WO2013076160A1 - Formulations à libération prolongée utiles dans le traitement de maladies - Google Patents

Formulations à libération prolongée utiles dans le traitement de maladies Download PDF

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WO2013076160A1
WO2013076160A1 PCT/EP2012/073266 EP2012073266W WO2013076160A1 WO 2013076160 A1 WO2013076160 A1 WO 2013076160A1 EP 2012073266 W EP2012073266 W EP 2012073266W WO 2013076160 A1 WO2013076160 A1 WO 2013076160A1
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gel
formulation
formulations
clonidine
forming formulation
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PCT/EP2012/073266
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English (en)
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Karim Amighi
Jonathan RÉEFF
Jonathan Goole
Carine DE VRIESE
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Université Libre de Bruxelles
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Publication of WO2013076160A1 publication Critical patent/WO2013076160A1/fr

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    • 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
    • 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
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • 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 concerns sustained release formulations and related kits.
  • the present invention further relates to such sustained release formulations for use in the treatment of diseases such as 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, its half-life after injection is only about 6 to 8 hours. However, treatments using chemically cross-linked hyaluronic acid have suggested an increase in the half-life and the residence time of the reticulated hyaluronic acid in the joint.
  • cytokines In addition to the alteration of the joint due to the degeneration of endogenous glycosaminoglycans, it is known that pro-inflammatory cytokines play a fundamental role in the pathogenesis of synovial inflammation, and that the levels of TNF-a, IL- ⁇ ⁇ or IL-6 are increased in inflamed joints.
  • cytokines etanercept, adalimumab and infliximab
  • IL- ⁇ ⁇ anakinra
  • MRA IL-6
  • TNF- ⁇ inhibitors have been shown to be effective on mono-arthritis when administered systemically. However, due to the potential severity of their side-effects (infections, neoplasia%) when administered systemically, their use is limited. In addition, the cost of injectable TNF-a inhibitors is high and their use is thereby limited to patients suffering to adverse reactions to steroids (Bliddal et al., 2006, Scand J Rheumatol. Sep-Oct;35(5): 341-5).
  • Clonidine is a centrally acting alpha-2 adrenergic receptor agonist that stimulates the alpha-2 adrenoreceptors in the brain stem. It is generally used as an anti-hypertensive agent. Clonidine is also commonly referred to as 2,6-dichloro-N-2-imidazolidinyldenebenzenamine (C 9 H 9 CI 2 N 3 ). Recently, antiinflammatory properties have been demonstrated for this molecule and new applications such as the treatment of arthritic diseases have been considered. For instance, WO 2010/031819 describes a pharmaceutical formulation comprising an alpha-2 adrenergic receptor agonist for preventing or treating inflammatory pain and diseases in mucosa of oral cavity, pharynx and larynx.
  • WO 2009/129460 further describes the administration of an effective amount of clonidine, provided within biodegradable polymers, at or near a target site in order to relieve pain caused by diverse sources, including but not limited to spinal disc herniation (i.e. sciatica), spondilothesis, stenosis, discogenic back pain and joint pain, as well as pain that is incidental to surgery.
  • spinal disc herniation i.e. sciatica
  • spondilothesis spondilothesis
  • stenosis stenosis
  • discogenic back pain and joint pain as well as pain that is incidental to surgery.
  • WO 2009/101194 describes a pharmaceutical formulation comprising optionally a pharmaceutical carrier or a diluent, a glycosaminoglycan and an alpha-2 adrenergic receptor agonist, for use in the treatment and/or the prevention of acute or chronic osteoarticular diseases and/or symptoms by intra-articular injection.
  • a pharmaceutical carrier or a diluent for use in the treatment and/or the prevention of acute or chronic osteoarticular diseases and/or symptoms by intra-articular injection.
  • the half-life in the joint of the high molecular weight hyaluronic acid is only about 6 to 8 hours. Therefore, it is necessary to repeat injections once a week for 3-5 weeks resulting in discomfort for the patient.
  • 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
  • a gel-forming formulation comprising a glycosaminoglycan, a sustained release agent and one or more pharmaceutical active ingredients.
  • Formulations applying the principles of the invention advantageously allow to prolong the release and hence the effect of the one or more pharmaceutical active ingredients, such as of an alpha-2 adrenergic receptor agonist and/or a corticosteroid, for instance in a joint.
  • 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 in contrast to solutions involving biopolymers, polymers or formulations based on liposomes.
  • the present formulations protect their enclosed active ingredients or other components from the physical environment, thereby improving the stability of the active ingredients or other components in vivo.
  • the present formulations provide a protection of their enclosed active ingredients or other components against enzymatic degradation.
  • the present formulations advantageously allow to improve the pharmacological effect of the pharmaceutical active ingredients.
  • the present formulations allow to improve the articular function by an extended lubricating action on the joint and are thus effective for restoring the mechanical integrity of the joint.
  • Also disclosed is a method for producing said formulation comprising combining (e.g., admixing) the glycosaminoglycan, the sustained release agent and the one or more pharmaceutical active ingredients.
  • the formulation may additionally comprise one or more pharmaceutically acceptable excipients (e.g., solvents, carriers, diluents, etc.), particularly 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.
  • kits of parts comprising the above gel-forming formulation.
  • a kit of parts comprising a gel- forming formulation comprising a glycosaminoglycan, a sustained release agent and one or more pharmaceutical active ingredients such as for instance but without limitation one or more alpha-2 adrenergic receptor agonists and/or one or more corticosteroids.
  • a method for producing said kit of parts comprising including the formulation in a kit of parts.
  • kit of parts comprising a glycosaminoglycan, a sustained release agent and one or more pharmaceutical active ingredients such as for instance but without limitation one or more alpha-2 adrenergic receptor agonists and/or one or more corticosteroids, wherein the glycosaminoglycan, the sustained release agent and the one or more pharmaceutical active ingredients are configured to allow for producing (forming or obtaining) a gel- forming formulation as defined herein.
  • kit of parts comprising including a glycosaminoglycan, a sustained release agent and one or more pharmaceutical active ingredients such as for instance but without limitation one or more alpha-2 adrenergic receptor agonists and/or one or more corticosteroids, in a kit of parts.
  • a further aspect provides a medical device comprising any one of the gel-forming formulations or kits of parts as taught herein.
  • a medical device comprising a gel-forming formulation comprising a glycosaminoglycan, a sustained release agent and one or more pharmaceutical active ingredients.
  • 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.
  • An aspect provides any one of the 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.
  • osteoarticular diseases including acute or chronic osteoarticular diseases, such as preferably but without limitation osteoarthritis, rheumatoid arthritis, mono-arthritis and poly-arthritis.
  • a gel-forming formulation comprising a glycosaminoglycan, a sustained release agent and one or more pharmaceutical active ingredients such as for instance but without limitation one or more alpha-2 adrenergic receptor agonists and/or one or more corticosteroids, for use in the treatment of acute or chronic osteoarticular diseases such as preferably osteoarthritis, rheumatoid arthritis, mono-arthritis and poly-arthritis.
  • active ingredients such as for instance but without limitation one or more alpha-2 adrenergic receptor agonists and/or one or more corticosteroids
  • the use of formulations of the present invention in the treatment of osteoarticular diseases is advantageous inter alia because these formulations allow efficient treatment during longer periods due to the extended release of the active ingredients.
  • a further advantage of the present formulations is that they can allow simultaneous delivery of several active ingredients over a prolonged period of time.
  • the inventors advantageously found that the present formulations allow for improving the articular function by their extended lubricating action on the joint.
  • 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 osteoarthritis, rheumatoid arthritis, monoarthritis and poly-arthritis.
  • acute or chronic osteoarticular diseases such as preferably osteoarthritis, rheumatoid arthritis, monoarthritis and poly-arthritis.
