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Classifications

    • 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
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • 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
    • A61K31/695—Silicon compounds
    • 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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/12—Magnesium silicate
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

  • a subject of this invention is a novel composition containing hyaluronic acid and/or its derivatives, phospholipids and/or soluble silicon compounds in a buffering system.
  • the subject of the invention is an implementation of the above described composition for treatment of joint pain, joint/tendon damage, or arthritis including Rheumatoid Arthritis (RA), or atelocollagen synthesis inductor or cosmetic filler.
  • RA Rheumatoid Arthritis
  • Osteoarthritis is a chronic inflammatory disease and the most commonly occurring cause of joint dysfunction in the world. It is characterized by symptoms such as progressive atrophy of cartilage tissue and loss of synovial fluid that cause chronic pain and reduce mobility. Risk factors that contribute to the development of OA include mechanical loads excreted on the knee joint (e.g. obesity or previous knee injuries), age, sex as well as genetic predisposition. People with osteoarthritis suffer from inconvenient and difficult to treat joint pain that remains as a challenge for today's medicine [Sarzi-Puttini P. et ai, 2005].
  • chondrocytes An important corrective factor is targeting of differentiation of mesenchymal cells into normal chondrocytes. It has a direct effect on reducing the inflammatory response in affected tissue and enhances regenerative processes in OA [Glenn J. et al., 2014]. Chondrogenesis occurs as a result of accumulation of mesenchymal cells that express collagen I, III and V and ability of differentiation into chondrocytes that produce collagen II, IX and XI. An influence on the differentiation of mesenchymal cells include factors such as BMP-5; FGF-4,8,10; N-cadherin, perlecan, TGF beta 1 and 2. The influx of mesenchymal cells to the site of inflammation is conditioned by secretion of stromal cell-derived factor 1 (SDF1) chemokine and overexpression of chemokine type 4 receptor (CXCR4) on the surface of cells.
  • SDF1 stromal cell-derived factor 1
  • CXCR4 chemokine type 4 receptor
  • HA hyaluronic acid
  • Hyaluronic acid is a polysaccharide that belongs to the glycosaminoglycans, which is made up of alternating units of D-glucuronic acid and N- acetyl-D-glucosamine [Zhang J., et al. ,2014].
  • HA is present in skin, synovium, vitreous body of an eye and is a component of body fluids and connective tissue.
  • HA endogenous HA role is also structural organization of extracellular matrix, cartilage support and mediation in the regulation of cell development (including proliferation, differentiation or migration) [Prasad N., et al., 2014].
  • Degradation of HA and associated increase of enzymes expression responsible for degradation of cartilage components - collagen and proteoglycan - occurs in progressive OA. This leads to loss of ability to absorb and transfer mechanical stresses through the knee joint, which results in stiffness of the joint and pain experienced by patient.
  • Intra-articular injection of hyaluronic acid is a method of treatment of early and intermediate OA.
  • the efficacy of intra-articular HA injection depends on properties of injected HA, such as molecular weight range, concentration, crosslinking degree and chemical modification.
  • Intra-articular delivery of hyaluronic acid with properly selected parameters allows to relieve pain perception and restore knee joint function [Kobayashi Y., et a/., 1994; Barbucci R., et al., 2000; Fam H, et al., 2009; Huin-Amargier C, et al., 2006].
  • hyaluronic acid produced by fermentation process, allows to restore the viscoelastic properties of synovial fluid and eliminates allergies that occur when animal-derived (isolated from rooster combs) hyaluronic acid is used.
  • the viscosity of the hyaluronic acid based gels depends on its molecular weight and concentration.
  • Literature indicates that viscosity of hyaluronic acid increases exponentially with its concentration and molecular weight and there is a non-linear increase in osmotic pressure with increased concentration.
  • the stability of hyaluronic acid is mainly dependent on presence of free radicals that are responsible for its degradation. The rate of degradation also depends on the temperature and the pH of its solution.
  • Hyaluronic acid is hydrolyzed both at low (pH ⁇ 4) and high (pH>10) pH values and rate of its degradation increases with increasing temperature.
  • the hyaluronic acid degradation rate can be limited by interaction with lecithin bilayer.
  • Lecithin is a natural component found in lipid membranes of all living cells.
  • the term "lecithin” describes the complex mixture of phospholipids and other components such as triglycerides, fatty acids, sterols and glycolipids.
  • Egg yolk, soybean, rapeseed and sunflower seed are primary industrial sources of lecithin.
