US20100285134A1 - Pharmaceutical composition for use in the treatment and/or the prevention of osteoarticular diseases - Google Patents

Pharmaceutical composition for use in the treatment and/or the prevention of osteoarticular diseases Download PDF

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US20100285134A1
US20100285134A1 US12/811,665 US81166509A US2010285134A1 US 20100285134 A1 US20100285134 A1 US 20100285134A1 US 81166509 A US81166509 A US 81166509A US 2010285134 A1 US2010285134 A1 US 2010285134A1
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pharmaceutical composition
alpha
glycosaminoglycan
hyaluronic acid
pain
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Enrico Bastianelli
Pierre Attali
Chris Vervaet
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Bone Therapeutics SA
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Bone Therapeutics SA
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    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
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Definitions

  • the present invention is in the pharmaceutical field and is related to a new pharmaceutical composition for use in the treatment and/or the prevention of acute and/or chronic osteoarticular diseases.
  • Osteoarthritis the most common form of arthritis, is a disease characterised by a slow degenerative processes in the articular cartilage, subchondral bone associated with marginal osteophyte formation, and low grade inflammation. Osteoarthritis is believed to affect 15% of the population in its chronic form. Of those, one-quarter are severely disabled. Most cases of osteoarthritis have no known cause and are referred to as primary osteoarthritis. When the cause of the osteoarthritis is known, the condition is referred to as secondary osteoarthritis. Secondary osteoarthritis is caused by another disease or 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 hormone disorders. Other forms of arthritis are systemic illnesses, such as rheumatoid arthritis and systemic lupus erythematosus (SLE).
  • SLE systemic illnesses
  • Osteoarthritis is characterized by a slow degradation of cartilage over several years. In normal cartilage, a delicate balance exists between matrix synthesis and degradation; in osteoarthritis, however, cartilage degradation exceeds synthesis. The balance between synthesis and degradation is affected by age and is regulated by several factors produced by the synovium and chondrocytes, including cytokines, growth factors, aggrecanases, and matrix metalloproteinases In addition to water, the extracellular matrix is composed of proteoglycans, made up of glycosaminoglycans attached to a backbone made of hyaluronic acid, entrapped within a collagenous framework or fibrillary matrix.
  • a significant proteoglycal in articular cartilage is aggrecan, which binds to hyaluronic acid and helps provide the compressibility and elasticity of cartilage.
  • Aggrecan is cleaved by aggrecanases, leading to its degradation and to subsequent erosion of cartilage.
  • the loss of aggrecan from the cartilage matrix is one of the first pathophysiological changes observed in OA.
  • Cytokines produced by the synovium and chondrocytes are also key players in the degradation of cartilage.
  • IL-1beta is spontaneously released from cartilage of osteoarthritis but not normal cartilage.
  • Both IL-1beta and TNF-alpha stimulate their own production and the production of other cytokines (e.g., IL-8, IL-6, and leukotriene inhibitory factor), proteases, and prostaglandin E 2 (PGE 2 ). Synthesis of the inflammatory cytokines IL-1beta and TNF-alpha and expression of their receptors are enhanced in osteoarthritis.
  • cytokines have been shown to potently induce degradation of cartilage in vitro.
  • Other proinflammatory cytokines overexpressed in osteoarthritis include IL-6, IL-8, IL-11, and IL-17, as well as leukotriene inhibitory factor.
  • the extracellular matrix (ECM) composing the cartilage is degraded by locally produced matrix metalloproteinases.
  • Proinflammatory cytokines including IL-1beta, TNF-alpha, IL-17, and IL-18, increase synthesis of matrix metalloproteinases, decrease matrix metalloproteinase enzyme inhibitors, and decrease extracellular matrix synthesis.
  • chondrocytes increase synthesis of matrix components including proteoglycans. Even though this activity increases, a net loss of proteoglycans in the upper cartilage layer is seen. Elevated anti-inflammatory cytokines found in the synovial fluid of osteoarthritis include IL-4, IL-10, and IL-13. Their role is to reduce production of IL-1beta, TNF-alpha, and matrix metalloproteinases, and inhibit prostaglandin release. Local production of growth and differentiation factors such as insulin-like growth factor 1, transforming growth factors, fibroblastic growth factors, and bone morphogenetic proteins also stimulate matrix synthesis.
