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WO2025068242A1 - Système d'administration de dexaméthasone - Google Patents

Système d'administration de dexaméthasone Download PDF

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Publication number
WO2025068242A1
WO2025068242A1 PCT/EP2024/076871 EP2024076871W WO2025068242A1 WO 2025068242 A1 WO2025068242 A1 WO 2025068242A1 EP 2024076871 W EP2024076871 W EP 2024076871W WO 2025068242 A1 WO2025068242 A1 WO 2025068242A1
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Prior art keywords
hydrogel
hydrogel formulation
component
formulation according
formulation
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Inventor
Birgit Lundskov FUHLENDORFF
Timothy J Eviston
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Hyamedix
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Hyamedix
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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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

  • the present invention relates to a hydrogel formulation facilitating controlled released of dexamethasone or a salt thereof over an extended period of time.
  • the hydrogel formulation comprises a crosslinked hyaluronic acid component formulated with a non-crosslinked hyaluronic acid component.
  • OA Osteoarthritis
  • Corticosteroids have played a crucial role over the past three decades in the multimodal pain management in the treatment of osteoarthritis pain.
  • Two different types of injectable steroids are mainly used as intra-articular injections for different types of osteoarthritis related pain conditions; particulate and non-particulate steroids.
  • Particulate steroids such as methylprednisolone acetate, triamcinolone acetonide, and prednisolone acetate, are long-acting but poorly soluble steroids.
  • Non-particulate steroids such as dexamethasone, are less toxic and soluble molecules that make them more suitable for pharmaceutical use.
  • their anti-inflammatory effects are only short-lived necessitating frequent administration.
  • Hyaluronic acid is an anionic and non-sulfated glycosaminoglycan that present several potential advantages as a delivery vehicle, including its inherent biodegradability in the body.
  • HA is a naturally occurring long linear polysaccharide of repeating disaccharide units of D-glucuronic acid and N-acetyl-D-glucosamine linked via glycosidic bonds and is recognized as a high value biopolymer with numerous proven and marketed applications within the cosmetic, biomedical, and pharmaceutical fields.
  • compositions may be formulated in carrier vehicles to improve their pharmacokinetics when administered to a subject.
  • Engineering a suitable vehicle is a complex task as medical formulations need to meet high standards of safety and efficiency.
  • hydrogel formulations loaded with dexamethasone that secure controlled and extended release of dexamethasone to improve patient compliance and prolong the anti-inflammatory effect.
  • the hydrogel formulations are based on the mixture of a hyaluronic acid (HA)-based hydrogel with non-crosslinked HA.
  • HA hyaluronic acid
  • the addition of non-crosslinked HA to the crosslinked HA component enables control of the rheology of the formulation and facilitates fine-tuning of the release profile.
  • the hydrogel formulations are prepared by a multi-step method including comminution and micronization of the HA-based hydrogel component. The resulting hydrogel formulations efficiently control and extend the release of dexamethasone.
  • an object of the present invention relates to a formulation for treatment of osteoarthritis to reduce pain and inflammation of arthritic joints thereby improving quality of life of patients and delay or avoid the need for joint replacement.
  • hydrogel formulation that serves both as a visco-supplement to lubricate the joints and release of dexamethasone over an extended period of time.
  • an aspect of the present invention relates to a hydrogel formulation comprising:
  • a first component comprising a hydrogel comprising hyaluronic acid (HA) crosslinked with a crosslinking agent, wherein the ratio between HA and crosslinking agent is in the range of about 10: 1 % (w/w) to about 18: 1 % (w/w),
  • a further aspect of the present invention relates to hydrogel formulation comprising:
  • a first component comprising a hydrogel comprising about 0.5-3% (w/w) of hyaluronic acid (HA) crosslinked with a crosslinking agent, wherein the ratio between HA and crosslinking agent is in the range of about 10: 1 % (w/w) to about 25: 1 % (w/w),
  • a second component comprising about 1-6% (w/w) non-crosslinked HA
  • Another aspect of the present invention relates to a method for preparing a hydrogel formulation as described herein, said method comprising the following steps:
  • Yet another aspect of the present invention relates to a hydrogel formulation as described herein obtainable by a method as described herein.
  • Still another aspect of the present invention relates to a hydrogel formulation as described herein for use as a medicament.
  • a further aspect of the present invention relates to a hydrogel formulation as described herein for use in the treatment, prevention or inhibition of one or more diseases or disorders selected from the group consisting of arthritis, tendonitis, synovitis, bursitis, metabolic joint conditions, gout, allergic disorders, dermatological diseases, endocrine disorders, gastrointestinal diseases, hematological disorders, neoplastic diseases, nervous diseases, ophthalmic diseases, renal diseases, respiratory diseases skin diseases, and pain, preferably arthritis.
