WO2013076162A1 - Formulations utiles dans le traitement de maladies ostéoarticulaires - Google Patents

Formulations utiles dans le traitement de maladies ostéoarticulaires Download PDF

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WO2013076162A1
WO2013076162A1 PCT/EP2012/073268 EP2012073268W WO2013076162A1 WO 2013076162 A1 WO2013076162 A1 WO 2013076162A1 EP 2012073268 W EP2012073268 W EP 2012073268W WO 2013076162 A1 WO2013076162 A1 WO 2013076162A1
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gel
formulation
formulations
forming formulation
glycosaminoglycan
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Karim Amighi
Jonathan RÉEFF
Jonathan Goole
Carine DE VRIESE
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Universite Libre de Bruxelles ULB
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Universite Libre de Bruxelles ULB
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    • 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
    • A61K31/33—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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K9/0012—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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to sustained release formulations and related kits.
  • the present invention further relates to sustained release formulations for use in the treatment of osteoarticular diseases.
  • Osteoarthritis the most common form of arthritis, is a disease characterized by slow degenerative processes in the articular cartilage, subchondral bone associated with marginal osteophyte formation and low grade inflammation. Most cases of osteoarthritis are characterized by unknown causes and are referred as primary osteoarthritis. When the cause of the osteoarthritis is known, the condition is referred as secondary osteoarthritis. Secondary osteoarthritis is caused by another disease or environmental condition. Conditions that can lead to secondary osteoarthritis include repeated trauma or surgery to the joint structures, abnormal joints at birth (congenital abnormalities), gout, diabetes and other hormonal disorders. Other forms of arthritis are systemic illnesses such as rheumatoid arthritis and systemic lupus erythematosus (SLE).
  • SLE systemic illnesses
  • Osteoarthritis involves mainly the hips, knees, spine and the inter-phalangeal joints.
  • the most common symptom of osteoarthritis is pain in the affected joint(s) after repeated use. Pain and stiffness of the joints can also occur after a long period of inactivity.
  • complete loss of cartilage cushion causes friction between bones, causing pain at rest or pain with limited motion.
  • Glucocorticoids are used for intra-articular treatment of acute arthritic flares: the short-term benefit of intra-articular corticosteroids in mono-arthritis flare is well established, but its longer term benefits have not been confirmed yet.
  • Glucocorticoids are thought to be responsible for accelerating cartilage damage by inducing osteonecrosis or increasing the risk of septic arthritis (Bellamy et al., 2006, Cochrane Database Syst. Rev, Apr 19; (2):CD005328). Due to their toxicity, injectable corticosteroids can only be administered a few times, which leads, in absence of alternative, to early surgical intervention. Intra-articular injection of hyaluronic acid of high molecular weight is effective for restoring the mechanical integrity of the joint. Nevertheless, due to a high enzymatic activity in inflammatory joints, the half-life of the glycosaminoglycan such as hyaluronic acid after injection into the joint is only about 6 to 8 hours.
  • compositions for the sustained delivery of glycosaminoglycans have been described. For instance, mono-injections of hyaluronic acid stabilized by chemical modification are commercially available and have been suggested to have an increased residence time in the joint.
  • WO 2006/071694 discloses a visco-supplement composition comprising a biodegradable polymer, a solvent, a visco-supplement such as particularly hyaluronic acid or a salt thereof, and a surfactant and further provides a method of ameliorating the symptoms of osteoarthritis in a patient, comprising injecting the composition into an afflicted joint of the patient.
  • WO 03/000190 describes a composition useful for the treatment of arthritic joints comprising at least one glycosaminoglycan, at least part of which are encapsulated in at least one liposome.
  • the present inventors have found through extensive testing a formulation addressing one or more of the above-mentioned problems of the prior art.
  • a first aspect relates to a gel-forming formulation comprising a glycosaminoglycan and a monoglyceride.
  • a formulation applying the principles of the invention displays advantageously enhanced gel-formation upon contact of the formulation with an aqueous liquid such as physiological or bodily fluids, for example synovial fluid.
  • Such a formulation further allows to prolong the release of the glycosaminoglycan for example in a joint, advantageously over a few weeks.
  • the present gel-forming formulation is a thermodynamically stable one phase formulation. Because of the regular structure, the present formulation provides a highly reproducible sustained release system contrary to solutions involving biopolymers, polymers or formulations based on liposomes.
  • the present formulation protects the glycosaminoglycan from the physical environment, thereby improving its stability in vivo.
  • the inventors indeed found that the present formulation provides a protection of the glycosaminoglycan against enzymatic degradation.
  • a method for producing the present formulation comprising combining the glycosaminoglycan and the monoglyceride.
  • the formulation may additionally comprise one or more pharmaceutically acceptable excipients (e.g., solvents, carriers, diluents, etc.), preferably excipients compatible with the intended mode of administration of the formulation, such as in particular parenteral and preferably intra-osseous or intra-articular administration of the formulation.
  • excipients e.g., solvents, carriers, diluents, etc.
  • excipients compatible with the intended mode of administration of the formulation such as in particular parenteral and preferably intra-osseous or intra-articular administration of the formulation.
  • compositions Any formulations disclosed herein that are configured for use in medicine, whether or not comprising one or more pharmaceutically acceptable excipients in addition to the other herein recited elements, may be denoted by as pharmaceutical formulations or pharmaceutical compositions.
  • kit of parts comprising a glycosaminoglycan and a monoglyceride, wherein the glycosaminoglycan and the monoglyceride are configured to allow for producing (forming or obtaining) any one of the formulations as taught herein.
  • a method for producing said kit of parts comprising including the glycosaminoglycan and the monoglyceride in a kit of parts.
  • kit of parts comprising the above formulation.
  • a kit of parts comprising a gel-forming formulation comprising a glycosaminoglycan and a monoglyceride.
  • a method for producing said kit of parts comprising including the gel-forming formulation in a kit of parts.
  • a further aspect provides a medical device comprising any one of the gel-forming formulations or the kits of parts as taught herein.
  • a medical device comprising a gel-forming formulation comprising a glycosaminoglycan and a monoglyceride.
  • Such medical device advantageously allows for parenteral administration, such as intra-osseous or intra-articular administration, of the formulation or kit of parts to a subject in need thereof.
  • the glycosaminoglycan is protected from its environment, and particularly from glycosaminoglycan-degrading enzymes, thereby improving the stability of the glycosaminoglycan in vivo when the formulation is administered to a subject, compared to glycosaminoglycan administered not in combination with a monoglyceride.
  • Another aspect thus provides use of any one of the gel-forming formulations or kits of parts as disclosed herein as a protectant against a glycosaminoglycanase.
  • a gel-forming formulation comprising a glycosaminoglycan and a monoglyceride as a protectant against a glycosaminoglycanase.
  • a related aspect provides any one of the gel-forming formulations or kits of parts as disclosed herein for use as a protectant against a glycosaminoglycanase. Further provided is any one of the gel-forming formulations or kits of parts as disclosed herein for use as a protectant of a glycosaminoglycan against a glycosaminoglycanase.
  • Another related aspect provides a method for protecting a glycosaminoglycan against a glycosaminoglycanase comprising formulating the glycosaminoglycan in a gel-forming formulation comprising the glycosaminoglycan and a monoglyceride.
  • a monoglyceride for protecting a glycosaminoglycan against a glycosaminoglycanase, wherein the glycosaminoglycan and the monoglyceride are formulated in any one of the gel- forming formulations or kits of parts as described herein.
  • a related aspect provides a monoglyceride for use as a protectant of a glycosaminoglycan against a glycosaminoglycanase, wherein the glycosaminoglycan and the monoglyceride are formulated in any one of the gel-forming formulations or kits of parts as disclosed herein.
  • the formulation or the monoglyceride may advantageously but without limitation act as a protectant against a glycosaminoglycanase particularly for the glycosaminoglycan contained in the formulations.
  • said glycosaminoglycanase may be preferably selected from a group consisting of a hyaluronidase, chondroitin B lyase, proteoglycanase, keratanase, chitosanase and chitinase.
  • the formulation or the kit of parts embodying the principles of the invention comprise hyaluronic acid
  • the formulation or the kit of parts may provide for protection of the hyaluronic acid from hyaluronidase.
  • a further aspect provides any one of the gel-forming formulations or kits of parts as taught herein for use as a medicament, preferably for use in the treatment (including throughout the present specification therapeutic and/or preventative measures) of osteoarticular diseases, including acute or chronic osteoarticular diseases, such as preferably but without limitation osteoarthritis, rheumatoid arthritis, mono-arthritis and poly-arthritis, preferably by intra-osseous or intra-articular injection.
  • osteoarticular diseases including acute or chronic osteoarticular diseases, such as preferably but without limitation osteoarthritis, rheumatoid arthritis, mono-arthritis and poly-arthritis, preferably by intra-osseous or intra-articular injection.
  • a gel-forming formulation comprising a glycosaminoglycan and monoglyceride for use in the treatment of acute or chronic osteoarticular diseases such as preferably osteoarthritis, rheumatoid arthritis, mono-arthritis and poly-arthritis, preferably by intra-osseous or intra-articular injection.
  • osteoarticular diseases such as preferably osteoarthritis, rheumatoid arthritis, mono-arthritis and poly-arthritis, preferably by intra-osseous or intra-articular injection.
  • the use of the formulations of the present invention in the treatment of osteoarticular diseases is advantageous because these formulations allow efficient treatment during longer periods due to the extended release of the glycosaminoglycan.
  • the present formulations allow to improve the articular function by their extended lubricating action on the joint.
  • the present formulations can also restore at least partly the mechanical integrity of the joint.
  • the present formulations advantageously allow to obtain an improved therapeutic effect with fewer injections and thus provide increased patient compliance.