  • a glycosaminoglycan, a sustained release agent and one or more pharmaceutical active ingredients such as for instance but without limitation one or more alpha-2 adrenergic receptor agonists and/or one or more corticosteroids, for the manufacture of a medicament for the treatment of 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
  • a method for treating osteoarticular diseases comprising administering to said subject any one of the formulations or kits of parts as taught herein.
  • a method for treating 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 formulation comprising a glycosaminoglycan, a sustained release agent and one or more pharmaceutical active ingredients such as for instance but without limitation one or more alpha-2 adrenergic receptor agonists and/or one or more corticosteroids.
  • Such method of treatment may typically involve parenteral administration, more preferably intra- osseous 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, a sustained release agent and one or more pharmaceutical active ingredients.
  • the sustained release agent as intended herein can be preferably 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 sustained release agent and particularly the gel- forming agent as intended herein can preferably be a glyceride.
  • glyceride refers to an ester formed from glycerol and one or more same or distinct fatty acid(s).
  • glyceride and “acylglycerol” can be used interchangeably.
  • the term glyceride encompasses monoglycerides (monoacylglycerol), diglycerides and triglycerides depending on whether one, two, or three fatty acids are esterified with glycerol.
  • the sustained release agent and particularly the gel-forming agent as intended herein can further be a glycerate such as for instance but without limitation oleyl glycerate or phytanyl glycerate.
  • the glyceride is a monoglyceride.
  • a 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 or glycerol monolaurate.
  • the glyceride may be preferably 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.
  • the glyceride is a monoglyceride with oleic acid, i.e., 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.
  • 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.
  • the present formulation can be preferably configured such that the monoglyceride performs or acts as a gel- forming agent in the formulation (i.e., the monoglyceride is provided as a gel-forming agent).
  • the present formulations can be preferably configured such that the monoglyceride allows the formulations to form a gel once administered parenterally, preferably intra-osseously or intra-articularly.
  • the formulation can comprise the sustained release agent in a concentration ranging between 5 and 85% by weight (w/w).
  • the formulation can comprise the sustained release agent 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 formulation can comprise the sustained release agent in a concentration ranging between 45 and 65% by weight (w/w).
  • the combination of a sustained release agent, and more preferably a sustained release agent as discussed above, with a glycosaminoglycan and one or more pharmaceutical active ingredients such as for instance but without limitation one or more alpha-2 adrenergic receptor agonists and/or one or more corticosteroids can enhance and improve the sustained release of any one of and preferably all of the one or more pharmaceutical active ingredients by amplification of the gel-forming process in situ.
  • a sustained release agent preferably intended herein, such a monoglyceride, allows or enhances gel-formation of the formulation upon contact of the formulation with an aqueous liquid such as physiological or bodily fluids, for example synovial fluid.
  • the present formulation can also be advantageous because it can enhance and improve the sustained release of the glycosaminoglycan.
  • Formulations as intended herein may preferably comprise glycerol monooleate as a sustained release agents and preferably gel- forming agent.
  • the present formulations can comprise glycerol monooleate in a concentration ranging between 5 and 85% by weight (w/w).
  • the present formulations can comprise 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 present formulations can comprise glycerol monooleate in a concentration ranging between 45 and 65% by weight (w/w), and more preferably in a concentration of about 55% by weight (w/w).
  • the formulations of the invention allow advantageously prolonged and potentially at least partly concomitant release of the active ingredients, namely the one or more pharmaceutical active ingredients such as the one or more alpha-2 adrenergic receptor agonist and/or one or more corticosteroids, and where applicable potentially also of the glycosaminoglycan.
  • the formulations of the invention ensure an immediate release of the active ingredients within the first hours after injection followed by a sustained release of any one of and preferably more of the active ingredients over an extended period of time.
  • 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 (bio)polymers such as for instance suspensions, emulsions and 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 formulations providing controlled release of the glycosaminoglycan over an extended period of time.
  • the formulations embodying the principles of the present invention comprising a sustained release agent such as a gel forming agent allow to protect their enclosed active ingredients or other components from the physical environment, thereby improving the stability of their active ingredients or other components in vivo.
  • a sustained release agent such as a gel forming agent
  • the present formulations comprising a sustained release agent can provide a protection of their enclosed active ingredients or other components against enzymatic degradation.
  • the formulations according to the present invention comprising a sustained release agent advantageously have mechanical and/or rheological properties close to healthy synovial fluid.
  • the present formulations comprising a sustained release agent such as a gel-forming agent therefore allow to improve the articular function by their lubricating action on the joint.
  • the present formulations further allow to effectively restore the mechanical integrity of the joint.
  • a glycosaminoglycan and a gel-forming agent as a sustained release pharmaceutical excipient or as a protectant against a glycosaminoglycanase, preferably selected from hyaluronidase, chondroitin B lyase, proteoglycanase, keratanase, chitosanase and chitinase.
  • another aspect relates to the use of a glycosaminoglycan and a gel-forming agent as a sustained release pharmaceutical excipient or as a protectant against a glycosaminoglycanase.
  • a glycosaminoglycan and a gel-forming agent as a sustained release pharmaceutical excipient or as a protectant against a glycosaminoglycanase.
  • Such use of the present formulations or kits of parts advantageously increases the stability of the pharmaceutical active ingredients or other components and hence, prolongs the presence of the pharmaceutical active ingredients or other components in situ.
  • These aspects use a glycosaminoglycan and a gel-forming agent, which components may thus be suitably denoted as being in combination.
  • glycosaminoglycan and gel-forming agent as taught herein for use as a sustained release pharmaceutical excipient, preferably for use as a sustained release pharmaceutical excipient in any one of the diseases as taught herein, and more preferably for use as a sustained release pharmaceutical excipient in the treatment of osteoarticular diseases, including acute or chronic osteoarticular diseases, such as preferably osteoarthritis, rheumatoid arthritis, monoarthritis and poly-arthritis.
  • a glycosaminoglycan and gel-forming agent as taught herein for the manufacture of a sustained release pharmaceutical excipient, preferably for the manufacture of a sustained release pharmaceutical excipient for the treatment of any one of the diseases as taught herein, and more preferably for the manufacture of a sustained release pharmaceutical excipient for the treatment of osteoarticular diseases, including acute or chronic osteoarticular diseases, such as preferably osteoarthritis, rheumatoid arthritis, mono-arthritis and poly-arthritis.
  • any one of the diseases as taught herein and preferably osteoarticular diseases including acute or chronic osteoarticular diseases, such as preferably osteoarthritis, rheumatoid arthritis, mono-arthritis and poly-arthritis, in a subject in need of such treatment, comprising administering to said subject a glycosammoglycan and gel-forming agent as a sustained release pharmaceutical excipient.
  • a method for treating any one of the diseases as taught herein and preferably osteoarticular diseases in a subject in need of such treatment comprising administering to said subject a therapeutically or prophylactically effective amount of a glycosammoglycan and gel-forming agent as a sustained release pharmaceutical excipient.
  • the glycosammoglycan and gel-forming agent as taught herein can be administered in combination with one or more pharmaceutical active ingredients, preferably one or more alpha-2 adrenergic receptor agonists and/or one or more corticosteroids.
  • a glycosammoglycan and gel- forming agent as taught herein for use as a sustained release pharmaceutical excipient, preferably for use as a sustained release pharmaceutical excipient in any one of the diseases as taught herein, and more preferably for use as a sustained release pharmaceutical excipient in the treatment of osteoarticular diseases, including acute or chronic osteoarticular diseases, such as preferably osteoarthritis, rheumatoid arthritis, mono-arthritis and poly-arthritis, wherein the glycosammoglycan and sustained release agent is to be administered in vivo together with one or more pharmaceutical active ingredients, preferably one or more alpha-2 adrenergic receptor agonists and/or one or more corticosteroids.
  • osteoarticular diseases including acute or chronic osteoarticular diseases, such as preferably osteoarthritis, rheumatoid arthritis, mono-arthritis and poly-arthritis, in a subject in need of such treatment, comprising administering to said subject a glycosammoglycan and gel-forming agent as a sustained release pharmaceutical excipient together with one or more pharmaceutical active ingredients, preferably one or more alpha-2 adrenergic receptor agonists and/or one or more corticosteroids.