  • diseases or disorders selected from the group consisting of arthritis, tendonitis, synovitis, bursitis, metabolic joint conditions, gout, allergic disorders, dermatological diseases, endocrine disorders, gastrointestinal diseases, hematological disorders, neoplastic diseases, nervous diseases, ophthalmic diseases, renal diseases, respiratory diseases skin diseases, and pain, preferably arthritis.
  • a still further aspect of the present invention relates to a kit comprising:
  • Figure 1 shows visco-elastic properties for the hydrogel formulations compared to commercial product Synvisc One.
  • Figure 2 shows the setup for measuring release profiles of dexamethasone.
  • A Schematic of the dexamethasone release system.
  • B Real-life photo of the dexamethasone release system. From left to right; Dissolution unit incl. water bath and cell block, piston pump, UV-spectrophotometer, and media reservoirs.
  • C Closeup of cell blocks comprising hydrogel formulation samples.
  • hyaluronic acid refers to polysaccharides with different molecular weights constituted by residues of D-glucuronic acid and N-acetyl- D-glucosamine acid.
  • Hyaluronic acid occurs naturally in cell surfaces, in the basic extracellular substances of the connective tissue of vertebrates, in the synovial fluid of the joints, in the endobulbar fluid of the eye, and in human umbilical cord tissue.
  • Hyaluronic acid is defined herein as a non-sulfated glycosaminoglycan composed of repeating disaccharide units of N-acetylglucosamine (GIcNAc) and glucuronic acid (GIcUA) linked together by alternating beta-1,4 and beta-1,3 glycosidic bonds.
  • Hyaluronic acid is also known as hyaluronan or abbreviated as HA. In the present context, these terms will cover also the conjugate base hyaluronate, and accordingly the terms are used interchangeably herein.
  • crosslinked hyaluronic acid refers to hyaluronic acid crosslinked with a crosslinking agent.
  • Crosslinked hyaluronic acid is therefore understood to comprise a plurality of HA polymeric strands connected by a crosslinking agent capable of reacting with one or more functional groups in the hyaluronic acid polymeric structure.
  • the functional groups in the hyaluronic acid backbone are hydroxyl, carboxylate and acetamide.
  • the crosslinking agent divinyl sulfone can covalently crosslink hyaluronic acid polymers via reaction of its vinyl groups with the primary hydroxyl group of N-acetyl-D-glucosamine.
  • the degree of crosslinking can be controlled by adjusting the ratio between hyaluronic acid and the crosslinking agent. A higher amount of crosslinking agent will cause a higher degree of crosslinking and therefore a tighter polymeric network.
  • Hyaluronic acid is preferably crosslinked using a single type of crosslinking agent, but crosslinked hyaluronic acid may also be obtained by reaction with two or more crosslinking agents.
  • crosslinking agent refers to any compound that is capable of chemically linking hyaluronic acid polymers together in a crosslinked polymeric network.
  • the reaction between the hyaluronic acid and the crosslinking agent is preferably covalent.
  • crosslinking agents preferably comprises functional groups capable of forming a covalent bond with hydroxyl, carboxylate and/or acetamide functional groups of the hyaluronic acid polymer.
  • Crosslinking agents are capable of linking two hyaluronic acid polymers together and therefore comprises at least two functional groups. Some variants of crosslinking agents comprise at least two identical functional groups.
  • crosslinking agents include, but are not limited to, divinyl sulfone (DVS), 1,4-butanediol diglycidyl ether (BDDE), polylactic acid, polyethylene glycol, and carboxymethylcellulose (CMC).
  • DVD divinyl sulfone
  • BDDE 1,4-butanediol diglycidyl ether
  • CMC carboxymethylcellulose
  • hydrogel refers to a macromolecular polymeric network swollen in an aqueous solution, buffer, or biological fluids. The degree of hydration is dependent on the degree of crosslinking.
  • the hydrogel may be processed to modify the properties of the hydrogel.
  • the hydrogel may be comminuted and micronized to reduce particle size of the macromolecular network and facilitate mixing with non-crosslinked hyaluronic acid, loading of dexamethasone and adjust viscosity.
  • controlled release refers to release of dexamethasone from the hydrogel formulation, wherein the release takes place over a prolonged period of time.
  • controlled release covers different scenarios wherein the release of dexamethasone is extended. Namely, dexamethasone is not necessarily released in a linear manner. The term covers that a fraction of dexamethasone may be released relatively fast from the hydrogel formulation, whereas the remaining fraction is released in a prolonged manner. Prolonged release may be caused by a continuous sustained release from the hydrogel formulation or may be dependent on the gradual degradation of the hydrogel formulation. The term also covers delayed release, wherein dexamethasone is only released after a certain period of time after administration. The term also includes burst release wherein a fraction of dexamethasone is released immediately followed by an optional lag phase and then release of the remaining fraction of dexamethasone is released in a prolonged manner.