  • Phospholipids such as lecithin consist of glycerol esters of phosphoric acid and fatty acids.
  • Lecithin stabilizes structure of HA and improves its lubricating effect has an influences on rheological and tribological properties.
  • Lecithin is a natural complex of phospholipids that are important building blocks of all human cell membranes. Lecithin is completely metabolized, which makes it a biocompatible and a biodegradable compound [Fiume Z., et al., 2001].
  • hyaluronic acid The inflammatory cell penetrate synovial membrane and production of pro-inflammatory agents (mostly IL- ⁇ and TNFa) occur commonly in all stages of OA.
  • Biological effect of hyaluronic acid depends on its molecular weight. It was shown that high molecular weight hyaluronic acid is an important factor in modulation of inflammatory response. As a component of glycocalyx, it has an ability to interact with membrane receptors, prevent cells from recognizing immune system, block phagocytosis by macrophages and inhibit T lymphocyte proliferation that have a direct effect on inflammation blocking.
  • the studies of inflammatory process showed a marked difference in molecular weight of endogenous hyaluronic acid.
  • Hyaluronic acid is also used for treatment of tendon injury because its anti-inflammatory and lubricating properties influence the treatment effectiveness.
  • HA prevents the proliferation of fibroblasts and stabilizes formation of type III collagen, thereby reducing the risk of tendons adhesion during regeneration.
  • exogenous hyaluronic acid decreases expression of proinflammatory cytokines and inhibits fragmentation as well as it stimulates the production of endogenous HA.
  • soluble silicates e.g. orthosilicic acid, metasilic acid, trisilicates and disilicates show a major influence on bone metabolism.
  • Efficiency of silicon compounds has been determined to be associated with loss of bone tissue as well as with insufficient synthesis of connective tissue elements such as collagen and glycosaminoglycans.
  • Silicon compounds that affect cartilage rebuilding are used to regenerate bone tissue.
  • orthosilicic acid stimulates the organism for collagen production [Reffitt et al. 2003].
  • silicates In growing bones, concentration of silicates is comparable to that of a calcium, magnesium and phosphorus. In the course of bones maturation process, silicates are replaced by calcium. They affect the decreasing of TNF gene expression, which inhibits osteoblast differentiation and production of extracellular matrix [Pawelec et al. 2015]. There are indications showing that silicates consumed interacted with estrogen hormones and increased bone density of women before menopause [Macdonald et al. 2012].
  • Silicates are also bound in large quantities with glycosaminoglycans, mainly with chondroitin sulphate. They are involved in glutamic acid synthesis, which is a precursor of proline integrated into collagen. In presence of vitamin C and iron, silicates mediate addition of hydroxyl groups to the rests of the pro-collagen proline and thus its conversion to collagen [Schwarz et al.,1972; Adams et al., 1980; Carlisle et ⁇ / 1984; Carlisle et al., 1981; Carlisle et al., 1982].
  • HA formula which contains orthosilicic acid and lecithin that stimulates collagen production in primary chondrocyte culture and induces the mesenchymal stem cell differentiation to chondrocytes, was developed.
  • Pharmacological treatments with hyaluronic acid may be divided into two groups depending on the chemical structure of the hyaluronic acid:
  • the usage of the native HA leads to immediate restoration of an appropriate physiological and biological properties of synovial fluid, reduces production and activity of proinflammatory mediators (cytokines), normalizes synthesis of endogenous HA and delays cartilage degradation by stimulating of the chondrocytes activity and proteoglycans synthesis.
  • cytokines proinflammatory mediators
  • HA hyaluronic acid
  • various groups of products based on HA may be distinguished. This includes those with a wide range of molecular masses (MW) that are isolated from rooster combs or obtained by bacterial fermentation. Products obtained by bacterial fermentation are considered safer due to lack of risks of allergic reactions caused by animal proteins.
  • MW molecular masses
  • phospholipids such as phosphatidylcholine
  • form tightly packed liposome boundary layers that contribute to reduction of friction coefficient and decrease of sliding friction.
  • the reduction of friction is a result of hydration-lubrication property of liposomes, where robust and tightly packed structure as well as highly hydrated phospholipids' head groups, located on the outer layer, respectively, allow to sustain high pressure and show a fluid-like response under the shear stress.
  • hyaluronan associates with the outer shell of dipalmitoyl phosphatidylcholine (DPPC) vesicles in silica-aqueous bulk solution. They proved that sequential adsorption of DPPC and hyaluronan can build a composite layer that allows a large amount of phospholipid to be present on the surface, and this layer provides low friction and high load bearing capacity on silica surfaces.