  • a glycosammoglycan and gel-forming agent as a sustained release pharmaceutical excipient together with one or more pharmaceutical active ingredients, preferably one or more alpha-2 adrenergic receptor agonists and/or one or more corticosteroids.
  • Another aspect provides use of a glycosammoglycan and gel-forming agent as taught herein as a protectant against a glycosammoglycanase. Also provided is the use of a glycosammoglycan and gel-forming agent as disclosed herein for protecting a glycosammoglycan, such as particularly the glycosammoglycan contained in the combination, against a glycosammoglycanase. A related aspect provides a glycosammoglycan and gel-forming agent as disclosed herein for use as a protectant against a glycosammoglycanase.
  • glycosammoglycan and gel-forming agent as disclosed herein for use as a protectant of a glycosammoglycan against a glycosammoglycanase.
  • the glycosammoglycan and gel-forming agent may advantageously but without limitation act as a protectant against a glycosammoglycanase particularly for the glycosammoglycan contained in the combination.
  • the glycosaminoglycan and gel-forming agent can potentially provide additional advantages as described herein.
  • glycosaminoglycan and a gel-forming agent such as particularly in combination, as a visco-elastic agent or as a lubricant.
  • glycosaminoglycan and gel-forming agent as described elsewhere in this application, also apply to the aforementioned uses of the glycosaminoglycan and the gel-forming agent as a pharmaceutical excipient; as a visco- elastic agent; as a lubricant; or as a protectant against a glycosaminoglycanase.
  • 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.
  • the gel-forming formulations taught herein comprise a glycosaminoglycan, a sustained release agent and one or more pharmaceutical active ingredients.
  • 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 glycosaminoglycans.
  • 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 containing hyaluronic acid.
  • proteoglycan refers to proteins with one or more covalently attached glycosaminoglycan (GAG) chain(s).
  • 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 -(l,4)-linked N-acetylglucosamine.
  • glycosaminoglycans used in accordance with the invention are known and commercially available.
  • the present formulations can comprise the glycosammoglycan in a concentration ranging between 0.1 and 15% by weight (w/w).
  • the formulations can comprise the glycosammoglycan 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 glycosammoglycan in a concentration ranging between 0.7 and 1.0% by weight (w/w).
  • the formulations can comprise the glycosammoglycan in a concentration ranging between 0.7 and 1.5% by weight (w/w). More preferably, the formulations can comprise the glycosammoglycan in a concentration of 0.75% by weight (w/w). Where the glycosammoglycan displays therapeutic benefit of its own, such as but without limitation in osteoarticular diseases, it may be included in a therapeutically effective amount, such as the exemplary amounts recited in this paragraph.
  • the glycosammoglycan and the alpha-2 adrenergic receptor agonist are not covalently linked or are covalently linked.
  • the glycosammoglycan and the corticosteroid are not covalently linked or are covalently linked.
  • the glycosammoglycan 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 glycosammoglycan can be for instance but is not limited to sodium hyaluronate characterized by a high molecular weight of about 1.9 MDa.
  • the present 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 derivative thereof in a concentration ranging between 0.7 and 1.0% by weight (w/w).
  • the formulations can comprise the hyaluronic acid or derivative thereof in a concentration ranging between 0.7 and 1.5% by weight (w/w).
  • the gel- forming formulations taught herein comprise a glycosaminoglycan, a sustained release agent and one or more pharmaceutical active ingredients.
  • the applicability of the present invention is not limited to any pharmaceutical active ingredient or class of pharmaceutical active ingredients.
  • the pharmaceutical active ingredient may be pharmacologically or chemotherapeutically active itself, or may be converted into a pharmacologically or chemotherapeutically active species by a chemical or enzymatic process in the body, i.e., the pharmaceutical active ingredient may be a prodrug.
  • the developed delivery system may be administered parenterally, such as intra-osseously, intra-articularly, subcutaneously, intramuscularly and/or in any biological cavity.
  • the present formulations may also be particularly useful for poorly-stable pharmaceutical active ingredients, used in chronic diseases or in any osteoarticular pathology.
  • poorly-stable pharmaceutical active ingredients include peptides and proteins, peptide-like active ingredients, antibodies and vaccines, sRNA, DNA, hormones (including glucocorticoids), immunoglobulins, insulin, thyroid hormones, estrogens, androgens, testosterone, somatorelin, growth hormone, somatostatin, desmopressin, terlipressin, monoclonal antibodies, recombinant antibodies, gonadorelin analogues, gonadorelin antagonists, etc.
  • hormones including glucocorticoids
  • immunoglobulins insulin, thyroid hormones, estrogens, androgens, testosterone, somatorelin, growth hormone, somatostatin, desmopressin, terlipressin, monoclonal antibodies, recombinant antibodies, gonadorelin analogues, gonadorelin antagonists, etc.
  • the present invention can be used for pharmaceutical active ingredients characterized by anticancer, antiviral, antimicrobial, anthelmintic, antimycotic activities such as beta-lactam antibiotics, macrolides, tetracyclines, aminoglycosides, quinolones, azolic derivates, AIDS antiviral agents, hepatite B and C drugs, herpetic drugs, polyen antimycotic drugs, echinocandins, antiprotozoaire drugs, alkylating agents, antimetabolites, antitumoral antibiotics, topo-isomerase inhibitors, microtubules inhibitors, tyrosin kinase inhibitors. Chronic diseases may also be treated with the present formulations.
  • the pharmaceutical active ingredients which may be administered for this purpose include one or more of antithrombic and antihemorrhagic drugs, therapeutic agents for cardiovascular diseases when chronic administration is needed, antipsychotics, antidepressants, stimulating agents, antiparkinsonians, antiepileptics, and active compounds used in neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease.
  • antalgic drugs for chronic pain such as NSAI drugs, foot drop drugs, active agents for osteoporosis and Paget diseases may also be administered.
  • pharmaceutical active ingredient or “pharmaceutical drug” also encompasses any pharmacologically active salts, esters, N-oxides or prodrugs of the title compound or substance.
  • combination of two or more pharmaceutical active ingredients or doses combinations may be included as the drug component.
  • the release of each active ingredient may be identical or different such as for instance in case of a combination of two active ingredients in which the first one is presented as an immediately release form and the second one as a controlled release.
  • a combination of immediate release and controlled release form may also be obtained for the same active ingredient, in order to provide a rapid and sustained effect.
  • the pharmaceutical active ingredient may be an alpha-2 adrenergic receptor agonist.
  • the alpha-2 adrenergic receptor agonist may be selected from the group consisting of clonidine and derivatives thereof, including 2,6-dimethylclonidine, 4-azidoclonidine, 4-carboxyclonidine-methyl 3,5-dichlorotyrosine, 4-hydroxyclonidine, 4-iodoclonidine, alinidine, apraclonidine, chlorethylclonidine, clonidine 4-isothiocyanate, clonidine 4-methylisothiocyanate, clonidine receptor, clonidine-displacing substance, hydroxyphenacetyl aminoclonidine, ⁇ , ⁇ '- dimethylclonidine, p-aminoclonidine, and tiamenidine; imidazolidines, including imidazolines, impromidine, detomidine, medetomidine, dexmedetomidine, levamisole, losartane, lofexidine, miconazole, naphazoline,
  • alpha-2 adrenergic receptor agonist as intended herein may be clonidine, p- aminoclonidine, tiamenidine, 5-bromo-6- (2 imidazolidine-2- ylamino) quinoxaline, dexmedetomidine, detomidine, medetomidine, oxymetazonline, tizanidine, mivazerol, lofexidine, formoterol fumarate, nicergoline, rilmenidine, xylazine, guanfacine, guanclofine, guanoxabenz, or a derivative or structural analogue thereof, alpha-methyinorepherine, azepexole, indoramin, 6-allyl- 2-amino- 5, 6, 7, 8-tetrahydro4H-thiazolo [4, 5-d] azepine diHCl or a compound selected from the table 1 and analogs thereof.