  • mean particle size refers to the D50 value (or median diameter) of a particle size distribution.
  • the D value is a percentile value that can be read directly form a cumulative particle size distribution, and D50 thus represents the value at which 50% of the particle have a smaller diameter and 50% of the particles have a larger diameter.
  • the D50 value as used herein refers to the number weighted distribution of particles.
  • Particle size distribution can be measured by laser diffraction. Measurements can be performed using a Malvern Mastersizer 2000 coupled with a Hydro2000 dispersion unit. It is possible to extract the D50 value from these measurements.
  • the particle size distribution can be determined by diluting the first component to a concentration of 0.1-2% (w/w) of HA using a PBS buffer containing NaCI in the range of 0.5-15% (w/w). Measurements are carried out under constant stirring and assuming spherical particles (refractive index of 1.343) and in the interval 0.02 - 2000 pm.
  • the term "storage modulus” refers to the storage modulus G' in Pascal (Pa) determined from shear experiments, i.e. the ability of a viscoelastic material to store energy elastically. At low frequency, the rate of shear is low, and therefore the capacity of retaining the original strength of media is high. When the frequency increases, the rate of shear also increases resulting in an increased amount of energy put into the polymeric chains. Accordingly, the storage modulus increases with frequency.
  • storage modulus is reported as the value at a frequency of 2.5 Hz.
  • viscous modulus refers to the viscous portion of the viscoelastic behaviour, which can be seen as the liquid-state behaviour of a sample.
  • the slope of the loading curve analogous to Young's modulus in a tensile testing experiment, is called the storage modulus, G' (as outlined above).
  • the storage modulus is a measure of how much energy must be put into the sample in order to distort it.
  • the difference between the "loading" and “unloading” curves is called the viscous modulus, G". It measures energy lost during that cycling strain.
  • viscous modulus and “loss modulus” may be used interchangeably.
  • Hyaluronic acid is a natural biological polymer with a linear, non-branched structure, which is found in many living organisms, from bacteria to higher animals including humans. It is biocompatible, non-immunogenic and can easily be broken down by natural enzymes within the body, making it a safe compound that over the last 20 years has been injected into millions of patients.
  • Hydrogels may be prepared from hyaluronic acid by chemically crosslinking the polymers and subjecting them to swelling in an aqueous medium.
  • HA-based hydrogels have successfully been used as dermal fillers or as lubrication means for treatment of osteoarthritis.
  • the use of HA-based hydrogels as delivery vehicles is however more complex as such formulations cannot purely rely on the mechanical properties of hyaluronic acid, but must also consider interactions with the active compounds and the recipient environment. Accordingly, HA-based hydrogels as drug delivery vehicles have at present had limited commercial success.
  • hydrogel formulations loaded with the glucocorticoid dexamethasone which may be administered to an articular site of a subject in need of treatment thereof (e.g. an affected joint at the knee, hips, spine, base of thumb, finger, shoulder, ankle or base of the big toe).
  • a subject in need of treatment thereof (e.g. an affected joint at the knee, hips, spine, base of thumb, finger, shoulder, ankle or base of the big toe).
  • the term “dexamethasone” as used herein encompasses any salt of dexamethasone, unless a specific salt, such as dexamethasone sodium phosphate, is explicitly mentioned.
  • the hydrogel formulation effectively controls the release of dexamethasone and retain the level of dexamethasone in the therapeutic window, i.e. an effective dose between toxic levels (or adverse effects) and an ineffective dose.
  • the hydrogel formulations can therefore improve patient compliance and safety, while at the same time optimise the therapeutic effect obtained from a given dosage. This will not only potentially reduce cost of treatment but also lessen patient discomfort as the frequency of administration can be reduced.
  • the hydrogel formulation provides several advantages compared to current treatment options of osteoarthritis, including rapid onset of action, improved analgesia in early stage of the disease, decrease in number of injections, less adverse effects and multiple mode of actions (analgesia, anti-inflammatory and chondroprotective).
  • hydrogel formulations disclosed herein are based on the mixture of a hydrogel component comprising crosslinked HA and a component comprising non-crosslinked HA (also referred to as linear HA).
  • Hydrogels are three-dimensional networks of polymers can swell in aqueous medium and retain a large amount of water while maintaining a well-defined structure.
  • the hydrogel form has improved resistance to hyaluronidase compared to non-crosslinked HA.
  • the structure of the hydrogel is well suited for loading of dexamethasone, the release of which may be tailored by adjusting the amount of crosslinking agent relative to the hyaluronic acid in the hydrogel component.
  • the addition of a fraction of non-crosslinked HA to the hydrogel formulation ensures suitable rheological properties and fine-tuning of the release profile.