  • a related aspect thus provides the use of any one of the formulations or kits of parts as taught herein for the manufacture of a medicament for the treatment of osteoarticular diseases, including acute or chronic osteoarticular diseases, such as preferably but without limitation osteoarthritis, rheumatoid arthritis, mono-arthritis and poly-arthritis.
  • osteoarticular diseases including acute or chronic osteoarticular diseases, such as preferably but without limitation osteoarthritis, rheumatoid arthritis, mono-arthritis and poly-arthritis.
  • a glycosaminoglycan and a monoglyceride for the manufacture of a gel-forming formulation for the treatment of osteoarticular diseases, including acute or chronic osteoarticular diseases such as preferably osteoarthritis, rheumatoid arthritis, mono-arthritis and poly-arthritis.
  • Such treatment may typically involve parenteral administration, more preferably intra-osseous or intra-articular administration (injection) of the formulation.
  • osteoarticular diseases including acute or chronic osteoarticular diseases, in a subject in need of such treatment, comprising administering to said subject a therapeutically or prophylactically effective amount of any one of the formulations or kits of parts as taught herein.
  • a method for treating osteoarticular diseases, including acute or chronic osteoarticular diseases, in a subject in need of such treatment comprising administering to said subject a therapeutically or prophylactically effective amount of a gel- forming formulation comprising a glycosaminoglycan and a monoglyceride.
  • Such method of treatment may typically involve parenteral administration, more preferably intraosseous or intra-articular administration (injection) of the formulation.
  • the formulations of the present invention are gel-forming formulations.
  • gel-forming means gel-forming formulations.
  • the terms "gel- forming”, “one phase” or “monophasic” can be used interchangeably herein.
  • the recitation "gel-forming formulation” as intended throughout this specification refers to the capacity of the formulation to form a solid, jelly-like material (gel) for instance with a pseudoplastic behaviour.
  • a gel- forming formulation forms a gel when combined with or exposed to materials and/or conditions conducive to gel formation, for example but without limitation, when dissolved or dispersed in a suitable liquid phase, such as in an aqueous solution or dispersion.
  • the formulations as taught herein are not liposome-based, i.e., the glycosaminoglycan is substantially not, or is not, encapsulated within lipid bilayer liposomes or microspheres.
  • Such non-liposome-based formulations are thus not subjected to a procedure or treatment intended to stimulate the formation of liposomes or microspheres such as typically sonication.
  • the present formulations may be solutions, which is particularly advantageous for parenteral and more preferably intra-osseous or intra-articular administration of the formulations.
  • the present formulations may be configured for parenteral administration, such as parenteral injection. More preferably, the present formulations may be configured for intra-articular administration, such as intra-articular injection. Further preferred, the present formulations may be configured for intra-osseous administration, such as intra-osseous injection.
  • the formulations as intended herein may consist of a solution or lamellar phase outside the body.
  • the present formulations comprising a combination of a monoglyceride such as glycerol monooleate with a glycosaminoglycan are characterized by a low viscosity, whereby they can be easily administered such as for example injected in the joint.
  • the formulations of the present invention can be converted into the cubic state as soon as the ambient water increases after parenteral administration such as for example after intra-osseous or intraarticular injection. Thereby, the viscosity of the present formulations may increase in situ.
  • the formulations of the invention thus advantageously reach a suitable viscosity in vivo, leading to optimal release of the glucosamine and other advantages as described herein.
  • the gel-forming formulations taught herein comprise a glycosaminoglycan and a monoglyceride.
  • the terms “monoglyceride” and “monoacylglycerol”, as used herein, can be used interchangeably.
  • the monoglyceride can be a 1 -monoacylglycerol or a 2-monoacylglycerol depending on the position of the ester bond on the glycerol moiety.
  • Non-limiting examples of monoglycerides are for instance glycerol mono(o)leate (GMO), glycerol monolinoleate, glycerol monolinolenate, glycerol monopalmitate, glycerol monostearate and glycerol monolaurate.
  • GMO glycerol mono(o)leate
  • glycerol monolinoleate glycerol monolinolenate
  • glycerol monopalmitate glycerol monostearate
  • glycerol monolaurate glycerol mono(o)leate
  • the monoglyceride allows gel formation of the formulation upon contact of said formulation with an aqueous liquid such as physiological or bodily fluids, providing for advantages as discussed herein.
  • the monoglyceride performs or acts as a gel-forming agent.
  • gel-forming agent encompasses agents capable of forming, a solid, jelly-like material (gel).
  • gel-forming agents form a gel when combined with or exposed to materials and/or conditions conducive to gel formation, for example but without limitation, when dissolved or dispersed in a suitable liquid phase, such as in an aqueous solution or dispersion.
  • the present formulations can comprise the monoglyceride in a concentration ranging between 5 and 85% by weight (w/w).
  • the formulations can comprise the monoglyceride in a concentration ranging between 35 and 75% by weight (w/w), for example between 40 and 70% by weight (w/w), for example between 45 and 65% by weight (w/w), for example, ranging between 50 and 60% by weight (w/w).
  • the formulations as taught herein can comprise the monoglyceride in a concentration ranging between 45 and 65% by weight (w/w).
  • the monoglyceride may be an ester of glycerol and oleic acid.
  • oleic acid refers to a monounsaturated omega-9 fatty acid, more particularly (9Z)-Octadec-9- enoic acid also known as cis-9-Octadecenoic acid or 18: 1 cis-9.
  • Particularly preferred monoglyceride is glycerol monooleate, also commonly denoted as glycerol monoleate, mono(o)lein, glyceryl monooleate, glyceryl oleate, (Z)-l-oleoyl-sn-glycerol, or 1,2,3-propanetriol 9-octadecenoic acid.
  • such formulations can comprise glycerol monooleate in a concentration ranging between 5 and 85% by weight (w/w).
  • the formulations can comprise said glycerol monooleate in a concentration ranging between 35 and 75% by weight (w/w), for example between 40 and 70% by weight (w/w), for example between 45 and 65% by weight (w/w), for example between 50 and 60% by weight (w/w).
  • the formulations can comprise said glycerol monooleate in a concentration ranging between 45 and 65% by weight (w/w).
  • the combination of a monoglyceride, more preferably glycerol monooleate, with a glycosaminoglycan can advantageously allow to increase the sustained release of the glycosaminoglycan by amplification of the gel-forming process in situ.
  • a monoglyceride, more preferably glycerol monooleate, with a glycosaminoglycan allows or enhances gel-formation of the formulation upon contact of the formulation with an aqueous liquid such as physiological or bodily fluids.
  • formulations embodying the principles of the invention comprising a combination of a monoglyceride, more preferably glycerol monooleate, with a glycosaminoglycan ensure a prolonged release of the glycosaminoglycan over an extended period of time.
  • any one of the gel-forming formulations or kits of parts as disclosed herein as a sustained release formulation.
  • a gel- forming formulation comprising a glycosaminoglycan and a monoglyceride as a sustained release formulation.
  • any one of the gel- forming formulations or kits of parts as disclosed herein for sustaining or prolonging the release of a glycosaminoglycan from the formulation.
  • a related aspect provides any one of the gel-forming formulations or kits of parts as disclosed herein for use as a sustained release formulation.
  • any one of the gel- forming formulations or kits of parts as disclosed herein for use in sustaining the release of a glycosaminoglycan from the formulation.
  • Another related aspect provides a method for sustaining the release of a glycosaminoglycan comprising formulating the glycosaminoglycan in a gel- forming formulation comprising the glycosaminoglycan and a monoglyceride.
  • a monoglyceride for sustaining the release of a glycosaminoglycan, wherein the glycosaminoglycan and the monoglyceride are formulated in any one of the gel-forming formulations or kits of parts as described herein.
  • a related aspect provides a monoglyceride for use in sustaining the release of a glycosaminoglycan, wherein the glycosaminoglycan and the monoglyceride are formulated in any one of the gel-forming formulations or kits of parts as disclosed herein.
  • the formulation or the kit of parts embodying the principles of the invention comprises hyaluronic acid
  • the formulation or the kit of parts may provide for sustaining the release of the hyaluronic acid.
  • the gel-forming formulations taught herein comprise a glycosaminoglycan and a monoglyceride.
  • the glycosaminoglycan may be selected from the group consisting of hyaluronic acid and derivatives thereof, a proteoglycan and derivatives thereof, a chondroitin sulfate, a keratan sulfate, a chitosan and derivatives thereof, a chitin and derivatives thereof.
  • the present formulations may comprise one or more gycosaminoglycans.
  • the present formulations may thus comprise one glycosaminoglycan or a mixture of glycosaminoglycans selected from the group consisting of hyaluronic acid and derivatives thereof, a proteoglycan and derivatives thereof, a chondroitin sulfate, a keratan sulfate, a chitosan and derivatives thereof, a chitin and derivatives thereof.
  • hyaluronic acid or “HA” may be used interchangeably with “hyaluronan” or “hyaluronate”.
  • hyaluronic acid refers to an anionic, non-sulfated polymer of disaccharides composed of D-glucuronic acid and N-acetyl-D-glucosamine, linked via alternating ⁇ -1,4 and ⁇ -1,3 glycosidic bonds.
  • Hyaluronic acid derivatives include but are not limited to salts of hyaluronate such as sodium hyaluronate or an ester of hyaluronic acid with an alcohol of the aliphatic, heterocyclic or cycloaliphatic series, or a sulphated form of hyaluronic acid or combination of agents comprising hyaluronic acid.
  • proteoglycan refers to proteins with one or more covalently attached glycosaminoglycan (GAG) chain(s).
  • GAG glycosaminoglycan
  • the glycosaminoglycan can be a proteoglycan selected from decorin, biglycan, testican, fibromodulin, lumican, versican, perlecan, neurocan or aggrecan.