  • DPPC dipalmitoyl phosphatidylcholine
  • the layers formed by adsorption of DPPC/hyaluronan self- assembly structures provide a lubrication advantage over that of DPPC alone by possessing self-healing ability in a mixture of a cationic polyelectrolyte and an anionic surfactant. This is due to the presence of DPPC/hyaluronan aggregates on the surface that allows the build-up of a reservoir of the lubricating phospholipids on the solid surfaces.
  • the inhomogeneous DPPC/hyaluronan layer formed by adsorption of self-assembly structures of these components provides excellent lubrication, and if such layers are also present on natural surfaces, favorable lubrication properties can be expected. [Raj A., et ai, 2017].
  • purpose of this invention is to provide a new product composition formulated of a hyaluronic acid.
  • the present invention relates the composition composed of Hyaluronic acid or its derivatives where concentration is between 1-3%, 10-30 mg/g/ml, phospholipids concentration is between 0,01-10 mg/g (ml) -> 0,001-lw% -> 12,7uM-12,7mM and/or soluble silicon compounds where concentration is between 0,001-0,2mg/g (ml) -> 0,0001-0,02w% -> 15 ⁇ -1,1 ⁇ , in a buffering system where concentration is between 1,0-5,0 mM and 1.0-200.0 mM physiological saline.
  • composition wherein hyaluronic acid molecular weight is between 1-3 MDa.
  • composition wherein hyaluronic acid is animal derived or produced by fermentation.
  • composition wherein hyaluronic acid is in native, modified and/or crosslinked form.
  • composition wherein phospholipids are phosphatidylcholine and/or lecithin in the form of liposomes.
  • silicon compounds are orthosilic acid, metasilicic acid, trisilicates, disilicates and fumed silica.
  • composition wherein buffer system is comprised of sodium phosphates and physiological saline.
  • composition wherein said composition is used to reduce inflammation.
  • composition which is administered by oral administration, subcutaneous injection, intravenous injection, or intra-articular injection.
  • composition which is for use in reducing joint pain, tendon and/or join injury joint inflammation including rheumatoid arthritis and aesthetic medicine.
  • composition wherein said composition is used to reduce gene activity of extracellular matrix degradation enzyme induced by inflammatory mediator.
  • Fig.l Level of relative mRNA expression for MMP-13. Inducer of inflammation promoted higher MMP-13 relative mRNA expression level when compared to control group in primary chondrocytes. However, presence of COMPOSITION 1 (HA with lecithin) was able to inhibit this effect. Addition of COMPOSITION 2 (HA alone ) was not able to show the same inhibitory effect. In vitro tests proved that said composition (Fig.l- HA with lecithin- COMPOSITION 1) is able to reduce MMP-13 m NA expression levels induced by inflammatory mediator (IL-1 beta). Composition without lecithin (Fig.l- HA alone- COMPOSITION 1) was not able to reduce MMP-13 mRNA expression levels induced by inflammatory mediator (IL-1 beta).
  • the primary bovine synovial fibroblasts were isolated from metacarpophalangeal joint and cultured in monolayer in a serum reduced (1%) medium DMEM/F:12. Inflammatory reaction was induced by 24 hour preincubation with IL- ⁇ (lng/ml). After preincubation, cell medium was replaced with different gel compositions (10 X diluted pure HA or HA with lecithin in serum reduced DMEM/F:12). After incubation of synovial fibroblasts with certain gel compositions (HA with lecithin- COMPOSITION 1 or pure HA- COMPOSITION 2) for 120 hour, experiment was finished and the culture medium was collected in order to quantify IL- ⁇ cytokine production level.
  • IL- ⁇ interieukin 1 ⁇
  • R&D Systems sandwich binding protein assay kit
  • Fig. 2 Interleukin 1 ⁇ concentration. Inducer of inflammation promoted substantial increase in IL- ⁇ production by synovial fibroblasts. Presence COMPOSITION 1 (HA with lecithin) reduced IL- ⁇ production more potently than presence of COMPOSITION 2 (HA alone).
  • composition Fig.2- HA with lecithin- COMPOSITION 1
  • Composition without lecithin Fig.l- HA alone- COMPOSITION 2
  • Obtained result are independent from the effect of the exogenous interleukin added initially to induce the inflammatory state.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Immunology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biophysics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cosmetics (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'objet de l'invention est une nouvelle composition constituée d'un acide hyaluronique, de phospholipides et/ou de composés de silicium solubles destinée à être utilisée dans un système tampon. L'invention a également pour objet l'utilisation de compositions pour le traitement de la douleur articulaire, de lésions articulaires/tendineuses, de l'arthrite comprenant la polyarthrite rhumatoïde (RA), et en tant qu'inducteur de collagène, charge cosmétique.
PCT/PL2018/000028 2017-03-20 2018-03-20 Composition sous forme de gel WO2018182436A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PLP.420907 2017-03-20
PL420907A PL235088B1 (pl) 2017-03-20 2017-03-20 Kompozycja w postaci żelu zawierająca kwas hialuronowy