  • osteoarthritis i.e. acetaminophen, cyclooxygenase-2-specific inhibitors, non-selective nonsteroidal anti-inflammatory drugs, tramadol, opioids.
  • analgesics i.e. acetaminophen, cyclooxygenase-2-specific inhibitors, non-selective nonsteroidal anti-inflammatory drugs, tramadol, opioids.
  • analgesics i.e. acetaminophen, cyclooxygenase-2-specific inhibitors, non-selective nonsteroidal anti-inflammatory drugs, tramadol, opioids.
  • intra-articularly e.g., glucocorticoids, hyaluronic acid
  • topically e.g., capsaicin, methylsalicylate.
  • the benefit of intra-articular glucocorticoids lasts only a few days (Barron, M. C., 2007, J. Am.
  • Polysaccharides form a class of materials whose recognition of the potential utility is growing. Apart from their biological activity, one of the most important properties of polysaccharides in general is their ability to form hydrogels. Hydrogel formation can occur by a number of mechanisms and is strongly influenced by the types of monosaccharide involved, as well as the presence and nature of substituent groups. Polysaccharide gel formation is generally of two types: hydrogen bonded and ionic. Hydrogen-bonded gels are typical of molecules such as agarose (thermal gellation) and chitosan (pH-dependent gellation), whereas ionically bonded gels are characteristic of alginates and carrageenans.
  • Proteoglycans are one of the major macromolecules found in articular cartilage. These molecules consist of a core protein and covalently attached glycosaminoglycans (GAG) chains.
  • GAGs are long, unbranched heteropolysaccharides, consisting of repeated disaccharide units, with the general structure: Muronic acid amino sugar.
  • the cartilage-specific GAGs include chondroitin 4-sulfate (glucuronic acid and N-acetyl-galactosamine with an SO 4 on the 4-carbon position), chondroitin 6-sulfate (glucuronic acid and N-acetyl-galactosamine with an SO 4 on the 6-carbon position) and keratan sulfate (galactose and N-acetyl-glucosamine with an SO 4 on the 6-carbon position).
  • hyaluronic acid glucuronic acid and N-acetyl-glucosamine
  • This molecule is one of the major components in synovial fluid.
  • Hyaluronic acid molecules are also present in cartilage matrix as the backbone structure in proteoglycan aggregates.
  • hyaluronic acid plays a major role as an organizer of the extracellular matrix. Purified hyaluronic acid is employed as a structural biomaterial because of its high molecular weight and gel forming ability.
  • the properties of the molecule may be broadly altered by chemical modification.
  • partial esterification of the carboxyl groups reduces the water solubility of the polymer and increases its viscosity.
  • Extensive esterification generates materials that form water-insoluble films or swellable gels.
  • Ethyl and benzyl esterified hyaluronate membranes have excellent healing responses and biodegradability properties.
  • the fully esterified membranes have in vivo lifetimes of several months, whereas the partially esterified forms have been shown to degrade within a few weeks.
  • Hyaluronic acid is responsible for the viscoelastic quality of synovial fluid that acts as both a lubricant and shock absorber.
  • hyaluronic acid coats the surface of the articular cartilage and shares space deeper in the cartilage among collagen fibrils and sulfated proteoglycans. It protects the cartilage and blocks the loss of proteoglycans from the cartilage matrix into the synovial space, maintaining the normal cartilage matrix.
  • concentrations of hyaluronic acid, glycosaminoglycans, and keratan sulfate are lower than in synovial fluid from normal knee joints.
  • hyaluronic acid synthetase which may contribute to the fragmentation of hyaluronic acid under inflammatory conditions.
  • Exogenous hyaluronic acid may facilitate the production of newly synthesized hyaluronic acid.
  • Hyaluronic acid and derivatives have been used as therapeutic aids in the treatment of osteoarthritis as a means of improving lubrication of articulating surfaces and thus reducing joint pain.