  • chondroitin sulfate refers to a polymer of disaccharides composed of N- acetylgalactosamine and glucuronic acid, each of which can be sulfated in variable positions and quantities.
  • the chondroitic sulfate can be selected from chondroitin-4-sulfate, chondroitin-6-sulfate, chondroitin-2,6-sulfate, chondroitin-4,6-sulfate.
  • keratan sulfate may be used interchangeably with “keratosulfate” and refers to a polymer of repeating disaccharides -3Gai i-4GlcNAc i- which can be sulfated at carbon position 6 (C6) of either or both the Gal or GlcNAc monosaccharides.
  • chitosan refers to a linear polymer composed of randomly distributed -(l-4)-linked D- glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit).
  • chitin refers to a polymer composed of P-(l,4)-linked N-acetylglucosamine.
  • glycosaminoglycans used in accordance with the invention are known and commercially available.
  • the glycosaminoglycan can be employed in a therapeutically effective amount.
  • the present formulations can comprise the glycosaminoglycan in a concentration ranging between 0.1 and 15% by weight (w/w).
  • the formulations can comprise the glycosaminoglycan in a concentration ranging between 0.5 and 10% by weight (w/w), for example between 0.6 and 7.5%) by weight (w/w), for example between 0.7 and 5.0% by weight (w/w), for example between 0.7 and 2.5% by weight (w/w), for example between 0.7 and 2.0% by weight (w/w), for example, the formulations can comprise the glycosaminoglycan in a concentration ranging between 0.7 and 1.0% by weight.
  • the formulations can comprise the glycosaminoglycan in a concentration ranging between 0.7 and 1.5% by weight (w/w). More preferably, the formulations can comprise the glycosaminoglycan in a concentration of 0.75% by weight (w/w).
  • the glycosaminoglycan is hyaluronic acid or a derivative thereof.
  • suitable derivatives may be salts of hyaluronic acid, such as preferably sodium hyaluronate.
  • the hyaluronic acid or derivative thereof can have a low ( ⁇ 900 kDa) or high (> 900 kDa) molecular mass.
  • Particularly preferred glycosaminoglycans are hyaluronic acid or derivatives thereof with high (> 900 kDa) molecular mass.
  • the glycosaminoglycan can be for instance but is not limited to sodium hyaluronate characterized by a high molecular weight of about 1.9 MDa.
  • the formulations can comprise the hyaluronic acid or derivative thereof in a concentration ranging between 0.1 and 15% by weight (w/w).
  • the formulations can comprise the hyaluronic acid or derivative thereof in a concentration ranging between 0.5 and 10%) by weight (w/w), for example between 0.6 and 7.5% by weight (w/w), for example between 0.7 and 5.0% by weight (w/w), for example between 0.7 and 2.5% by weight (w/w), for example between 0.7 and 2.0%) by weight (w/w), for example, the formulations can comprise the hyaluronic acid or a derivative thereof in a concentration ranging between 0.7 and 1.0% by weight (w/w).
  • the formulations as taught herein can comprise the hyaluronic acid or derivative thereof in a concentration ranging between 0.7 and 1.5% by weight (w/w).
  • the formulations embodying the principles of the invention comprising the monoglyceride such as preferably glycerol monooleate and the glycosaminoglycan such as preferably sodium hyaluronate advantageously provide a highly reproducible sustained release system.
  • Prior art formulations comprising biopolymers such as for instance suspensions, emulsions or vesicles are thermodynamically unstable and typically consist of at least two phases.
  • the present formulations can differ from these in that the present formulations are thermodynamically stable one phase or gel-forming formulations providing sustained release of the glycosaminoglycan over an extended period of time.
  • the present formulations allow to protect the glycosaminoglycan from the physical environment, thereby improving the stability of the glycosaminoglycan in vivo, such as but without limitation through protecting the glycosaminoglycan against enzymatic degradation.
  • the formulations according to the present invention further advantageously have mechanical and/or rheological properties close to healthy synovial fluid.
  • the formulations therefore allow to improve the articular function by their lubricating action on the joint.
  • the glycosaminoglycan is sodium hyaluronan and the monoglyceride is glycerol monooleate.
  • such formulations can comprise sodium hyaluronan in a concentration ranging between 0.5 and 15% by weight (w/w) and glycerol monooleate in a concentration ranging between 5 and 85%> by weight (w/w).
  • the formulations can comprise sodium hyaluronan in a concentration ranging between 0.7 and 1.5% by weight (w/w) and glycerol monooleate in a concentration ranging between 45 and 65% by weight (w/w).
  • the formulations as disclosed herein may further comprise one or more excipients selected from a solvent, a vegetable oil and an antioxidant.
  • the present formulations may further comprise one or more solvents.
  • solvents may be polar solvents, more preferably protic solvents.
  • protic solvent generally refers to a solvent which has a dissociable hydrogen, for instance, a solvent that has a hydrogen atom bound to an oxygen such as in a hydroxyl group or to a nitrogen such as in an amine group.
  • the one or more solvents may be selected from water, ethanol, glycerol, ethylene glycol and/or propylene glycol.
  • the one or more solvents may be selected from water, ethanol or propylene glycol.
  • the formulation may comprise water, ethanol and propylene glycol.
  • the one or more solvents may allow the optimization of the viscosity of the present formulations.
  • the one or more solvents may allow the sterilization of the lipidic phase of the formulations by filtration.
  • such formulations may comprise ethanol in a concentration ranging between 0 and 95% by weight (w/w).
  • the formulations can comprise ethanol in a concentration ranging between 0 and 20% by weight (w/w), for example, between 5%> and 15%> by weight.
  • the formulations can comprise ethanol in a concentration ranging between 5 and 10%) by weight (w/w).
  • the formulations may comprise propylene glycol in a concentration ranging between 0 and 95% by weight (w/w).
  • the formulations can comprise propylene glycol in a concentration ranging between 0 and 40% by weight (w/w), for example, between 5 and 20% by weight (w/w), for example between 10 and 17.5 %> by weight (w/w).
  • the formulations can comprise propylene glycol in a concentration ranging between 5 to 15%) by weight (w/w).
  • the formulations may comprise water in a concentration ranging between 0 and 50% by weight (w/w).
  • the formulations can comprise water in a concentration ranging between 5 to 25% by weight (w/w).
  • the present formulation can comprise ethanol, propylene glycol and water as solvents, more preferably may comprise ethanol in a concentration of 10%> by weight (w/w), propylene glycol in a concentration of 15%> by weight (w/w) and water in a concentration of 15%> by weight (w/w).
  • the present formulations may further comprise one or more oils.
  • the oil may be a vegetable oil, a mineral oil or an organic oil.
  • vegetable oil as used herein may encompass any lipid material derived from plants. Suitable non-limiting examples of vegetable oils which can be added to the present formulation are for instance coconut oil, corn oil, cottonseed oil, olive oil, palm oil, peanut oil (Ground nut oil), rapeseed oil, safflower oil, sesame oil, soybean oil, sunflower oil or nut oil.
  • mineral oil as used herein may encompass any lipid material derived from a mineral (non- vegetable) source, particularly a distillate of petroleum.
  • a suitable non-limiting example of a mineral oil which can be added to the present formulation is for instance paraffin oil.
  • organic oil as used herein may encompass any lipid material produced by plants, animals, or other organisms through natural metabolic processes.
  • the oil may allow to induce a decrease in the water uptake of the formulations.
  • the oil may further prolong the sustained release of the glycosaminoglycan from the formulations.
  • the formulations may further comprise one or more vegetable oils.
  • the formulations can comprise the vegetable oil in a concentration ranging between 0 and 95% by weight (w/w).
  • the formulations can comprise the vegetable oil in a concentration ranging between 0 and 10%) by weight (w/w), for example, the formulations can comprise the vegetable oil in a concentration ranging between 2.5 and 7.5% by weight (w/w).
  • the formulations can comprise the vegetable oil in a concentration ranging between 2.5 and 5% by weight (w/w).
  • the formulations as described herein may comprise soybean oil as a vegetable oil.
  • the present formulations may preferably comprise soybean oil in a concentration ranging between 0 and 95% by weight (w/w).
  • the formulation can comprise soybean oil in a concentration ranging between 0 and 10%> by weight (w/w), for example, the present formulations can comprise soybean oil in a concentration ranging between 2.5 and 7.5% by weight (w/w).
  • the present formulations can comprise soybean oil in a concentration ranging between 2.5 and 5% by weight (w/w).
  • the present formulations may further comprise one or more antioxidants.
  • antioxidant as used herein may encompass any molecule capable of inhibiting the oxidation of other molecules thereby preventing the production of free radicals.
  • Suitable non-limiting examples of antioxidants which can be added to the present formulation are for instance ascorbic acid (vitamin C), polyphenols, sulfites, sodium metabisulphite and tocopherols.
  • antioxidants included in such formulations may be those approved for parenteral administration such as for intra-osseous or intra-articular administration.
  • the formulations can comprise the antioxidant in a concentration ranging between 0 and 3% by weight (w/w).
  • the present formulations can comprise the antioxidant in a concentration ranging between 0.01 and 1% by weight (w/w), for example, the present formulations can comprise the antioxidant in a concentration ranging between 0.1 and 0.6% by weight (w/w).
  • the present formulations can comprise the antioxidant in a concentration ranging between 0.1 and 0.3% by weight (w/w).
  • the present formulations can comprise the antioxidant in a concentration ranging between 0.01 and 0.6% by weight (w/w).
  • the present formulations can comprise the antioxidant in a concentration ranging between 0.01 and 0.06% by weight (w/w), such as, e.g., 0.02% w/w, 0.03% w/w, 0.04% w/w, or 0.05% w/w.