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WO2018182436A2 true WO2018182436A2 (fr) 2018-10-04
WO2018182436A3 WO2018182436A3 (fr) 2018-12-20

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021121566A1 (fr) * 2019-12-17 2021-06-24 Aa Healthcare Sàrl Utilisation d'une composition comprenant de la silice organique pour l'amélioration de la qualité de tissus cartilagineux

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2496121C (fr) * 2002-08-16 2010-03-30 Yoshiaki Miyata Formulations stables d'acide hyaluronique pour le traitement therapeutique des arthropathies
US9216164B2 (en) * 2009-07-23 2015-12-22 U.S. Nutraceuticals, LLC Composition and method to alleviate joint pain using a mixture of fish oil and fish oil derived, choline based, phospholipid bound fatty acid mixture including polyunsaturated EPA and DHA
RU2473352C2 (ru) * 2011-04-21 2013-01-27 Закрытое акционерное общество "Институт прикладной нанотехнологии" Состав, имитирующий внутрисуставную жидкость, и способ получения добавки к ней
US10646574B2 (en) * 2014-07-21 2020-05-12 Board Of Regents, The University Of Texas System Formulations of intraarticular pharmaceutical agents and methods for preparing and using the same

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021121566A1 (fr) * 2019-12-17 2021-06-24 Aa Healthcare Sàrl Utilisation d'une composition comprenant de la silice organique pour l'amélioration de la qualité de tissus cartilagineux

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Publication number Publication date
WO2018182436A3 (fr) 2018-12-20
PL420907A1 (pl) 2018-09-24
PL235088B1 (pl) 2020-05-18

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