  • hyaluronic acid has a beneficial effect by inhibiting chondrocytic chondrolysis mediated by fibronectin fragment.
  • Hyaluronic acid has also been shown to have anti-inflammatory effects, as well as inhibitory effects on prostaglandin synthesis, and proteoglycan release and degradation.
  • Chitosan a partially de-acetylated derivative of chitin, found in arthropod exoskeletons is another proteoglycan, a linear polysaccharide consisting of beta (1-4) linked D-glucosamine residues with a variable number of randomly located N-acetyl-glucosamine groups. It thus shares some characteristics with various GAGs and hyaluronic acid present in articular cartilage, Depending on the source and preparation procedure, chitosan's average molecular weight may range from about 50 to about 1000 kDa. Commercially available preparations have degrees of deacetylation ranging from about to about 90%.
  • Chitosan is a semi-crystalline polymer and the degree of crystallinity is a function of the degree of deacetylation. Crystallinity is maximum for both chitin (i.e. 0% deacetylated) and fully deacetylated (i.e. 100%) chitosan. Minimum crystallinity is achieved at intermediate degrees of deacetylation.
  • chitosan Much of the potential of chitosan as a biomaterial stems from its cationic nature and high charge density.
  • the charge density allows chitosan to form insoluble ionic complexes or complex coacervates with a wide variety of water-soluble anionic polymers.
  • chitosan oligosaccharides have been shown to have a stimulatory effect on macrophages, and the effect has been linked to the acetylated residues.
  • both chitosan and its parent molecule, chitin have been shown to exert chemoattractive effects on neutrophils in vitro and in vivo.
  • chitosan is degraded by enzymatic hydrolysis.
  • the mechanical properties of chitosan scaffolds are mainly dependent on the pore sizes and pore orientations.
  • Hyaluronic acid a glycosaminoglycan
  • Hyaluronic acid is widely used for the treatment of osteoarthritis of the knee.
  • a survey of 2 general practices in the United Kingdom showed that about 15% of patients with osteoarthritis received intra-articular treatment with hyaluronic acid preparations. Because of its viscoelastic quality, it may replace synovial fluid. Furthermore, it may reduce the perception of pain. Beneficial molecular and cellular effects have also been reported.
  • Hyaluronic acid is frequently applied by intra-articular injection, yet the evidence concerning its clinical relevance is conflicting.
  • intra-articular hyaluronic acid at best, has a small effect; a clinically meaningful effect meaning an improvement of at least 15 mm on the visual analogue scale of pain (Bellamy et al, 2006).
  • These data form the basis for the use of intra-articular administration of hyaluronic acid in patients with osteoarthritis.
  • the benefits are sometimes noticed only one year after injections and, in some experiments, injections must be performed three to five-times a week (Barron, M. C., 2007).
  • Alpha-2-adrenergic receptor ligands especially agonists are drugs commonly used in medical practice as antihypertensive substance and in clinical anaesthesiology as component of general and locoregional anaesthesia and analgesia. They produce anxiolysis, analgesia, sedation, anaesthetic sparing effects and peri-operative hemodynamic stabilizing effects. Negative neurotoxicity studies allow their use (mainly clonidine) by systemic and perimedullar routes and for peripheral nerve blocks. Among the clinically available alpha-2-adrenoreceptors agonists, clonidine remains widely used: the substance is devoid of neurotoxicity and displays fewer side effects (i.e.
  • Clonidine a potent alpha-2-adrenergic receptors partial agonist, was used primarily for the treatment of hypertension. This drug stimulates alpha-2-adrenergic receptors in the vasomotor centres, causing a reduction of sympathetic outflow from the central nervous system. Both cardiac output and peripheral resistance are reduced resulting in a decrease in blood pressure. Higher concentrations cause a vasoconstriction by activation of postsynaptic receptors in vascular smooth muscle.
  • the significant advantages of the drug are counter balanced by side effects including dryness of the mouth, sedation and dizziness. Furthermore, other activities of these compounds such as anti-inflammatory effect have never been reported by oral administration.