  • the antioxidant may prevent oxidation of the lipidic compounds present in the formulations.
  • the present formulations may comprise alpha-tocopherol acetate as an antioxidant.
  • the formulations can comprise alpha-tocopherol acetate in a concentration ranging between 0 and 3% by weight (w/w).
  • the formulations can comprise alpha-tocopherol acetate in a concentration ranging between 0.01 and 1% by weight (w/w), for example, the formulations can comprise alpha-tocopherol acetate in a concentration ranging between 0.1 and 0.6% by weight (w/w).
  • the formulation can comprise alpha-tocopherol acetate in a concentration ranging between 0.1 and 0.3% by weight (w/w).
  • the present formulations can comprise alpha-tocopherol acetate in a concentration ranging between 0.01 and 0.6% by weight (w/w).
  • the present formulations can comprise alpha-tocopherol acetate in a concentration ranging between 0.01 and 0.06% by weight (w/w), such as, e.g., 0.02% w/w, 0.03% w/w, 0.04% w/w, or 0.05% w/w.
  • the formulations may have a pH ranging from 6.0 to 7.0. Such a pH advantageously improves or maintains the stability of the glycosaminoglycan, such as sodium hyaluronate, in the formulations, for instance, during storage at temperatures equal to or above room temperature.
  • the formulations may have a pH ranging from 6.2 to 6.8.
  • the present formulations may have a pH of 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, or 6.8.
  • the present formulations have a pH of 6.5.
  • adjusting the pH of formulations illustrating the present invention to the aforementioned values, such as in particular to 6.5, advantageously maintained the rheological properties of the formulation at least after 1 month of storage, for example after 3 months, for example after 6 months, for example after 12 months (1 year) of storage at a temperature above room temperature such as at 25 °C or 30°C.
  • the pH of the formulation may be adjusted to the desired pH during the preparation of the formulation.
  • the pH of the formulation may be adjusted after dissolution of its constituting components.
  • the pH of the present formulations may be adjusted to the desired pH as known in the art.
  • the pH of the present formulations is adjusted with a base, such as preferably with an alkali hydroxide, more preferably with NaOH.
  • Figure 1 represents a graph illustrating the water uptake of different formulations illustrating the invention in function of time.
  • Figure 3 represents a graph illustrating the chromatograms obtained by gel permeation chromatography (GPC) analysis showing the rate of degradation by 2 Ul/ml of ovine hyaluronidase of a solution of 1 mg/ml of sodium hyaluronate at pH 7 and 37°C.
  • GPC gel permeation chromatography
  • Figure 5 represents a graph illustrating the chromatograms obtained by gel permeation chromatography (GPC) analysis showing the protection of sodium hyaluronan against degradation by 2 Ul/ml of ovine hyaluronidase at pH 7 and 37°C of a solution of 1 mg/ml of sodium hyaluronate and of a formulation illustrating the invention (gel).
  • GPC gel permeation chromatography
  • Figure 6 represents an agarose gel illustrating release of hyaluronic acid from (1) a hyaluronic acid standard, (2) 0.5 mg/ml hyaluronic acid after incubation in cell culture medium with serum at day 0, (3) 0.5 mg/ml hyaluronic acid after incubation in cell culture medium with serum at day 21, and (4) a formulation illustrating the invention at day 0, (5) at day 7, (6) at day 14 and (7) at day 21.
  • the term "one or more”, such as one or more members of a group of members, is clear per se, by means of further exemplification, the term encompasses inter alia a reference to any one of said members, or to any two or more of said members, such as, e.g., any >3, >4, >5, >6 or >7 etc. of said members, and up to all said members.
  • the invention broadly relates to a gel-forming formulation comprising a glycosaminoglycan and a monoglyceride, as well as to related kits, uses and methods.
  • the glycosaminoglycan can be conveniently considered to represent a therapeutically active principle, i.e., an active ingredient.
  • the term "active ingredient” broadly refers to a compound, substance or component which, when provided in an effective amount, achieves a desired therapeutic and/or prophylactic outcome(s).
  • an active ingredient may achieve such outcome(s) through interacting with and/or modulating living cells or organisms.
  • the gel- forming formulation comprises a glycosaminoglycan (i.e., one or more glycosaminoglycans) as an active ingredient and further comprises one or more other active ingredients.
  • a glycosaminoglycan i.e., one or more glycosaminoglycans
  • the glycosaminoglycan i.e., one or more glycosaminoglycans
  • the present formulations advantageously allow sustained release of the active ingredient following parenteral administration, for instance following injection of the formulation to a damaged and/or inflamed joint.
  • sustained release or “prolonged release” as used herein broadly refer to the release of a compound from a formulation over an extended, prolonged or increased period of time compared with the release of said compound from a reference formulation such as a formulation know in the prior art.
  • the sustained release refers to the prolonged release of a glycosaminoglycan from the present formulations. For instance, it is know from the prior art that the half-life of high molecular weight hyaluronic acid in the joint is about 6 to 8 hours.
  • the sustained release thus refers to the extended release of a glycosaminoglycan such as hyaluronic acid from the present formulations, for example release during one or more days, such as during 2 days, 3 days, 4 days, 5 days, 6 days, or during one or more weeks such as during 1.5 week, 2 weeks, 3 weeks, or during one or more months. These terms may thus also specifically encompass extended release, delayed release or controlled release.
  • the present formulations are suitable for use as a protectant against a glycosaminoglycanase.
  • protecting refers to the ability to provide or afford protection of one or more compounds of a formulation against degradation or inactivation.
  • sustained protection broadly refer to the protection of a compound of a formulation against degradation or inactivation over an extended, prolonged or increased period of time compared with the protection of said compound in a reference formulation such as a formulation know in the prior art.
  • the formulation of the invention can be a pharmaceutical formulation. Accordingly, the invention encompasses pharmaceutical formulations as taught herein.
  • a pharmaceutical formulation may comprise in addition to the herein particularly specified components one or more pharmaceutically acceptable excipients. Suitable pharmaceutical excipients depend on the dosage form and identities of the active ingredients and can be selected by the skilled person (e.g. by reference to the Handbook of Pharmaceutical Excipients 6 th Edition 2009, eds. Rowe et al.).
  • carrier or “excipient” includes any and all solvents, diluents, buffers (such as, e.g., neutral buffered saline or phosphate buffered saline), solubilisers, colloids, dispersion media, vehicles, fillers, chelating agents (such as, e.g., EDTA or glutathione), amino acids (such as, e.g., glycine), proteins, disintegrants, binders, lubricants, wetting agents, emulsifiers, sweeteners, colorants, flavourings, aromatisers, thickeners, agents for achieving a depot effect, coatings, antifungal agents, preservatives, stabilisers, antioxidants, tonicity controlling agents, absorption delaying agents, and the like.
  • buffers such as, e.g., neutral buffered saline or phosphate buffered saline
  • solubilisers colloids
  • dispersion media vehicles
  • compositions may be in the form of a parenterally acceptable aqueous solution, which is pyrogen- free and has suitable pH, isotonicity and stability.
  • the formulations may comprise pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, preservatives, complexing agents, tonicity adjusting agents, wetting agents and the like, for example, sodium acetate, sodium lactate, sodium phosphate, sodium hydroxide, hydrogen chloride, benzyl alcohol, parabens, EDTA, sodium oleate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, etc.
  • the pH value of the formulation is in the physiological pH range, such as particularly the pH of the formulation is between about 5 and about 9.5, more preferably between about 6 and about 8.5, even more preferably between about 7 and about 7.5.
  • the preparation of such pharmaceutical formulations is within the ordinary skill of a person skilled in the art.
  • Another aspect of the invention provides a kit of parts comprising the formulations as defined herein.
  • a further aspect provides a medical device comprising any one of the formulations or kits of parts as taught herein.
  • a medical device comprising a gel-forming formulation comprising a glycosaminoglycan and a monoglyceride.
  • kits of parts comprising a surgical instrument or medical device for administration of any one of the formulations or kits of parts as taught herein to a subject, such as for example systemically or locally, for example at a site of osteoarticuar disease, for example, by injection, and further comprising the formulation or kit of parts as taught herein.
  • such arrangement or kit of parts may comprise a vial with any one of the formulations as taught herein, a medical device for delivering the formulation to an inflamed joint of a mammal subject and having reservoir means for storing the formulation, piston means movable along the longitudinal axis of the reservoir for dispensing the formulation, and a hollow needle mounted on said reservoir means for delivering the formulation to an inflamed and/or damaged joint of the mammal subject.
  • kits of parts comprising a vial with a gel-forming formulation comprising a glycosaminoglycan and a monoglyceride; a device for delivering the formulation to an inflamed and/or damaged joint of a mammal subject and having reservoir means for storing the formulation, piston means movable along the longitudinal axis of the reservoir for dispensing the formulation, - and an hollow needle mounted on said reservoir means for delivering the formulation to an inflamed and/or damaged joint of the mammal subject.
  • the formulations or kit of parts as taught herein may be configured for local administration.
  • the present formulations or kits of parts may be configured for parenteral administration i.e., including one or more of intra-osseous, intra-articular, intramuscular, subcutaneous, intravenous and intrasternal administration.
  • Intra-osseous administration or delivery generally refers to a method whereby a treatment is delivered, directly or indirectly, into the marrow of a bone.
  • Intra-articular administration or delivery generally refers to a method whereby a treatment is delivered, directly or indirectly, into the synovial capsule of an articulating joint.
  • formulations or kit of parts as taught herein display excellent characteristics such as gel- formation upon administration and sustained release of the active ingredient, which make said formulations or kit of parts suited for prophylactic or therapeutic use.
  • formulations or kit of parts as taught herein may be used for the treatment and/or prevention of osteoarticular diseases.