  • Table 1 provides a view of an applicable classification of alpha-2- adrenergic receptor agonists.
  • the alpha-2 adrenergic receptor agonists used in accordance with some embodiments of the invention are known. Pharmaceutical preparations of alpha-2 adrenergic receptor agonists are commercially available.
  • the alpha-2 adrenergic receptor agonists can be manufactured in a known manner essentially in accordance with processes described in the prior art.
  • the alpha-2 adrenergic receptor agonist including salts thereof can be employed in a therapeutically effective amount.
  • the formulations can comprise the alpha-2 adrenergic receptor agonist in a concentration ranging between 0.0150 and 6.75% by weight (w/w).
  • the formulations can comprise the alpha-2 adrenergic receptor agonist in a concentration ranging between 0.
  • the formulations can comprise the alpha-2 adrenergic receptor agonist in a concentration ranging between 0.0150 and 0.225%) by weight (w/w).
  • the formulations can comprise the alpha-2 adrenergic receptor agonist in a concentration ranging between 0.0150 and 0.0675%) by weight (w/w).
  • the alpha-2 adrenergic receptor agonist is clonidine.
  • clonidine refers to N-(2,6-dichlorophenyl)-4,5-dihydro-lH-imidazol-2-amine and includes the pharmaceutically acceptable salts thereof, e.g., salts with inorganic acids, such as hydrohalic acids, or with organic acids, for example lower aliphatic monocarboxylic or dicarboxylic acids such as acetic acid, fumaric acid or tartaric acid or aromatic carboxylic acids such as salicylic acid are also suitable.
  • inorganic acids such as hydrohalic acids
  • organic acids for example lower aliphatic monocarboxylic or dicarboxylic acids such as acetic acid, fumaric acid or tartaric acid or aromatic carboxylic acids such as salicylic acid are also suitable.
  • formulations comprising clonidine in a therapeutically effective amount.
  • the formulations can comprise clonidine in a concentration ranging between 0.0150 and 6.75%) by weight (w/w).
  • the formulations can comprise clonidine in a concentration ranging between 0.0150 and 4.50% by weight (w/w), for example between 0.0150 and 2.25% by weight (w/w), for example between 0.0150 and 0.675% by weight (w/w), for example between 0.0150 and 0.45% by weight (w/w), for example, the formulations can comprise clonidine in a concentration ranging between 0.0150 and 0.225%) by weight (w/w).
  • the formulations can comprise clonidine in a concentration ranging between 0.0150 and 0.0675%) by weight (w/w).
  • the glycosaminoglycan is sodium hyaluronan
  • the sustained release agent is glycerol monooleate
  • the pharmaceutical drug is clonidine.
  • such formulations can comprise sodium hyaluronan in a concentration ranging between 0.1 and 15%) by weight (w/w), glycerol monooleate in a concentration ranging between 5 and 85% by weight (w/w) and clonidine in a concentration ranging between 0.0150 and 6.75%) by weight (w/w).
  • the present formulations may comprise sodium hyaluronan in a concentration ranging between 0.7 and 1.5% by weight (w/w), glycerol monooleate in a concentration ranging between 45 and 65% by weight (w/w) and clonidine in a concentration ranging between 0.0150 and 0.0675%) by weight (w/w).
  • the present formulations may be particularly useful for pharmaceutical active ingredients including hormones, such as inter alia glucocorticoids.
  • the pharmaceutical active ingredient may thus be a steroid hormone, preferably a corticosteroid, such as a glucocorticoid or a mineralocorticoid.
  • the pharmaceutical active ingredient may be a glucocorticoid.
  • Corticosteroids such as in particular glucocorticoids, are currently used for treatment of acute arthritic flares such as mono-arthritis flares, in particular by intra-articular administration.
  • the sustained-release formulation described herein can provide a new suitable alternative to the current ways of administration of corticosteroids.
  • the pharmaceutical active ingredient may be a corticosteroid, preferably a glucocorticoid.
  • a corticosteroid such as a glucocorticoid, as intended herein may be, without limitation, of hydrocortisone type (e.g., hydrocortisone (i.e., Cortisol), hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, or prednisone); or an acetonide (e.g., triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, or halcinonide); or of betamethasone type (e.g., betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, or fluocortolone); or of ester type (e.g., hydrocortis
  • the corticosteroid such as a glucocorticoid
  • the corticosteroid may be selected from the group consisting of betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, prednisone, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, halcinonide, hydrocortisone- 17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone- 17-butyrate
  • the corticosteroids such as glucocorticoids, used in accordance with certain embodiments of the invention are known. Pharmaceutical grade preparations of corticosteroids, such as glucocorticoids, are commercially available.
  • the corticosteroids, such as glucocorticoids can be manufactured in known manners essentially in accordance with processes described in the prior art.
  • the corticosteroids, such as glucocorticoids, including salts thereof can be employed in a therapeutically effective amount.
  • the formulations can comprise the corticosteroid, such as glucocorticoid, in a concentration ranging between 0.100 and 10.00% by weight (w/w).
  • the formulations can comprise the corticosteroid, such as glucocorticoid, in a concentration ranging between 0.200 and 5.00% by weight (w/w), for example between 0.250 and 2.50% by weight (w/w), for example, the formulations can comprise the corticosteroid, such as glucocorticoid, in a concentration ranging between 0.250 and 1.00% by weight (w/w).
  • the formulations can comprise the corticosteroid, such as glucocorticoid, in a concentration ranging between 0.250 and 0.750%> by weight (w/w).
  • the corticosteroid is betamethasone.
  • betamethasone refers to a glycocorticoid steroid and includes the pharmaceutically acceptable salts or esters thereof.
  • the pharmaceutically active ingredient may be selected from the group consisting of betamethasone, betamethasone sodium phosphate, betamethasone valerate, and betamethasone dipropionate.
  • Betamethasone is available in a number of compound forms: betamethasone dipropionate for example branded as Diprosone, Diprolene, Celestamine, and others; betamethasone sodium phosphate for example branded as Bentelan; and betamethasone valerate for example branded as Betnovate, Celestone, Fucibet, and others. In the United States and Canada, betamethasone may be mixed with clotrimazole and may be sold as Lotrisone and Lotriderm.
  • formulations comprising betamethasone in a therapeutically effective amount.
  • the formulations can comprise betamethasone in a concentration ranging between 0.100 and 10.00%) by weight (w/w).
  • the formulations can comprise betamethasone in a concentration ranging between 0.200 and 5.00%> by weight (w/w), for example between 0.250 and 2.50%) by weight (w/w), for example, the formulations can comprise betamethasone in a concentration ranging between 0.250 and 1.00%> by weight (w/w).
  • the formulations can comprise betamethasone in a concentration ranging between 0.250 and 0.750%o by weight (w/w).
  • the glycosaminoglycan is hyaluronic acid or a derivative thereof, more preferably sodium hyaluronan
  • the sustained release agent is a glyceride, preferably a monoglyceride, more preferably glycerol monooleate
  • the pharmaceutical active ingredient is a steroid hormone, preferably a corticosteroid, more preferably a glucocorticoid.
  • the glycosaminoglycan is hyaluronic acid or a derivative thereof, more preferably sodium hyaluronan
  • the sustained release agent is a glyceride, preferably a monoglyceride, more preferably glycerol monooleate
  • the pharmaceutical active ingredient is betamethasone, such as, e.g., betamethasone, betamethasone sodium phosphate, betamethasone valerate, or betamethasone dipropionate, preferably betamethasone dipropionate.
  • the glycosaminoglycan is sodium hyaluronan
  • the sustained release agent is glycerol monooleate
  • the pharmaceutical active ingredient is betamethasone.