  • alpha-2-adrenergic (alpha-2-adrenoceptors) agonists their peripheral use has been commonly reported in acute pain conditions.
  • clonidine is added to local anaesthetic in peritroncular nerve blocks to enhance potency and duration of analgesia.
  • Alpha-2-adrenoceptors agonists are known to block the tissue content increase of pro-inflammatory cytokines, such as TNF-alpha and IL1beta and increase the tissue content of anti-inflammatory cytokine TGF beta. This has been shown in inflammatory neuropathic pain model by partial ligation of sciatic nerve, by applying locally alpha-2-adrenergic receptor agonists by peripheral nerve block.
  • the invention is related to a intra-articular pharmaceutical composition for use in the treatment and/or the prevention of acute or chronic osteoarticular diseases and acute or chronic osteoarticular symptoms, especially osteoarthritis, this composition comprising
  • the glycosaminoglycan is present as a film or as a matrix, preferably in the form of a paste or a gel, more preferably an hydrogel with a sufficient amount of an aqueous solvent.
  • the compound interacting with the alpha-2-adrenergic receptor is an alpha-2-adrenergic receptor agonist.
  • glycosaminoglycan and the compound activating the alpha-2-adrenergic receptor are not covalently linked or are covalently linked.
  • the glycosaminoglycan is selected from the group consisting of hyaluronic acid with low ( ⁇ 900 kDa) or high (>900 kDa) molecular mass.
  • the hyaluronic acid and the alpha 2 adrenergic receptor agonist are not covalently linked or are covalently linked.
  • the glycosaminoglycan is selected from the group consisting of proteoglycan, chondroitin sulfate, keratin sulphate, hyaluronic acid (including their derivatives), chitosan, a chitosan or chitin derivative, or a mixture thereof.
  • the alpha-2-adrenergic receptor agonist is selected from the group consisting of clonidine, p-aminoclonidine, tiamenidine, 5-bromo-6-(2 imidazolidine-2-ylamino)quinoxaline, dexmedetomidine, detomidine, medetomidine, oxymetazonline, tizanidine, mivazerol, lofexidine, xylazine, guanfacine, guanclofine, guanoxabenz, or a derivative or structural analogue thereof, alpha-methylnorepherine, azepexole, indoramin, 6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine diHCl.
  • the pharmaceutical composition according to the invention is suitable for a treatment or prevention of acute and chronic osteoarticular diseases and associated symptoms (especially osteoarticular pain, loss of mobility or function), of inflammatory origin, such as osteoarthritis, degenerative arthritis, gonarthrosis, coxarthrosis, and other inflammatory general conditions in which joints are involved, such as autoimmune diseases, especially rheumatoid arthritis and systemic lupus erythematosus (SLE) 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), neuropathic arthropathy, acute rheumatic fever, gout, chondrocalcinosis, calcium hydroxyapatite crystal deposition disease, Lyme disease and all other degenerative joint diseases.
  • autoimmune diseases especially r
  • Another aspect of the present invention is related to the use of the pharmaceutical composition for the manufacture of a medicament in the treatment and/or the prevention of these mentioned diseases and/or symptoms (pain) induced by these diseases, possibly combined with an anti-inflammatory effect useful for the treatment and/or the prevention of diseases or symptoms of inflammatory origin.
  • the composition presents a preferred formulation, preferably being an injectable solution for delivering an efficient amount (therapeutic dose) of the active compound present in the composition to a mammal subject including a human patient, especially in the knees, the hips and the spine of the subject.
  • this injectable solution comprises from about 0.1 mg to about 100 mg/kg preferably from about 1 mg to about 10 mg/kg of body weight of this proteoglycan and/or glycosaminoglycan, preferably in the form of a proteoglycan-based hydrogel and may comprise from about 0.1 mg to about 100 mg/kg of patient body weight preferably from about 0.1 mg to about 0.8 mg/kg of patient body weight of a(n anti-inflammatory compound being) compound activating the alpha-2-adrenergic receptor, preferably an alpha-2-adrenergic receptor agonist, more preferably from about 3 ⁇ g to about 1500 ⁇ g of said alpha-2-adrenergic receptor agonist, still more preferably from about 30 ⁇ g to about 500 ⁇ g and even from 50 ⁇ g to 350 ⁇ g, or about 150 ⁇ g (of said alpha-2 adrenergic receptor agonist).