  • osteoarticular diseases as intended herein encompass bone diseases, articular diseases or combinations thereof.
  • osteoarticular diseases as intended herein encompass osteoporosis including focal osteoporosis, multifocal osteoporosis, primary osteoporosis or secondary osteoporosis; fracture; non-union fracture; delayed union fracture; malunion fracture; pseudarthrosis; osteonecrosis; bone cyst; bone defect; osteoarthritis; degenerative arthritis; gonarthrosis; coxarthrosis; rheumatoid arthritis; spondyloarthropathies, including ankylosing spondylitis, psoriatic arthritis, enteropathic arthropathy, undifferentiated spondyloarthritis, reactive arthritis; systemic lupus erythematosus and related syndromes; scleroderma and related disorders; Sjogren's Syndrome; systemic vasculitis, including Giant cell arteritis (Horton's disease), Takayasu's arteritis, polymyalgia rheumatica, ANCA-
  • the osteoarticular disease as intended herein may be selected from the group consisting of osteoarthritis, degenerative arthritis, gonarthrosis, coxarthrosis, and other inflammatory general conditions or symptoms in which joints are involved, such as systemic lupus erythematosus, spondyloarthropathies, polymyalgia rheumatica, ankylosing spondylitis, Reiter' s Syndrome, psoriatic arthropathy, enteropathic arthritis (related to inflammatory bowel disease such as haemorrhagic colitis and Crohn's disease), rheumatoid arthritis, neuropathic arthropathy, acute rheumatic fever, gout, chondrocalcinosis, calcium hydroxyapatite crystal deposition disease, and Lyme disease.
  • systemic lupus erythematosus spondyloarthropathies, polymyalgia rheumatica, ankylosing spondylitis
  • the osteoarticular disease as intended herein may be selected from the group consisting of osteoarthritis, rheumatoid arthritis, mono- arthritis and poly-arthritis.
  • the term “monoarthritis” generally refers to inflammation of one joint at a time.
  • the term “poly-arthritis” generally refers to any type of arthritis which involves at least five joints simultaneously.
  • Osteoarticular diseases treatable with the formulations of the present invention include chronic and acute osteoarticular diseases.
  • the term “chronic”, as used herein, refers to long-lasting pain.
  • the term “acute”, as used herein, refers to (often severe) pain for a short period of time.
  • the treatment may also be used to prevent or delay the osteoarticular disease.
  • the gel-forming formulations or kits of parts as taught herein, preferably for use as a medicament and more preferably for use in the treatment and/or prevention of osteoarticular diseases, wherein the gel-forming formulations or the kits of parts are to be administered parenterally.
  • the gel-forming formulations or the kits of parts are to be administered intra-osseously or intra-articularly.
  • the present gel-forming formulations or kits of parts may be administered by parenteral, more preferably intra-articular route.
  • the gel-forming formulations or kits of parts as taught herein, preferably for use as a medicament and more preferably for use in the treatment and/or prevention of osteoarticular diseases, wherein the gel-forming formulations or the kits of parts may be administered in the form of an injection.
  • the gel-forming formulation or the kits of parts are to be administered in the form of a parenteral injection, more preferably intra-osseous or intraarticular injection.
  • the present formulations and kits of parts advantageously allow local and hence effective treatment of the osteoarticular diseases.
  • the gel-forming formulations or kits of parts as taught herein preferably for use as a medicament and more preferably for use in the treatment and/or prevention of osteoarticular diseases, wherein the gel-forming formulations or the kits of parts may be administered twice a month, once a month, or once in two or more months.
  • the formulations or kits of parts as taught herein preferably for use as a medicament and more preferably for use in the treatment and/or prevention of osteoarticular diseases, wherein the gel- forming formulations or kits of parts may be parenterally injected twice a month, once a month, or once in two or more months.
  • the formulations or kits of parts as taught herein preferably for use as a medicament and more preferably for use in the treatment and/or prevention of osteoarticular diseases
  • the gel- forming formulations or kits of parts may be intra-osseously or intra-articularly injected twice a month, once a month, or once in two or more months.
  • the present formulations allow a reduction of the administration frequency and increase the compliancy of the patients by decreasing the pain produced by repeated injections.
  • the present formulations allow a prolonged therapeutic effect in the treatment of particularly osteoarticular diseases.
  • Suitable dosage forms include solutions for intra-osseous or intra-articular injection.
  • prophylactically effective amount refers to an amount of an active compound or pharmaceutical agent that inhibits or delays in a subject the onset of a disorder as being sought by a researcher, veterinarian, medical doctor or other clinician.
  • therapeutically effective amount refers to an amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a subject that is being sought by a researcher, veterinarian, medical doctor or other clinician, which may include inter alia alleviation of the symptoms of the disease or condition being treated. Methods are known in the art for determining therapeutically and prophylactically effective doses for the present formulations or pharmaceutical formulations.
  • a “therapeutically effective dose” means an amount of a active ingredient or formulation that when administered brings about a positive therapeutic response with respect to treatment of a patient with osteoarticular disease.
  • a typical dose to be administered may range from about 5 mg to 100 mg of the glycosaminoglycan per injection.
  • the dose to be administered may range from about 7.5 mg to 60 mg of the glycosaminoglycan per injection, for example, from about 15 mg to 50 mg of the glycosaminoglycan per injection.
  • the dose to be administered ranges from about 7.5 mg to 30 mg of the glycosaminoglycan per injection.
  • the treatments of the invention may comprise administration of a single therapeutically effective dose or administration of multiple therapeutically effective doses of formulations or pharmaceutical formulations.
  • subject or “patient” are used interchangeably and refer to animals, preferably warm-blooded animals, more preferably vertebrates, even more preferably mammals, still more preferably primates, and specifically includes human patients and non-human mammals and primates.
  • Preferred patients are human subjects.
  • a phrase such as "a subject in need of treatment” includes subjects that would benefit from treatment of a given condition, particularly of osteoarticular disease. Such subjects may include, without limitation, those that have been diagnosed with said condition, those prone to develop said condition and/or those in whom said condition is to be prevented.
  • treat or “treatment” encompass both the therapeutic treatment of an already developed disease or condition, as well as prophylactic or preventative measures, wherein the aim is to prevent or lessen the chances of incidence of an undesired affliction, such as to prevent the chances of progression of the disease or condition.
  • beneficial or desired clinical results may include, without limitation, alleviation of one or more symptoms or one or more biological markers, diminishment of extent of disease, stabilised (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and the like.
  • Treatment can also mean prolonging survival as compared with expected survival if not receiving treatment.
  • formulations described in the following examples may contain an additional active ingredient, in particular the alpha-2 adrenergic receptor agonist, clonidine, the results obtained using such formulations are considered to be adequately representative of formulations not containing this additional active ingredient, and in particular of formulations containing a glycosaminoglycan as the sole active ingredient.
  • Example 1 Preparation of a glycerol monooleate (GMO) based gel-forming formulation comprising sodium hyaluronate
  • a formulation as described in Table 1 was prepared as follows. Basically, under aseptic conditions, 1.1 g of GMO was gently melted at 45°C and then blended under stirring (e.g. magnetic stirring) with 0.2 g of ethanol and 0.4 g of PG at 45°C. The obtained solution was filtrated through a 0.22 ⁇ filter in order to ensure the sterility of the GMO phase. To the filtrate, 15 mg of sodium hyaluronate was added and put in suspension during 3 minutes with a high-speed homogenizer (e.g. Ultra-Turrax ® ) at 24000 rpm. To this suspension, 0.3 g of sterile and apyrogenic water was added under stirring till sodium hyaluronate was completely dissolved. Table 1 : Composition of a formulation according to an embodiment of the invention
  • GMO based gel-forming formulation comprising 30 mg of sodium hyaluronate
  • a formulation as described in Table 2 was prepared as follows. Basically, under aseptic conditions, 1.1 g of GMO was gently melted at 45°C and then blended under stirring (e.g. magnetic stirring) with 0.2 g of ethanol and 0.4 g of PG at 45°C. The obtained solution was filtrated through a 0.22 ⁇ filter in order to ensure the sterility of the GMO phase. To the filtrate, 30 mg of sodium hyaluronate was added and put in suspension during 3 minutes with a high-speed homogenizer (e.g. Ultra-Turrax ® ) at 24000 rpm. To this suspension, 0.3 g of sterile and apyrogenic water was added under stirring till sodium hyaluronate was completely dissolved.
  • a high-speed homogenizer e.g. Ultra-Turrax ®
  • Table 2 Composition of a formulation according to an embodiment of the invention
  • Example 2 Preparation of a GMO based gel-forming formulation comprising sodium hyaluronate and purified Soybean oil
  • a formulation as described in Table 3 was prepared as follows. Basically, under aseptic conditions, l .lg of GMO was gently melted at 45°C and then blended under stirring (e.g. magnetic stirring) with 0.2 g of ethanol, 0.3 g of PG and 0,lg of purified soybean oil at 45°C. The obtained solution was filtrated through a 0,22 ⁇ filter in order to ensure the sterility of the GMO phase. To the filtrate, 15 mg of sodium hyaluronate was added and put in suspension during 3 minutes with a high-speed homogenizer (e.g. Ultra-Turrax ® ) at 24000 rpm. To this suspension, 0.3 g of sterile and apyrogenic water was added under stirring till sodium hyaluronate was completely dissolved.