  • such formulations can comprise sodium hyaluronan in a concentration ranging between 0.1 and 15% by weight (w/w), glycerol monooleate in a concentration ranging between 5 and 85% by weight (w/w) and betamethasone in a concentration ranging between 0.100 and 10.00%) by weight (w/w).
  • the present formulations may comprise sodium hyaluronan in a concentration ranging between 0.7 and 1.5% by weight (w/w), glycerol monooleate in a concentration ranging between 45 and 65%) by weight (w/w) and betamethasone in a concentration ranging between 0.250 and 0.750% by weight (w/w).
  • the pharmaceutical active ingredients may be i) an alpha-2 adrenergic receptor agonist as defined herein, preferably clonidine or a derivative thereof; and ii) a steroid hormone as defined herein, preferably a corticosteroid, more preferably a glucocorticoid, even more preferably betamethasone.
  • the glycosaminoglycan is hyaluronic acid or a derivative thereof, more preferably sodium hyaluronan
  • the sustained release agent is a glyceride, preferably a monoglyceride, more preferably glycerol monooleate
  • the pharmaceutical active ingredients are i) an alpha-2 adrenergic receptor agonist, preferably clonidine or a derivative thereof; and ii) a steroid hormone, preferably a corticosteroid, more preferably a glucocorticoid, even more preferably betamethasone.
  • the glycosaminoglycan is sodium hyaluronan
  • the sustained release agent is glycerol monooleate
  • the pharmaceutical drugs are clonidine and betamethasone.
  • the gel- forming formulations may further comprise one or more excipients selected from a solvent, an 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. Hence, the one or more solvents may further increase the injectability of the present formulations. In addition, the one or more solvents may allow the sterilization of the lipidic phase of the formulations by filtration in an aseptic environment.
  • such formulations may comprise ethanol in a concentration ranging between 0 and 95% by weight (w/w).
  • the formulation can comprise ethanol in a concentration ranging between 0 and 20% by weight (w/w), for example, between 5%> and 15%> by weight (w/w).
  • the formulation 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 formulation 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 formulation 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 present formulation 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 soybean oil, coconut oil, corn oil, cottonseed oil, olive oil, palm oil, peanut oil (ground nut oil), rapeseed oil, safflower oil, sesame 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.
  • 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. In addition and possibly related to the aforementioned, the oil may further prolong the sustained release of the active ingredients 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 present formulations can comprise the vegetable oil in a concentration ranging between 0 and 10% by weight (w/w), for example, the present formulations can comprise the vegetable oil in a concentration ranging between 2.5 and 7.5% by weight (w/w).
  • the present formulations can comprise the vegetable oil in a concentration ranging between 2 and 5% by weight (w/w).
  • the present 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 present formulation can comprise soybean oil in a concentration ranging between 0 and 10% by weight (w/w), for example, the present formulation can comprise soybean oil in a concentration ranging between 2.5 and 7.5% by weight (w/w).
  • the present formulation can comprise soybean oil in a concentration ranging between 0 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, sulphites, 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 present formulations can comprise an antioxidant or a combination of antioxidative agents 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 formulation 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(s) may prevent both the oxidation of the lipidic and hydrophilic compounds present in the formulations.
  • the present formulations may comprise alpha-tocopherol acetate as an antioxidant.
  • the present formulations can comprise alpha-tocopherol acetate in a concentration ranging between 0 and 3% by weight (w/w).
  • the present formulations can comprise alpha-tocopherol acetate in a concentration ranging between 0.01 and 1% by weight (w/w), for example, the present formulations can comprise alpha-tocopherol acetate in a concentration ranging between 0.1 and 0.6% by weight (w/w).
  • the present formulations 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 rheological properties of the present formulations during storage in particular at temperatures equal to or above room temperature. Such a pH advantageously improves or maintains the stability of the glycosaminoglycan such as sodium hyaluronate in the present formulations during storage in particular 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 dissolution profiles of clonidine loaded in a cubic phase structure of GMO (CUBIC REF), in a mixture of GMO with solvent (CGS REF) and in a formulation illustrating the invention (F2, see Tables 14 and 15).
  • Figure 2 represents a graph illustrating the dissolution profiles of clonidine loaded in a cubic phase structure of GMO (CUBIC REF) and in two formulations illustrating the invention with different concentrations of clonidine (F2 and F6, see Tables 14 and 15).
  • Figure 3 represents a graph illustrating the dissolution profiles of clonidine loaded in a cubic phase structure of GMO (CUBIC REF), in a mixture of GMO with solvent (CGS REF) and in four formulations illustrating the invention with different concentrations of sodium hyaluronate (Fl to F4, see Table 14 and 15).
  • Figure 4 represents a graph illustrating the dissolution profiles of clonidine loaded in two formulations illustrating the invention with different concentrations of propylene glycol (F2 and F7, see Table 14).
  • Figure 5 represents a graph illustrating the dissolution profiles of clonidine loaded in two formulations exemplifying the invention with different concentrations of sodium oleate (F2 and F8, see Table 14).
  • Figure 6 represents a graph illustrating the dissolution profiles of clonidine loaded in three formulations illustrating the invention with different concentrations of soybean oil and propylene glycol (F2, F9 and F10, see Table 14).
  • Figure 7 represents a graph illustrating the water uptake of different formulations exemplifying the invention in function of time.
  • Figure 9 represents a graph illustrating the chromatograms obtained by gel permeation chromatography (GPC) analysis showing the fast degradation of a solution of 1 mg/ml of sodium hyaluronate at pH 7 and 37°C in presence of 2 Ul/ml of ovine hyaluronidase.
  • GPC gel permeation chromatography
  • the control comprises 1 mg/ml sodium hyaluronate, without hyaluronidase in the medium.
  • Figure 11 represents a graph illustrating the chromatograms obtained by gel permeation chromatography (GPC) analysis showing the protection of sodium hyaluronate 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 a formulation illustrating the invention.
  • GPC gel permeation chromatography
  • Figure 12 represents an agarose gel illustrating the 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 comparative formulation without clonidine (Fl l of Table 14 without clonidine) at day 0, (5) at day 7, (6) at day 14 and (7) at day 21, and (8) a formulation illustrating the invention (Fl l, Table 14) at day 0, (9) at day 14 and (10) at day 21.
  • a comparative formulation without clonidine Fl l of Table 14 without clonidine
  • Figure 14 represents a graph illustrating the cytokine secretion in the supernatant of stimulated peripheral blood mononuclear cells (PBMCs) left untreated (LPS) or treated with dexamethasone (DEX) or clonidine (Clo).
  • PBMCs peripheral blood mononuclear cells
  • LPS peripheral blood mononuclear cells
  • DEX dexamethasone
  • Clo clonidine
  • Figures 15A and 15B represent graphs illustrating the secretion of tumor necrosis factor alpha (TNFa) and interleukine-6 (IL6) respectively, in the supernatant of stimulated peripheral blood mononuclear cells (PBMCs) left untreated (LPS) or treated with triamcinolone (Triam) or clonidine (Clo) and different concentrations of hyaluronic acid (HA).
  • TNFa tumor necrosis factor alpha
  • IL6 interleukine-6
  • 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, a sustained release agent and one or more pharmaceutical active ingredients, as well as to related kits, uses and methods.
  • sustained release broadly refers 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 formulation know in the prior art.
  • the sustained release refers to the prolonged release of the active ingredients from the present formulations.
  • the sustained release refers to the extended release of one or more pharmaceutical active ingredients such as one or more alpha-2 adrenergic receptor agonists and/or optionally a glycosaminoglycan from the present formulations.
  • the half-life of high molecular weight hyaluronic acid in the joint is about 6 to 8 hours.
  • the sustained release as used herein refers to the extended release of one or more pharmaceutical active ingredients such as one or more alpha-2 adrenergic receptor agonists and/or optionally 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.
  • pharmaceutical active ingredients such as one or more alpha-2 adrenergic receptor agonists and/or optionally 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.
  • the one or more pharmaceutical active ingredients can be conveniently considered to represent a therapeutically active principle, i.e., an active ingredient.