  • an alpha-2-adrenergic receptor agonist more preferably from about 3 ⁇ g to about 1500
  • the injectable solution is adequate for intra-articular administration (percutaneous injection) in a joint of a mammal subject, preferably of a human patient.
  • This formulation is also adequate for local administration (percutaneous injection in/or in the vicinity of an inflamed joint of a mammal subject, preferably of a human patient), local administration injection that does concern the epidermis, the muscle or any deep organs.
  • the present invention is related to the surprising discovery that this intraarticular administration to a mammal subject, particularly a human patient of this pharmaceutical composition results in an improvement of symptoms associated with osteoarticular diseases such as a relief of osteoarticular pain, an improvement of joint mobility and/or function, a decrease in articular accumulation of inflammatory liquid, a shortening of the time to onset of the therapeutic activity of the first component, an increase in the duration of action of the first component and a reduction of joint degeneration or its progress possibly induced by the above mentioned diseases or pathologies.
  • osteoarticular diseases such as a relief of osteoarticular pain, an improvement of joint mobility and/or function, a decrease in articular accumulation of inflammatory liquid, a shortening of the time to onset of the therapeutic activity of the first component, an increase in the duration of action of the first component and a reduction of joint degeneration or its progress possibly induced by the above mentioned diseases or pathologies.
  • the invention is also directed to a method for a treatment and/or a prevention (prophylaxis) of a condition selected from the group consisting of the above mentioned diseases or symptoms through an administration to a mammal subject, preferably a human patient of a sufficient amount of the pharmaceutical composition of the invention, through an intra-articular administration, particularly in the knees, the hips and the spine of the mammal subject; preferably the human patient.
  • a combined intra-articular administration of hyaluronic acid and an alpha 2 adrenergic receptor agonist allows for a shorter onset of action, a longer duration of action, for a superior or at least equivalent efficacy and/or a possible decrease of side-effects associated with hyaluronic acid and with administration of alpha 2 adrenergic receptor agonists.
  • composition and method of the present invention also allows a decrease of the number of required administrations to obtain a desired efficacy and allows for a faster onset of action.
  • a last aspect of the present invention is related to a kit of parts comprising one or more vials with the elements (carrier/diluent, glycosaminoglycan, 2-2-adrenergic receptor compound, anti-inflammatory agent, stem cells or a combination thereof) of the composition of the invention and a device for delivering this composition to an inflamed joint of a mammal subject preferably a human patient suffering from the above mentioned osteoarticular diseases or symptoms (pain) and having
  • FIG. 1 shows the VAS scale assessing pain from 0 “no pain at all” to 100 “maximum pain” after 3 intraarticular administration of clonidine 150 ⁇ g and hyaluronic acid at day 0, day 7 and day 14 in 2 patients suffering from gonarthritis.
  • FIG. 4 shows the VAS scale assessing pain from 0 “no pain at all” to 100 “maximum pain” after one intra-articular administration of clonidine 150 ⁇ g and hyaluronic acid at day 0 in 1 patient suffering from coxarthrosis.
  • FIG. 5 shows the WOMAC score assessing pain and function of the hip after one intraarticular administration of clonidine 150 ⁇ g and hyaluronic acid at day 0 in 1 patient suffering from coxarthrosis.
  • FIG. 6 shows the Lequesne score assessing pain and function of the hip after one intra-articular administration of clonidine 150 ⁇ g and hyaluronic acid at day 0 in 1 patient suffering from coxarthrosis.
  • FIG. 7 shows the percentage of IL-1 beta release by different alpha-2-adrenergic agonists, induced by LPS stimulation of TH1 cells.
  • intra-articular refers to a percutaneous injection of a joint with the pharmaceutical composition of the invention.