  • a high-speed homogenizer e.g. Ultra-Turrax ®
  • Table 3 Composition of a formulation according to an embodiment of the invention
  • a formulation as described in Table 4 was prepared as follows. Basically, under aseptic conditions, l .lg of GMO was gently melted at 45°C and then blended under stirring (e.g. magnetic stirring) with 0.2 g of ethanol, 0.3 g of PG and 0.1 g of purified soybean oil at 45°C. The obtained solution was filtrated through a 0.22 ⁇ filter in order to ensure the sterility of the GMO phase. To the filtrate, 30 mg of sodium hyaluronate was added and put in suspension during 3 minutes with a high-speed homogenizer (e.g. Ultra-Turrax ® ) at 24000 rpm. To this suspension, 0.3 g of sterile and apyrogenic water was added under stirring till sodium hyaluronate was completely dissolved.
  • a high-speed homogenizer e.g. Ultra-Turrax ®
  • Table 4 Composition of a formulation according to an embodiment of the invention
  • Example 3 Preparation of a GMO based gel-forming formulation comprising sodium hyaluronate, purified Soybean oil and acetate alpha-tocopherol
  • a formulation as described in Table 5 was prepared as follows. Basically, under aseptic conditions, 1.1 g of GMO was gently melted at 45°C and then blended under stirring (e.g. magnetic stirring) with 0.2 g of ethanol, 0.3 g of PG, 0.1 g of purified soybean oil and 600 ⁇ g of acetate alpha- tocopherol at 45°C. The obtained solution was filtrated through a 0.22 ⁇ filter to ensure the sterility of the GMO phase. To the filtrate, 15 mg of sodium hyaluronate was added and put in suspension during 3 minutes with a high-speed homogenizer (e.g. Ultra-Turrax ® ) at 24000 rpm. To this suspension, 0.3 g of sterile and apyrogenic water was added under stirring till sodium hyaluronate was completely dissolved.
  • a high-speed homogenizer e.g. Ultra-Turrax ®
  • Table 5 Composition of a formulation according to an embodiment of the invention
  • a formulation as described in Table 6 was prepared as follows. Basically, under aseptic conditions, l .lg of GMO was gently melted at 45°C and then blended under stirring (e.g. magnetic stirring) with 0.2 g of ethanol, 0.3 g of PG, 0.1 g of purified soybean oil and 600 ⁇ g of acetate alpha- tocopherol at 45°C. The obtained solution was filtrated through a 0.22 ⁇ filter in order to ensure the sterility of the GMO phase. To the filtrate, 30 mg of sodium hyaluronate was added and put in suspension during 3 minutes with a high-speed homogenizer (e.g. Ultra-Turrax ® ) at 24000 rpm. To this suspension, 0.3 g of sterile and apyrogenic water was added under stirring till sodium hyaluronate was completely dissolved.
  • a high-speed homogenizer e.g. Ultra-Turrax ®
  • Table 6 Composition of a formulation according to an embodiment of the invention
  • Example 4 Preparation of a GMO based gel-forming formulation comprising sodium hyaluronate and clonidine A. Preparation of a GMO based gel-forming formulation comprising 15 mg of sodium hyaluronate and 0,450 mg of clonidine
  • a formulation as described in Table 7 was prepared as follows. Basically, under aseptic conditions, 1.1 g of GMO was gently melted at 45°C and then blended under stirring (e.g. magnetic stirring) with 0.2 g of ethanol and 0.4 g of PG at 45°C. The obtained solution was filtrated through a 0.22 ⁇ filter in order to ensure the sterility of the GMO phase. To the filtrate, 15 mg of sodium hyaluronate was added and put in suspension during 3 minutes with a high-speed homogenizer (e.g. Ultra-Turrax ® ) at 24000 rpm. To this suspension, 0.3 g of an aqueous solution of clonidine (1.5 mg/ml) passed through a 0.22 ⁇ filter was added under stirring till sodium hyaluronate was completely dissolved.
  • a high-speed homogenizer e.g. Ultra-Turrax ®
  • Table 7 Composition of a formulation according to an embodiment of the invention
  • a formulation as described in Table 8 was prepared as follows. Basically, under aseptic conditions, 1.1 g of GMO was gently melted at 45°C and then blended under stirring (e.g. magnetic stirring) with 0.2 g of ethanol and 0.4 g of PG at 45°C. The obtained solution was filtrated through a 0.22 ⁇ filter in order to ensure the sterility of the GMO phase. To the filtrate, 15 mg of sodium hyaluronate was added and put in suspension during 3 minutes with a high-speed homogenizer (e.g. Ultra-Turrax ® ) at 24000 rpm.
  • a high-speed homogenizer e.g. Ultra-Turrax ®
  • a formulation as described in Table 9 was prepared as follows. Basically, under aseptic conditions, 1.1 g of GMO was gently melted at 45°C and then blended under stirring (e.g. magnetic stirring) with 0.2 g of ethanol and 0.4 g of PG at 45°C. The obtained solution was filtrated through a 0.22 ⁇ filter in order to ensure the sterility of the GMO phase. To the filtrate, 30 mg of sodium hyaluronate was added and put in suspension during 3 minutes with a high-speed homogenizer (e.g. Ultra-Turrax) at 24000 rpm. To this suspension, 0.3 g of an aqueous solution of clonidine (1.5 mg/ml) passed through a 0.22 ⁇ filter was added under stirring till sodium hyaluronate was completely dissolved.
  • a high-speed homogenizer e.g. Ultra-Turrax
  • Table 9 Composition of a formulation according to an embodiment of the invention
  • a formulation as described in Table 10 was prepared as follows. Basically, under aseptic conditions, 1.1 g of GMO was gently melted at 45°C and then blended under stirring (e.g. magnetic stirring) with 0.2 g of ethanol and 0.4 g of PG at 45°C. The obtained solution was filtrated through a 0.22 ⁇ filter in order to ensure the sterility of the GMO phase. To the filtrate, 30 mg of sodium hyaluronate was added and put in suspension during 3 minutes with a high-speed homogenizer (e.g. Ultra-Turrax ® ) at 24000 rpm. To this suspension, 0.3 g of an aqueous solution of clonidine (4.5 mg/ml) passed through a 0.22 ⁇ filter was added under stirring till sodium hyaluronate was completely dissolved.
  • a high-speed homogenizer e.g. Ultra-Turrax ®
  • Table 10 Composition of a formulation according to an embodiment of the invention
  • Example 5 Preparation of a GMO based gel-forming formulation comprising sodium hyaluronate, clonidine and purified Soybean oil
  • a formulation as described in Table 11 was prepared as follows. Basically, under aseptic conditions, 1.1 g of GMO was gently melted at 45°C and then blended under stirring (e.g. magnetic stirring) with 0.2 g of ethanol, 0.3 g of PG and 0.1 g of purified soybean oil at 45°C. The obtained solution was filtrated through a 0.22 ⁇ filter in order to ensure the sterility of the GMO phase. To the filtrate, 15 mg of sodium hyaluronate was added and put in suspension during 3 minutes with a high-speed homogenizer (e.g. Ultra-Turrax ® ) at 24000 rpm.
  • a high-speed homogenizer e.g. Ultra-Turrax ®
  • a formulation as described in Table 12 was prepared as follows. Basically, under aseptic conditions, 1.1 g of GMO was gently melted at 45°C and then blended under stirring (e.g. magnetic stirring) with 0.2 g of ethanol, 0.3 g of PG and 0.1 g of purified soybean oil at 45°C. The obtained solution was filtrated through a 0.22 ⁇ filter in order to ensure the sterility of the GMO phase. To the filtrate, 15 mg of sodium hyaluronate was added and put in suspension during 3 minutes with a high-speed homogenizer (e.g. Ultra-Turrax ® ) at 24000 rpm. To this suspension, 0.3 g of an aqueous solution of clonidine (4.5 mg/ml) passed through a 0.22 ⁇ filter was added under stirring till sodium hyaluronate was completely dissolved.
  • a high-speed homogenizer e.g. Ultra-Turrax ®
  • Table 12 Composition of a formulation according to an embodiment of the invention
  • a formulation as described in Table 13 was prepared as follows. Basically, under aseptic conditions, 1.1 g of GMO was gently melted at 45°C and then blended under stirring (e.g. magnetic stirring) with 0.2 g of ethanol, 0.3 g of PG and 0.1 g of purified soybean oil at 45°C. The obtained solution was filtrated through a 0,22 ⁇ filter in order to ensure the sterility of the GMO phase. To the filtrate, 30 mg of sodium hyaluronate was added and put in suspension during 3 minutes with a high-speed homogenizer (e.g. Ultra-Turrax ® ) at 24000 rpm. To this suspension, 0.3 g of an aqueous solution of clonidine (1.5 mg/ml) passed through a 0.22 ⁇ filter was added under stirring till sodium hyaluronate was completely dissolved.
  • a high-speed homogenizer e.g. Ultra-Turrax ®
  • Table 13 Composition of a formulation according to an embodiment of the invention
  • a formulation as described in Table 14 was prepared as follows. Basically, under aseptic conditions, 1.1 g of GMO was gently melted at 45°C and then blended under stirring (e.g. magnetic stirring) with 0.2 g of ethanol, 0.3 g of PG and 0.1 g of purified soybean oil at 45°C. The obtained solution was filtrated through 0.22 ⁇ filter in order to ensure the sterility of the GMO phase. To the filtrate, 30 mg of sodium hyaluronate was added and put in suspension during 3 minutes with a high-speed homogenizer (e.g. Ultra-Turrax ® ) at 24000 rpm. To this suspension, 0.3 g of an aqueous solution of clonidine (4.5 mg/ml) passed through a 0.22 ⁇ filter was added under stirring till sodium hyaluronate was completely dissolved.