  • the glycosaminoglycan can have some therapeutic benefit (e.g., in osteoarticular diseases)
  • the glycosaminoglycan can also be conveniently considered to represent a therapeutically active principle.
  • 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). Typically, an active ingredient may achieve such outcome(s) through interacting with and/or modulating living cells or organisms.
  • An aspect relates to the use of a glycosaminoglycan and a sustained release agent as a pharmaceutical excipient; as a visco-elastic agent; as a lubricant; or as a protectant against a glycosaminoglycanase, preferably selected from hyaluronidase, chondroitin B lyase, proteoglycanase, keratanase, chitosanase and chitinase.
  • glycosaminoglycan and sustained release agent are suitable for use as a protectant against a glycosaminoglycanase.
  • protecting refers to the ability of the glycosaminoglycan and sustained release agent 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 glycosaminoglycan and sustained release agent are further suitable for use as a visco-elastic agent.
  • visco-elastic agent refers to the ability of the glycosaminoglycan and sustained release agent to provide visco- elasticity to a formulation.
  • visco-elasticity generally refers to the property of a material to exhibit both viscous and elastic characteristics, i.e. time dependent strain when undergoing deformation.
  • glycosaminoglycan and sustained release agent are further suitable for use as a lubricant.
  • lubricant refers to the ability of the glycosaminoglycan and sustained release agent to reduce friction between moving surfaces. For instance, in certain indications such as in osteoarticular diseases where the glycosaminoglycan and sustained release agent are administered intra-articularly, the glycosaminoglycan and sustained release agent can be conveniently considered to reduce friction between (i.e., lubricate) the joint surfaces.
  • the formulation of the invention can be a pharmaceutical formulation. Accordingly, the invention encompasses pharmaceutical formulations as taught herein.
  • a pharmaceutical formulation generally comprises the active ingredient(s) and 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
  • the composition 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.
  • kits 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.
  • 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, a sustained release agent and one or more pharmaceutical active ingredients such as one or more alpha-2 adrenergic receptor agonists; 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.
  • the formulations or kit of parts as taught herein may be used for the treatment and/or prevention of any disease wherein a subject would benefit from the sustained release of one or more pharmaceutical active ingredients (and potentially one or more glycosaminoglycans) after the administration of the one or more pharmaceutical active ingredients (and potentially one or more glycosaminoglycans) to the subject.
  • the formulations or kits of parts as taught herein may be used for the treatment and/or prevention of one or more diseases selected from osteoarticular diseases, chronic diseases, cancer, viral infections, bacterial infections, parasitic diseases, fungal diseases, vascular diseases, cardiac diseases, cardiovascular diseases, mental disorders, depression, Parkinson, epilepsy and Alzheimer's disease, etc.
  • formulations or kit of parts as taught herein may be used for the treatment and/or prevention of osteoarticular diseases or chronic diseases.
  • the chronic diseases as intended herein encompass but are not limited to chronic pain, osteoporosis and Paget' s disease of bone.
  • 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 spondylarthritis, 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-associated
  • 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-osseous or intra-articular route.
  • the gel-forming formulations or kits of parts for use 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 intra- articular 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 for use as taught herein 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. Accordingly, disclosed are also 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 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 an active ingredient or formulation that when administered brings about a positive therapeutic response with respect to treatment of a patient with osteoarticular disease.
  • Appropriate therapeutically effective doses of a pharmaceutical active ingredient in a formulation or kit of parts as taught herein can be determined by a qualified physician with due regard to the nature of the glycosaminoglycan, the disease condition and severity, and the age, size and condition of the patient.
  • appropriate therapeutically effective doses of an alpha-2 adrenergic receptor agonist in a formulation or pharmaceutical formulation of the invention can be determined by a qualified physician with due regard to the nature of the alpha-2 adrenergic receptor agonist, the disease condition and severity, and the age, size and condition of the patient.
  • the dose to be administered may range from about 0.30 to 1.5 mg of the alpha-2 adrenergic receptor agonist such as clonidine per injection, for example, from about 0.35 to 1.40 mg of the alpha-2 adrenergic receptor agonist such as clonidine per injection.
  • the dose to be administered ranges from about 0.450 to 1.35 mg of the alpha-2 adrenergic receptor agonist such as clonidine per injection.
  • 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 such as hyaluronic acid 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.
  • a GMO based formulation comprising 0.450 mg of clonidine was prepared as follows. Basically, under aseptic conditions, l . lg of glycerol monooleate (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, 0.3 g of an aqueous solution of clonidine (clonidine HC1; 1.5 mg/ml) passed through a 0.22 ⁇ filter was added under stirring and stirred until complete dissolution.
  • GMO glycerol monooleate
  • a GMO based formulation comprising 0.450 mg of clonidine was prepared as follows. Basically, under aseptic conditions, l .lg of glycerol monooleate (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. The obtained solution was filtrated through a 0.22 ⁇ filter in order to ensure the sterility of the GMO phase. To the filtrate, 0.3 g of an aqueous solution of clonidine (clonidine HC1; 1.5 mg/ml) passed through a 0.22 ⁇ filter was added under stirring and stirred until complete dissolution.
  • GMO glycerol monooleate
  • a GMO based formulation comprising 15 mg of sodium hyaluronate 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 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 magnetic stirring till sodium hyaluronate was completely dissolved.
  • a high-speed homogenizer e.g. Ultra-Turrax ®
  • GMO glycerol monooleate
  • Soybean oil A GMO based formulation comprising 15 mg of sodium hyaluronate 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. The obtained solution was filtrated through a 0.22 ⁇ filter in order to ensure the sterility of the GMO phase.
  • stirring e.g. magnetic stirring
  • Example 1 Preparation of a GMO based gel-forming formulation comprising sodium hyaluronate and clonidine
  • 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, 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 2 Composition of a formulation according to an embodiment of the invention
  • a formulation as described in Table 3 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, 0.3g 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 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, 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 4 Composition of a formulation according to an embodiment invention
  • 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 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 5 Composition of a formulation according to an embodiment of the invention
  • Example 2 Preparation of a GMO based gel-forming formulation comprising sodium hyaluronate, clonidine and purified Soybean oil
  • a formulation as described in Table 6 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 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, 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 (e.g. magnetic 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, 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 8 Composition of a formulation according to an embodiment of the invention
  • 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 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 9 Composition of a formulation according to an embodiment of the
  • Example 3 Preparation of a GMO based gel-forming formulation comprising sodium hyaluronate, clonidine, purified Soybean oil and alpha-tocopherol acetate
  • 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, 0.3 g of PG, O.lg of purified soybean oil and 600 ⁇ g of alpha- tocopherol acetate 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 10 Composition of a formulation according to an embodiment of the invention
  • 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, 0.1 g of purified soybean oil and 600 ⁇ g of alpha- tocopherol acetate 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, 0.1 g of purified soybean oil and 600 ⁇ g of alpha- tocopherol acetate 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 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, 0,lg of purified soybean oil and 600 ⁇ g of alpha- tocopherol acetate 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 13 Composition of a formulation according to an embodiment of the invention
  • Example 4 Dissolution profiles of clonidine from GMO based gel-forming formulations and water uptake profiles of said GMO based gel formulations
  • Table 14 Composition of formulations Fl to Fl 1 as examples of the invention
  • CLO clonidine
  • HA sodium hyaluronate
  • PG propylene glycol
  • GMO glycerol monooleate
  • CLO clonidine
  • HA sodium hyaluronate
  • PG propylene glycol
  • GMO glycerol monooleate
  • dissolution tests were perfomed.
  • a Disteck 2100C USP 32 dissolution apparatus (Distek Inc. North Brunswick, NJ, USA), Type II (paddle method) was used for the dissolution tests.
  • This dissolution apparatus was equipped with small volume bath vessels (200 ml) characterized by a flat bottom.
  • Topical drug dissolution cells (Distek ® 2100C Series, Etten-Leur, Holland) were used as sinker devices in order to immerse the samples.