  • the main advantages to local administration are to selectively restrict the analgesic and other effects to the injured areas. Furthermore, the local administration allows for high local concentration levels with little or no systemic release.
  • the local administration and the intra-articular injection of hyaluronic acid is a recognised treatment of the above mentioned conditions.
  • alpha 2 adrenergic agonists are easily realizable and provide long lasting effect in combination with proteoglycans.
  • problems related to placement of an invasive drug delivery system and the problems of bothersome side-effects, due to systemic release can be strongly minimized.
  • Health-related quality of life, patient satisfaction and economic assessment might be improved with such a treatment, especially in chronic conditions.
  • the administrated compound is selected from the group consisting of a glycosaminoglycan, for example hyaluronic acid or a salt thereof 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.
  • a glycosaminoglycan for example hyaluronic acid or a salt thereof 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.
  • Suitable dosages of a proteoglycan-based hydrogel or a glycosaminoglycan or a derivative thereof will typically be from about 0.1 mg to about 100 mg/kg body weight per day or from about 0.5 mg to about 10 mg/kg body weight per day more preferably from about 2 mg to about 8 mg by body weight per day and suitable dosage amounts for alpha 2 adrenergic receptor agonists.
  • guanidines agmatine betanidine biguanides cimetidine creatine gabexate guanethidine guanfacine guanidine impromidine iodo-3 benzylguanidine methylguanidine mitoguazone nitrosoguanidines pinacidil robenidine sulfaguanidine zanamivir imidazoles 4-(3-butoxy-4-methoxybenzyl)imidazolidin-2-one urocanic acid amino-imidazole carboxamide antazoline biotine bis(4-methyl-1-homo piperazinylthiocarbonyl)disulfide carbimazole cimetidine clotrimazole creatinine dacarbazine dexmedetomidine econazole enoximone ethymizol etomidate fadrozole fluspiri
  • clonidine refers to N-(2,6-dichlorophenyl)-4,5-dihydro-1H-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.
  • Clonidine is employed in a therapeutically effective amount.
  • the present invention also encompasses the use of alpha 2 adrenergic receptor agonist for the manufacture of injectable formulations for a delivery to a joint or a close region thereof, a therapeutic dose of said agonist by intra-articular injection, wherein said solution comprises from about 3 ⁇ g to about 1500 ⁇ g of said alpha-2-adrenergic receptor agonist.
  • said formulation comprises from about 30 ⁇ g to about 500 ⁇ g of said alpha-2-adrenergic receptor agonist. More preferably said solution comprises from 50 ⁇ g to 350 ⁇ g of said alpha-2 adrenergic receptor agonist.
  • an injection of the combination of hyaluronic acid and an alpha 2 adrenergic receptor agonist form induces a long lasting pain relief, both in human case and in an animal model of osteoarticular pain.
  • the method is safe, devoid of major drug's side effects and allows for acute as well as chronic treatment and or prophylaxis without the use of too invasive technique.
  • preservatives may be incorporated in an amount effective for inhibiting growth of microbes, such as bacteria, yeast and molds, in the composition. Any conventional preservative against microbial contamination of the product can be employed so long as it is pharmaceutically acceptable and is unreactive with clonidine.
  • Preferred preservatives are antimicrobial aromatic alcohols, such as benzyl alcohol, phenoxyethanol, phenethyl alcohol, and the like, and esters of parahydroxybenzoic acid commonly referred to as paraben compounds, such as methyl, ethyl, propyl, and butyl esters of parahydroxybenzoic acid and the like and mixtures thereof, but are not limited thereto. Particularly preferred are benzyl alcohol and phenoxyethanol.
  • anaesthetic agent such as lidocaine and the like
  • the active quantities of the compounds that alleviate neuropathic pain can be contained together with customary pharmaceutical excipients and/or additives in solid or liquid pharmaceutical formulations.