  • a high-speed homogenizer e.g. Ultra-Turrax ®
  • Table 14 Composition of a formulation according to an embodiment invention
  • Example 6 Preparation of a GMO based gel-forming formulation comprising sodium hyaluronate, clonidine, purified Soybean oil and acetate alpha-tocopherol
  • a formulation as described in Table 15 was prepared as follows. Basically, under aseptic conditions, 1.1 g of GMO was gently melted at 45°C and then blended under stirring (e.g. magnetic stirring) with 0.2 g of ethanol, 0.3 g of PG, O.lg of purified soybean oil and 600 ⁇ g of acetate alpha-tocopherol at 45°C. The obtained solution was filtrated through a 0.22 ⁇ filter in order to ensure the sterility of the GMO phase. To the filtrate, 15 mg of sodium hyaluronate was added and put in suspension during 3 minutes with a high-speed homogenizer (e.g. Ultra-Turrax ® ) at 24000 rpm. To this suspension, 0.3 g of an aqueous solution of clonidine (1.5 mg/ml) passed through a 0.22 ⁇ filter was added under stirring till sodium hyaluronate was completely dissolved.
  • a high-speed homogenizer e.g. Ultra-Turrax ®
  • Table 15 Composition of a formulation according to an embodiment of the invention
  • a formulation as described in Table 16 was prepared as follows. Basically, under aseptic conditions, 1.1 g of GMO was gently melted at 45°C and then blended under stirring (e.g. magnetic stirring) with 0.2 g of ethanol, 0.3 g of PG, 0.1 g of purified soybean oil and 600 ⁇ g of acetate alpha-tocopherol at 45°C. The obtained solution was filtrated through a 0.22 ⁇ filter in order to ensure the sterility of the GMO phase. To the filtrate, 15 mg of sodium hyaluronate was added and put in suspension during 3 minutes with a high-speed homogenizer (e.g. Ultra-Turrax ® ) at 24000 rpm.
  • a high-speed homogenizer e.g. Ultra-Turrax ®
  • a formulation as described in Table 17 was prepared as follows. Basically, under aseptic conditions, 1.1 g of GMO was gently melted at 45°C and then blended under stirring (e.g. magnetic stirring) with 0.2 g of ethanol, 0.3 g of PG, 0.1 g of purified soybean oil and 600 ⁇ g of acetate alpha-tocopherol at 45°C. The obtained solution was filtrated through a 0.22 ⁇ filter in order to ensure the sterility of the GMO phase. To the filtrate, 30 mg of sodium hyaluronate was added and put in suspension during 3 minutes with a high-speed homogenizer (e.g. Ultra-Turrax ® ) at 24000 rpm. To this suspension, 0.3 g of an aqueous solution of clonidine (1.5 mg/ml) passed through a 0.22 ⁇ filter was added under stirring till sodium hyaluronate was completely dissolved.
  • a high-speed homogenizer e.g. Ultra-Turrax ®
  • Table 17 Composition of a formulation according to an embodiment of the invention
  • a formulation as described in Table 18 was prepared as follows. Basically, under aseptic conditions, 1.1 g of GMO was gently melted at 45°C and then blended under stirring (e.g. magnetic stirring) with 0.2 g of ethanol, 0.3 g of PG, 0,lg of purified soybean oil and 600 ⁇ g of acetate alpha- tocopherol at 45°C. The obtained solution was filtrated through a 0.22 ⁇ filter in order to ensure the sterility of the GMO phase. To the filtrate, 30 mg of sodium hyaluronate was added and put in suspension during 3 minutes with an Ultra-Turrax device at 24000 rpm. To this suspension, 0.3 g of an aqueous solution of clonidine (4.5 mg/ml) passed through a 0.22 ⁇ filter was added under stirring till sodium hyaluronate was completely dissolved.
  • clonidine 4.5 mg/ml
  • Table 18 Composition of a formulation according to an embodiment of the invention
  • Example 7 Water uptake profiles of GMO based gel-forming formulations
  • CLO clonidine
  • HA sodium hyaluronate
  • PG propylene glycol
  • GMO glycerol monooleate
  • W f is the final weight and W; is the initial weight.
  • Example 8 Rheological properties of GMO based gel-forming formulations
  • the instrument was used in the flow-sweep mode and shear stress was evaluated from 0,1 to 100 s "1 shear rate.
  • the instrument was also used in the oscillation- frequency mode where strain was set at 1% and angular frequency was set from 100 to 0.1 rad/s.
  • This application allowed to study the evolution of the elastic modulus (G') and loss modulus (G") in function of the angular frequency applied.
  • the Power Law as given in the equation of Formula (II), is widely used as a model for non- Newtonian fluids,
  • ⁇ is the shear stress (Pa)
  • ⁇ is the shear rate (s 1 )
  • k is the consistency coefficient (Pa.s n ).
  • n also called the flow behavior index
  • n value is less than 1, the fluid can be considered as shear-thinning, and if it is greater than 1, the fluid can be considered as shear-thickening.
  • a test of whether the power law applies and means of determining n are to plot the log shear stress vs log shear rate. If the plot is linear, the power law applies.
  • the value of n which is the reciprocal of the slope of the line, can be used as a measure of the degree of shear-thinning or shear-thickening (Kroschwitz, 1990). Indeed, the lower the flow behavior index n, the higher is the pseudoplasticity of the shear-thinning system.
  • Structovial ® is an aquous solution comprising 1% sodium hyaluronate and is currently used in the treatment of arthritis.
  • Structovial ® showed lower viscosity values and lower pseudoplasticity (higher n value) compared with the formulations Fl -Fl 1 which illustrate the present invention.
  • formulation F10 was selected as a preferred formulation. It was decided to add an antioxidant, alpha-tocopherol, in order to prevent any oxidation of lipidic compounds (formulation 26K10/2 or Fl l). This formulation was chosen for subsequent experiments and rheological properties were compared with the commercially available product, Structovial ® ( Figure 2).
  • the frequency of crossover between the elastic modulus G' and the viscous modulus G" is equal to 0.41 ⁇ 0.12 Hz for an uncontaminated (non-osteoarthritic) synovial fluid of the knee (Mazzuco et al., J. Orthopedic Res., 1 157-1 163, 2002). This value of crossover frequency is confirmed by Fam et al., 2007, Biorheology, 44, 59-74. Below 0.41 Hz: G">G', the synovial fluid has a predominantly viscous function which means that the joint is strongly lubricated when the patient is at rest.
  • the synovial fluid has a predominantly elastic function which means that impacts are strongly absorbed when the patient runs or jumps.
  • formulation Fl 1 had rheological properties close to the healthy synovial fluid.
  • Syringeability can be considered as the ability of a preparation to be successfully administered by syringe with an appropriate needle.
  • the principle consists in applying a given displacement rate to the plunger of the syringe filled with the formulation and in measuring the resulting force (N).
  • the study was performed using a 5 ml syringe equipped with a 21GG needle.
  • the pH of the formulation seemed to be modified by addition of sodium oleate in the composition (F8). This neutral pH seemed to induce a color modification of the final formulation. Indeed, at pH 7 the formulation F8 was yellow.
  • the present formulations show advantageous rheological properties and syringeability. These properties of the formulations illustrating the invention demonstrate the superiority of such formulations in the treatment of osteoarticular diseases.
  • Example 9 Protection of a GMO based gel-forming formulation to degradation by hyaluronidase activity
  • Sodium azide (0.02% w/w) was added in order to prevent bacterial contamination.
  • the degradation of sodium hyaluronate was extremely fast at the three evaluated concentrations of enzyme (as shown in Figure 3 for the degradation with 2 Ul/ml of ovine hyaluronidase).
  • the concentration of ovine hyaluronidase was set at 2 Ul/ml for the subsequent study.
  • the protection of sodium hyaluronate in different gel formulations was assessed in triplicate on lg of formulation immersed in 50 ml of phosphate buffer containing 2 Ul/ml of ovine hyaluronidase.
  • the temperature of the dissolution media was maintained at 37°C and the shaking speed employed was about 80 min "1 .
  • Sodium azide (0.02% w/w) was added in order to prevent bacterial contamination. Every three days, fresh solution of ovine hyaluronidase was added to the media.
  • gels were withdrawn from the media, put in 7.5 ml of fresh phosphate buffer H 7 and extraction of sodium hyaluronate was performed at 100°C during 10 minutes. The aqueous solutions were filtered through 0.22 ⁇ filters and analyzed by GPC.
  • the present formulations protect their enclosed active ingredients against enzymatic degradation during at least 24 hours.
  • the protection of the active ingredients from the physical environment increases the stability of the present formulations in vivo.
  • the protection of the active ingredients of the present formulations demonstrates the superiority of the formulations of the invention for treatment of osteoarticular diseases.
  • Example 10 Release profiles of hyaluronic acid from glycerol monooleate (GMO) based gel- forming formulations
  • HA-GMO formulation In order to determine the protective role of GMO in the sustained release of HA, the HA release from a formulation of the invention, hereinafter referred to as HA-GMO formulation, is compared with the compounds (HA and GMO) alone and with comparators in the presence of degrading enzymes (hyaluronidases).
  • the HA-GMO formulation is prepared as described in Example 3A.
  • the HA release from the HA-GMO formulation is compared with the HA release form: (i) hyaluronic acid alone, (ii) GMO alone, (iii) a commercially available product, Structovial® and (iv) prior art comparators.
  • the HA release is studied by agarose gel electrophoresis (qualitative), ELISA (quantitative) and indirect quantification by measuring the degradation time by the hyaluronidases.
  • Example 2A a formulation illustrating the invention was prepared as described in Example 2A.
  • the HA release from said formulation was evaluated in complete cell culture medium comprising 10% of serum and compared with the HA release from HA alone.
  • 500mg of the formulation was incubated at 37°C during 7, 14, or 21 days in 0,5ml of complete cell culture medium.