  • the dissolution tests were performed in triplicate on lg of the formulation. Release testing was carried out in 50 ml of saline phosphate buffer solutions (1.06mM Potassium phosphate monobasic / 2.97mM Sodium phosphate dibasic / 155.17mM Sodium Chloride) at pH 7.4 ⁇ 0,05 (Invitrogen ® , Merelbeke, Belgium). The temperature of the dissolution media was maintained at 37 ⁇ 0.1 °C. The rotational speed employed was 50 rpm. Sodium azide (0.02% w/w) was added to the dissolution medium in order to prevent bacterial contamination.
  • the similarity f 2 factor was used in order to determine the similarity of dissolution profiles (Shah V.P. and al., 1998).
  • the compared dissolution profiles were obtained under the same conditions and their dissolution time points were similar.
  • the apparent drug diffusion coefficient (D) within the formulations was determined by a mathematical model described by Siepmann and co-workers (Siepmann J. and Siepmann F, 2008). This model allows the quantification of the effect of the composition of the formulation on D within the gel. The higher the value of D, the higher the release rate of the drug or active ingredient from the gel.
  • the apparent drug diffusion coefficient within the formulations was determined by fitting an analytical solution of Fick's second law of diffusion to experimentally determined drug release kinetics from gels, in which the drug was molecularly dispersed. As only one edge was exposed to the release medium, the mathematical analysis could be restricted to one dimension. Hence, the release kinetics could be described by Fick's second law of diffusion in a plane sheet as shown in Formula (I), dt dx 2 (I)
  • c denotes the concentration of the drug within the formulation, being a function of time and position x.
  • M t and M ⁇ represent the absolute cumulative amounts of active ingredient released at time t and infinite time, respectively; L denotes the height of the gel.
  • the dissolution profile of clonidine from a cubic phase structure gel of GMO (CUBIC REF in Figure 1) was performed as a reference because this known formulation presented high viscosity and the cubic phase is the most suitable crystalline phase structure for sustained delivery systems. Nevertheless, the CUBIC REF preparation is uninjectable. In consequence of uninjectability of this kind of preparations, the addition of solvents was considered (CGS REF in Figure 1). Nevertheless, the CGS REF formulation provided a very fast release of clonidine in about 2 hours as shown in Figure 1.
  • formulation F2 was considered as a reference gel-forming formulation for further testing.
  • the release profile of clonidine seemed to not be influenced by the concentration of clonidine in the formulation ( Figure 2).
  • a formulation comprising 0.0225%) of clonidine (F2, Figure 2) had a similar release profile compared with a formulation comprising 0.0675%) of clonidine (F6, Figure 2).
  • f2 ' factor values of a formulation comprising 0.0225%o of clonidine (F2) and a formulation comprising 0.0675%o of clonidine (F6) showed no significant difference with both references (Table 16).
  • 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.
  • ⁇ 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).
  • Structovial ® (Croma-Pharma GmbH, Austria) is an example of a commercially available product currently used in the treatment of arthritis.
  • Structovial ® is an aqueous solution comprising 1% sodium hyaluronate.
  • Structovial ® showed lower viscosity values and lower pseudoplasticity (higher n value) compared with the formulations Fl-Fl 1 which illustrate the present invention.
  • formulation FIO 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 8).
  • 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., 1157-1163, 2002). This value of crossover frequency is confirmed by Fam et al., Biorheology, 44, 59-74, 2007.
  • 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.
  • Table 18 Rheological properties of the selected formulation in comparison with the Structovial® and healthy synovial fluid
  • formulation Fl 1 had rheological properties close to the healthy synovial fluid.
  • Syringeability was tested using a Stable Micro Systems TA-XT.plus Texture Analyser (Stable Micro systems,UK) equipped with a 50 kg loading cell. 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.
  • Syringeability of the formulations was directly dependent on the sodium hyaluronate concentration. The higher the concentration of sodium hyaluronate, the higher was the force required to apply a given displacement rate to the plunger of the syringe filled with the formulation. Indeed, the formulations comprising 5 mg sodium hyaluronate/g of formulation (Fl) and 15mg sodium hyaluronate/g of formulation (F4) showed a syringeability of about 62.4N ⁇ 1.6N and 142.5N ⁇ 3.2N, respectively (Table 19). For instance, the syringeability of formulation Fl l was significantly higher than the syringeability of the commercially available product Structovial ® (Table 19).
  • the present formulations show advantageous rheological properties and syringeability. These properties of the present formulations demonstrate the superiority of the present formulations in the treatment of osteoarticular diseases.
  • Example 6 Protection of a GMO based gel-forming formulation to degradation by hyaluronidase activity
  • 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 pH 7 and extraction of sodium hyaluronate was performed at 100°C during 20 minutes. The aqueous solutions were filtered through 0.22 ⁇ filters and analyzed by GPC.
  • Structovial ® was chosen as a reference product.
  • the formulation Fl l (as given in Table 14 and prepared as in Example 3A) protected sodium hyaluronate inside the formulation against enzymatic degradation during at least 24 hours.
  • 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 in the treatment of osteoarticular diseases.
  • Example 7 Release profiles of clonidine and hyaluronic acid from GMO based gel-forming formulations
  • Release profile of HA from a formulation according to an embodiment of the invention formulation Fl l (composition of the formulation as given in Table 14 and prepared as in Example 3A) is compared with the release profile of HA (i) from the comparative formulation CGS REF (composition of the formulation as given in Table 15 and as prepared in Comparative Example 2), (ii) from a formulation comprising HA and clonidine as known in the prior art and (iii) from a commercially available product (Structovial®).
  • the release profile is studied in an inflammatory environment such as in the presence of stimulated peripheral blood monocytes (PBMC) or in other environments such as in the presence of degrading enzymes, for instance in the presence of hyaluronidases.
  • the HA release profiles are assessed by agarose gel electrophoresis, by ELISA and by indirect HA quantification such as the measurement of the degradation time by degrading enzymes.
  • the hyaluronic acid release from a formulation illustrating the invention (formulation Fl l, Table 14), and from a comparative formulation (formulation Fl l without clonidine) was evaluated in complete cell culture medium containing 10% of serum.
  • 500mg of formulations were incubated at 37°C during 7, 14 or 21 days in 0.5 ml of complete cell culture medium. After incubation, supernatant was retrieved and diluted in charging buffer containing Stain- All® (Sigma Aldrich) and charged on a 1% agarose gel. The gel migrated in TA buffer at 100V during 4 to 5 hours.
  • ELISA Enzyme Linked Immunosorbent Assay
  • Example 8 Resistance of GMO based gel-forming formulations to degradation in situ
  • Example 5 Similar in vitro experiments as described in Example 5 are performed but the results are focused on the remaining formulation and its resistance to degradation.
  • the resistance to degradation is evaluated by measuring the residual HA inside the remaining formulation and compared with a formulation without clonidine in order to outline the possible protective role of clonidine.
  • the resistance to degradation is tested in in vitro experiments and/or subcutaneous implantation and in diffusion in vivo experiments.
  • Example 9 Efficacy of GMO based gel-forming formulations in a rat model of osteoarthritis
  • the following formulations are tested for their efficacy in the treatment of osteoartitis by intraarticular injection in a rat model: (i) a formulation according to an embodiment of the invention, formulation Fl l as given in Table 14 and prepared as in Example 3 A, (ii) a comparative formulation CGS REF as given in Table 15 and as prepared in Comparative Example 1, (iii) a comparative formulation comprising HA and clonidine as known in the prior art and (iv) a commercially available product (Structovial®).
  • the efficacy protection, regeneration of cartilage is studied by the investigation of the general behavior and clinical signs of the rat model, histology and (blood) biomarkers.
  • PBMCs peripheral blood mononuclear cells
  • LPS Lipopolysaccharide
  • PBMCs When stimulated with Lipopolysaccharide (LPS), PBMCs generally secrete different pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFa) and interleukine-6 (IL6).