  • Liquid preparations such as solutions, suspensions or emulsions of the active ingredients, prepared by dissolving or dispersing the compounds, can contain the usual diluents such as water, oil and/or suspending aids such as polyethylene glycols and optional pharmaceutical adjuvants, in a carrier, such as, for example, aqueous saline, aqueous dextrose, glycerol, or ethanol, to form a solution or suspension and such like. Further additives such as preservatives, flavouring agents and such like may also be added.
  • a carrier such as, for example, aqueous saline, aqueous dextrose, glycerol, or ethanol, to form a solution or suspension and such like.
  • Further additives such as preservatives, flavouring agents and such like may also be added.
  • intra-articular injection of about 20 mg of hyaluronic acid and about 150 ⁇ g of clonidine in the injured knee.
  • a second and a third intra-articular injections were realized 7 and 14 days later. Before each injection, the intra-articular liquid was removed and measured. Pain and mobility were evaluated at baseline (day 0), 48-72 hours after the intra-articular injections, before the next injection (day 7 and day 14) and at day 21.
  • VAS score which additionally evaluated mobility of the injured knee.
  • the WOMAC score decreased from 61 at baseline to 44, 41 and 37 at days 7, 14 and 21.
  • the efficacy is measured by a reduction in score value (which demonstrates an improvement), such as pain scores or functional scores.
  • PBMCs Peripheral blood mononuclear cells
  • MNC Mononuclear cells
  • RPMI-1640 medium supplemented with 100 U/mL penicillin, 100 ⁇ g/mL streptomycin, and 10% heat-inactivated FBS.
  • Cells were seeded at 100.000 cells in 96-well plate in a total volume of 200 ⁇ L/well.
  • PBMC peripheral blood mononuclear cells
  • HA hyaluronic acid
  • A2A p-aminoclonidine
  • IL-1 ⁇ detection Boy ELISA. Levels of IL-1 ⁇ from PBMC or culture supernatants were measured by Quantikine ELISA kit (R&D Systems Inc, Mineapolis, USA). The minimum detectable concentration of IL-1 ⁇ was estimated at 1.0 pg/mL.
  • IL-1beta The release of IL-1beta by PBMC and the proliferation of PBMC, induced by PHA stimulation, were set as controls, and compared with the measures for PBMC treated with HA and/or A2A.
  • IL-1beta secretion induced by PHA stimulation shows a significant increase over basal condition (where IL-1beta levels were undetectable) and was set at 100. Proliferation of PMBC cells also significantly increased, by a factor of about ⁇ 20. Surprisingly, a similar cytokine increase—over basal condition—was observed with addition of HA alone, while PBMC proliferation was not affected. When stimulated by PHA, the addition of HA synergistically increases IL-1beta secretion, 3 times over the stimulated conditions, but was able to reduce PBMC proliferation by a factor 2.
  • A2A has no effect on basal—unstimulated—conditions. Interestingly, when stimulated by PHA, the addition of A2A totally suppresses the increase in IL-1beta secretion due to PHA stimulation, to undetectable levels, but was not able to inhibit PBMC proliferation.
  • the combination HA/A2A demonstrates a potent anti-inflammatory effect over the PHA/HA condition.
  • the addition of A2A was able to significantly revert—by over 50%—the increase in IL-1beta secretion due to PHA/HA stimulation, bringing its level to the one of the PHA alone condition.
  • A2A was further able to inhibit PBMC proliferation, by another 35%.
  • hyaluronan During inflammation, lower molecular weight fragments of hyaluronan are known to be inflammatory and immune-stimulatory agents by inducing the secretion of cytokines such as IL-6 and monocyte chemoattractant protein (MCP-1). HA has also the property to enhance the adhesion of lymphocytes and monocytes to the extracellular matrix (Yamawaki et al., 2009). These experiments show that hyaluronic acid has a potent stimulatory effect on cytokine (e.g., IL-1 ⁇ ) production without PBMC proliferation.
  • cytokine e.g., IL-1 ⁇
  • the combination HA/A2A demonstrates a potent anti-inflammatory effect both on cytokine production and inflammatory cell proliferation. Indeed, the addition of A2A to HA was able to significantly inhibit the increase in IL-1beta secretion and was further able to inhibit PBMC proliferation.
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