  • ELISA Enzyme Linked Immunosorbent Assay
  • hyaluronic acid In healthy synovial fluid, the concentration of hyaluronic acid may vary from 0.35 to 4.22mg/ml (Fam et al., 2007, Biorheology 44:59-74). However, this concentration seems to be decreased in osteoarthritis. Relying on the above-mentioned ELISA data on the release of HA in vitro ( Figure 7), 20% of the HA is released at 5.5 days which corresponds to 3 mg of HA.
  • the volume of synovial fluid present in the joint is around 2 to 4 ml which means that at day 5.5 post-injection of the formulation illustrating the invention, the HA concentration in the joint is around 1 mg/ml which is in the range of HA concentration in a healthy synovial fluid.
  • an indirect evaluation of the HA release is performed by the evaluation of the remaining HA content in the formulation.
  • Subcutaneous injection in healthy mice is performed with the HA-GMO formulation as described in Example 3A and compared with: (i) hyaluronic acid alone, (ii) GMO alone, (iii) a commercially available product, Structovial® and (iv) prior art comparators. The general behavior and clinical sign are studied. Histology is studied. The residual HA content is extracted from the remaining formulation and evaluated.
  • the gel-based formulations are dissolved in an equal amount of All-Stain® solution (Sigma Aldrich) for at least 24h prior to deposition on an agarose gel. Evaluation on agarose gel is performed as described in Example 10A.
  • the release profiles may demonstrate a prolonged release of HA from the formulations of the invention compared with the release of HA from HA or GMO alone, from a commercially available product (Structovial®) and/or from other comparators.
  • Example 11 Resistance of GMO based gel-forming formulations to degradation in situ
  • the residual HA in the remaining formulation is evaluated in presence of hyaluronidases.
  • the residual HA is studied in the HA-GMO formulation as described in Example 3A and compared with: (i) hyaluronic acid alone, (ii) GMO alone, (iii) a commercially available product, Structovial® and (iv) prior art comparators.
  • the residual HA content is extracted from the remaining formulation and evaluated by the same techniques as described in Example 4A.
  • HA-GMO formulation as described in Example 3A and compared with: (i) hyaluronic acid alone, (ii) GMO alone, (iii) a commercially available product, Structovial® and (iv) prior art comparators.
  • the general behaviour and clinical sign are studied. Histology is studied.
  • the residual HA content is extracted from the remaining formulation and evaluated by the same techniques as described in Example 4A.
  • the protection of HA from the physical environment such as from hyaluronidases may be increased in the formulations of the invention compared with the protection of HA in a commercially available product (Structovial®) and/or in other comparators.
  • the protection of HA of the present formulations may demonstrate the superiority of the formulations of the invention in the treatment of osteoarticular diseases compared with the compounds HA and GMO alone, a commercially available product (Structovial®) and other comparators.
  • Example 12 Rheological properties of GMO based gel-forming formulations
  • Example 3A In order to test the viscosity and elasticity of the formulations, the rheological properties of the HA- GMO formulation as described in Example 3A are studied as described in Example 8 and compared with the rheological properties of: (i) hyaluronic acid alone, (ii) GMO alone, (iii) a commercially available product, Structovial® and (iv) prior art comparators.
  • the rheological and mechanical properties of the present formulations may demonstrate to be superior compared with the properties of the compounds HA and GMO alone, a commercially available product (Structovial®) and other comparators.
  • the rheological and mechanical properties of the present formulations may demonstrate the superiority of the formulations of the invention in the treatment of osteoarticular diseases compared with the compounds HA and GMO alone, a commercially available product (Structovial®) and other comparators.
  • Example 13 Efficacy of GMO based gel-forming formulations in a rat model of osteoarthritis
  • intra-articular injection is performed in an osteoarthritis induced rat model with the HA-GMO formulation as described in Example 3A and compared with: (i) hyaluronic acid alone, (ii) GMO alone, (iii) a commercially available product, Structovial® and (iv) prior art comparators prepared.
  • the efficacy e.g. protection, regeneration of cartilage is determined.
  • the general behaviour and clinical signs are studied. Histology and (blood) biomarkers are studied.
  • Efficacy studies of the present formulations in an osteoarthritis induced rat model may demonstrate the superiority of the formulations of the invention in the treatment of osteoarticular diseases compared with the compounds HA and GMO alone, a commercially available product (Structovial®) and other comparators.
  • formulations of the invention allow to prolong the release of a glycosaminoglycan such as hyaluronic acid in the joint over an extended period of time such as over a few weeks.
  • the formulations illustrating the invention further allow to protect the glycosaminoglycan against enzymatic degradation.
  • the present formulations show rheological properties close to healthy synovial fluid.
  • the present formulations allow to improve the articular function by their extended lubricating action on the joint.
  • Example 14 Preparation of a GMO based gel formulation comprising sodium hyaluronate wherein pH was adjusted to 6.5 with NaOH IN in order to improve the stability of sodium hyaluronate A. Preparation of a GMO based gel formulation pH 6.5 comprising 15 mg of sodium hyaluronate
  • a formulation as described in Table 23 was prepared as follows. Basically, under aseptic conditions, 1.1 g of GMO was gently melted at 45°C and then blended under magnetic stirring with 0.2 g of ethanol and 0.4 g of PG at 45°C. Solution was filtrated through a 0.22 ⁇ filter in order to ensure the sterility of the GMO phase. At the filtrate, 15 mg of sodium hyaluronate was added and put in suspension during 3 minutes with a high-speed homogenizer (e.g. Ultra-Turrax ® ) at 24000 rpm. At this suspension, 0.3 g of sterile and apyrogenic water was added under magnetic stirring till sodium hyaluronate was completely dissolved. Finally, pH of the formulation was adjusted to 6.5 with NaOH IN (about 3 ⁇ of NaOH IN added).
  • a high-speed homogenizer e.g. Ultra-Turrax ®
  • Table 23 Composition of a formulation according to an embodiment of the invention
  • a formulation as described in Table 24 was prepared as follows. Basically, under aseptic conditions, 1.1 g of GMO was gently melted at 45°C and then blended under magnetic stirring with 0.2 g of ethanol and 0.4 g of PG at 45°C. Solution was filtrated through a 0.22 ⁇ filter in order to ensure the sterility of the GMO phase. At the filtrate, 30 mg of sodium hyaluronate was added and put in suspension during 3 minutes with a high-speed homogenizer (e.g. Ultra-Turrax ® ) at 24000 rpm. At this suspension, 0.3 g of sterile and apyrogenic water was added under magnetic stirring till sodium hyaluronate was completely dissolved. Finally, pH of the formulation was adjusted to 6.5 with NaOH IN (about 3 ⁇ of NaOH IN added). Table 24: Composition of a formulation according to an embodiment of the invention
  • Figure 8 shows that the rheological properties of the developed formulation (Fl l) decreased considerably at least after 1 month of storage at 25°C and 30°C. Nevertheless, as illustrated in Figure 9, this problem was solved by adjusting the pH of the formulation to pH between 6.0 and 7.0, such as preferably to pH between 6.2 and 6.8, such as particularly to pH of 6.5. Indeed, adjusting the pH of the formulation illustrating the present invention conserved the rheological properties of the formulation during storage, even at temperatures above room temperature such as at 30°C, as shown in Figure 9. Same was observed for the carrier without incorporated drug.
  • Example 15 Preparation of a GMO based gel formulation comprising sodium hyaluronate, purified Soybean oil and acetate alpha-tocopherol wherein pH was adjusted to 6.5 with NaOH IN in order to improve the stability of sodium hyaluronate
  • a formulation as described in Table 25 was prepared as follows. Basically, under aseptic conditions, 1.1 g of GMO was gently melted at 45°C and then blended under magnetic stirring with 0.2 g of ethanol, 0.3 g of PG, O.lg of purified soybean oil and 600 ⁇ g of acetate alpha-tocopherol at 45°C. Solution was filtrated through a 0.22 ⁇ filter in order to ensure the sterility of the GMO phase. At the filtrate, 15 mg of sodium hyaluronate was added and put in suspension during 3 minutes with a high-speed homogenizer (e.g. Ultra-Turrax ® ) at 24000 rpm. At this suspension, 0.3 g of sterile and apyrogenic water was added under magnetic stirring till sodium hyaluronate was completely dissolved. Finally, pH of the formulation was adjusted to 6.5 with NaOH IN (about 3 ⁇ of NaOH IN added).
  • NaOH IN about 3 ⁇ of NaOH IN added
  • Table 25 Composition of a formulation according to an embodiment of the invention
  • a formulation as described in Table 26 was prepared as follows. Basically, under aseptic conditions, 1.1 g of GMO was gently melted at 45°C and then blended under magnetic stirring with 0.2 g of ethanol, 0.3 g of PG, O.lg of purified soybean oil and 600 ⁇ g of acetate alpha-tocopherol at 45°C. Solution was filtrated through a 0.22 ⁇ filter in order to ensure the sterility of the GMO phase. At the filtrate, 30 mg of sodium hyaluronate was added and put in suspension during 3 minutes with a high-speed homogenizer (e.g. Ultra-Turrax ® ) at 24000 rpm.
  • a high-speed homogenizer e.g. Ultra-Turrax ®

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Abstract

La présente invention concerne une formulation de formation de gel comprenant un glycosaminoglycane et un monoglycéride. L'invention concerne également un dispositif médical comprenant la formulation de formation de gel et la formulation de formation de gel destinée à une utilisation en tant que médicament, de préférence destinée à une utilisation dans le traitement et/ou la prévention de maladies ostéoarticulaires. La formulation de formation de gel peut de manière adaptée être administrée par injection parentérale, de préférence par injection intra-osseuse ou intra-articulaire.
PCT/EP2012/073268 2011-11-21 2012-11-21 Formulations utiles dans le traitement de maladies ostéoarticulaires Ceased WO2013076162A1 (fr)

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