  • TNFa tumor necrosis factor alpha
  • IL6 interleukine-6
  • PBMCs were co- treated with clonidine or a positive control, dexamethasone.
  • Pro-inflammatory cytokine secretion was evaluated by ELISA using specific antibodies against TNFa and IL6.
  • PBMC peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • formulations embodying the principles of the invention allow to prolong the release and effects of both an alpha-adrenergic receptor agonist such as clonidine and of a glycosaminoglycan such as hyaluronic acid in the joint over a few weeks.
  • the formulations of the invention further allow to protect the glycosaminoglycan against enzymatic degradation.
  • the formulations of the invention show rheological properties close to healthy synovial fluid.
  • the present formulations provide by their lubricating action on the joint an improved and prolonged articular function.
  • Example 10 Preparation of a GMO based gel formulation comprising sodium hyaluronate, clonidine, 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 20 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.
  • a high-speed homogenizer e.g. Ultra-Turrax ®
  • Table 20 Composition of a formulation according to an embodiment of the invention
  • a formulation as described in Table 21 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, 0.1 g 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.
  • a high-speed homogenizer e.g. Ultra-Turrax ®
  • Table 21 Composition of a formulation according to an embodiment of the invention
  • a formulation as described in Table 22 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, 0.1 g 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 ®
  • Table 22 Composition of a formulation according to an embodiment of the invention
  • 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, 0.3 g of PG, 0,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 an Ultra-Turrax device at 24000 rpm.
  • Table 23 Composition of a formulation according to an embodiment of the invention
  • Example 11 Preparation of a GMO based gel formulation comprising sodium hyaluronate, betamethasone dipropionate, 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
  • Glucocorticoids are currently used for treatment of acute arthritic flares.
  • the short-term benefit of intraarticular (IA) corticosteroids in mono-arthritis flare is well-established. Due to their sustained- release properties, the present formulations represent a suitable alternative for the administration of corticosteroids.
  • IA intraarticular
  • a formulation as described in Table 27 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 an ethanolic solution of 5 mg of betamethasone, 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
  • Table 27 Composition of a formulation according to an embodiment of the invention
  • a formulation as described in Table 28 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 an ethanolic solution of 10 mg of betamethasone, 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.
  • a high-speed homogenizer e.g. Ultra-Turrax ®
  • a formulation as described in Table 29 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 ethanolic solution of 5 mg of betamethasone, 0.3 g of PG, 0.1 g 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. 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
  • Table 29 Composition of a formulation according to an embodiment invention
  • a formulation as described in Table 30 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 ethanolic solution of 10 mg of betamethasone, 0.3 g of PG, 0.1 g 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. 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
  • Table 30 Composition of a formulation according to an embodiment of the invention
  • Example 12 Preparation of a GMO based gel formulation comprising sodium hyaluronate, clonidine, betamethasone dipropionate, 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
  • Glucocorticoids are currently used for treatment of acute arthritic flares. Indeed, the short-term benefit of intra-articular (IA) corticosteroids in mono-arthritis flare is well-established. Intraarticular use of alpha2-adrenergic receptor agonists such as clonidine are thought to produce analgesia mainly through an inhibition of the transmission of nociceptive stimulation.
  • the present formulations represent a suitable alternative to the administration of both corticosteroids and clonidine. Indeed, the burst release of clonidine could produce analgesia a few times after injection and the sustained-release of corticosteroids could provide an extended period of activity.
  • a formulation as described in Table 31 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 ethanolic solution of 5 mg of betamethasone, 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.
  • a high-speed homogenizer e.g. Ultra-Turrax ®
  • Table 31 Composition of a formulation according to an embodiment of the invention
  • a formulation as described in Table 32 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 ethanolic solution of 5 mg of betamethasone, 0.3 g of PG, 0.1 g 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.
  • a high-speed homogenizer e.g. Ultra-Turrax ®
  • Table 32 Composition of a formulation according to an embodiment of the invention
  • a formulation as described in Table 33 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 ethanolic solution of 5 mg of betamethasone, 0.3 g of PG, 0.1 g 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 ®
  • GMO based gel formulation pH 6.5 comprising 30 mg of sodium hyaluronate; 1.350 mg of clonidine; 5 mg of betamethasone, purified Soybean oil and acetate alpha-tocopherol
  • a formulation as described in Table 34 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 ethanolic solution of 5 mg of betamethasone, 0.3 g of PG, 0,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.
  • Table 34 Composition of a formulation according to an embodiment invention
  • Figure 19 shows substantially linear sustained release of betamethasone from the formulation over the duration of 20 days, and comparatively more burst like release of clonidine during this period.
  • a formulation as described in Table 35 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 ethanolic solution of 10 mg of betamethasone, 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.
  • a high-speed homogenizer e.g. Ultra-Turrax ®
  • Table 35 Composition of a formulation according to an embodiment of the invention
  • a formulation as described in Table 36 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 ethanolic solution of 10 mg of betamethasone, 0.3 g of PG, 0.1 g 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.
  • a high-speed homogenizer e.g. Ultra-Turrax ®
  • Table 36 Composition of a formulation according to an embodiment of the invention
  • G Preparation of a GMO based gel formulation pH 6.5 comprising 30 mg of sodium hyaluronate; 0.450 mg of clonidine; 10 mg of betamethasone; purified Soybean oil and acetate alpha-tocopherol
  • a formulation as described in Table 37 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 ethanolic solution of 10 mg of betamethasone, 0.3 g of PG, 0.1 g 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 ®
  • I.350 mg of clonidine; 10 mg of betamethasone, purified Soybean oil and acetate alpha-tocopherol A formulation as described in Table 38 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 ethanolic solution of 10 mg of betamethasone, 0.3 g of PG, 0,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.
  • Table 38 Composition of a formulation according to an embodiment invention
  • Figure 19 shows substantially linear sustained release of betamethasone from the formulation over the duration of 20 days, and comparatively more burst like release of clonidine during this period.

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Abstract

La présente invention concerne une formulation de formation de gel comprenant un glycosaminoglycane, un agent à libération prolongée et un ou plusieurs principes actifs pharmaceutiques. L'invention concerne également la formulation de formation de gel destinée à une utilisation en tant que médicament et 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 administration parentérale, de préférence par injection intra-osseuse ou intra-articulaire.
PCT/EP2012/073266 2011-11-21 2012-11-21 Formulations à libération prolongée utiles dans le traitement de maladies WO2013076160A1 (fr)

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WO2018125904A1 (fr) * 2016-12-27 2018-07-05 Board Of Regents Of The University Of Nebraska Compositions antimicrobiennes contenant une combinaison synergétique de créatinine activée et un agent antifongique imidazole
US10111956B2 (en) 2013-06-03 2018-10-30 Tolmar, Inc. Corticosteroid compositions
CN109431986A (zh) * 2018-12-17 2019-03-08 江西润泽药业有限公司 硫酸软骨素注射液及其制备方法
CN110114059A (zh) * 2017-01-06 2019-08-09 克雷西奥生物科技有限公司 地托咪定局部制剂
US10869955B2 (en) * 2015-01-28 2020-12-22 Allergan, Inc. Joint fat pad formulations, and methods of use thereof
WO2021005069A1 (fr) 2019-07-08 2021-01-14 Theravet Sa Procédé de préparation d'une composition gélifiante
WO2021005071A1 (fr) 2019-07-08 2021-01-14 Theravet Sa Composition, trousse et utilisation associée
WO2021005064A1 (fr) 2019-07-08 2021-01-14 Theravet Sa Composition, kit et utilisation associée
USRE48948E1 (en) 2008-04-18 2022-03-01 Warsaw Orthopedic, Inc. Clonidine compounds in a biodegradable polymer
EP4122450A1 (fr) * 2021-07-20 2023-01-25 Rosemont Pharmaceuticals Ltd Composition pharmaceutique liquide de clonidine

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