  • the hydrogel formulation provides a lubricating and cushioning effect which mitigate the symptoms associated with arthritis.
  • the exogenous HA enhance chondrocyte HA synthesis, prevent degradation of cartilage and promote its regeneration.
  • an aspect of the present invention relates to a hydrogel formulation comprising:
  • a first component comprising a hydrogel comprising hyaluronic acid (HA) crosslinked with a crosslinking agent, wherein the ratio between HA and crosslinking agent is in the range of about 10: 1 % (w/w) to about 18: 1 % (w/w),
  • % (w/w) given for crosslinked HA and non-crosslinked HA is with respect to the total weight of the first component and second component, respectively.
  • HA is diluted and the final % (w/w) HA of the first component is therefore lower than the % (w/w) HA initially provided during preparation of the hydrogel.
  • the ratio between the first and second components may be used to tailor the release profile of dexamethasone. Hydrogel formulations with large fractions of the first component comprising the hydrogel will release dexamethasone slower than hydrogel formulations with relatively larger fractions of the second component comprising non- crosslinked HA.
  • the ratio between the first and second components of the hydrogel formulation may also be referred to as the formulation ratio and also influences the rheology and injectability of the final hydrogel formulation.
  • an embodiment of the present invention relates to the hydrogel formulation as described herein, wherein ratio between said first component and said second component is in the range of about 65:35 % (w/w) to about 97:3 % (w/w), such as about 70:30 % (w/w) to about 96:4 % (w/w), such as about 75:25 % (w/w) to about 95:5 % (w/w), such as about 80:20 % (w/w) to about 95:5 % (w/w), such as about 85:30 % (w/w) to about 95:5 % (w/w) preferably about 90: 10 % (w/w).
  • Another embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the first component comprises about 0.8-2 % (w/w) HA, such as about 1.0-1.5 % (w/w), such as about 1.2-1.4 % (w/w).
  • a further embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the first component comprises about 1.3 % (w/w).
  • a still further embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the second component comprises about 1.5-4.5 % (w/w) non-crosslinked HA, such as about 2-4 % (w/w), preferably about 3 % (w/w).
  • the viscosity of the hydrogel formulation can also be modified by modifying the ratio of HA to crosslinking agent in the first component or by changing the total concentration of HA in the hydrogel formulation.
  • the total concentration of HA can be changed by adjusting the concentration of crosslinked HA and/or noncrosslinked HA in the hydrogel formulation. If only the total concentration of HA and not the ratio between cross-linked and non-crosslinked HA is to be changed, then both the amount of HA in the first and second component should be changed correspondingly.
  • An embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the concentration of crosslinked HA is in the range of about 0.2% (w/w) to about 2 % (w/w), such as about 0.4 % (w/w) to about 1.8 % (w/w), such as about 0.6 % (w/w) to about 1.6 % (w/w), such as about 0.8 % (w/w) to about 1.4 % (w/w), such as about 1.0 % (w/w) to about 1.2 % (w/w), based on the total weight of the hydrogel formulation.
  • Another embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the concentration of crosslinked HA is about 1.1 % (w/w) based on the total weight of the hydrogel formulation.
  • Yet another embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the concentration of crosslinked HA is in the range of about 5 mg/g to about 20 mg/g, such as about 8 mg/g to about 15 mg/g, such as about 10 mg/g to about 12 mg/g, based on the total weight of the hydrogel formulation.
  • a further embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the concentration of non-crosslinked HA is in the range of about 0.05% (w/w) to about 1 % (w/w), such as about 0.1 % (w/w) to about 0.75 % (w/w), such as about 0.2 % (w/w) to about 0.5 % (w/w), such as about 0.25 % (w/w) to about 0.35 % (w/w), based on the total weight of the hydrogel formulation.
  • a still further embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the concentration of non-crosslinked HA is about 0.3 % (w/w) based on the total weight of the hydrogel formulation.
  • Yet another embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the concentration of non-crosslinked HA is in the range of about 1 mg/g to about 10 mg/g, such as about 2 mg/g to about 5 mg/g, such as about 3 mg/g to about 4 mg/g, based on the total weight of the hydrogel formulation.
  • An even further embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the total concentration of HA is in the range of about 10 mg/g to about 25 mg/g, such as about 12 mg/g to about 20 mg/g.
  • Another embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the total concentration of HA is in the range of about 15 mg/g to about 17 mg/g.
  • the release of dexamethasone from the hydrogel formulation can also be adjusted by changing the crosslinking degree (or crosslinking ratio), i.e. the ratio of HA and crosslinking agent in the hydrogel of the first component.
  • the crosslinking degree or crosslinking ratio
  • the hydrogel will contain a tighter polymeric network and therefore release dexamethasone at a slower pace than a less dense polymeric network.
  • formulations with relatively higher amount of crosslinking agents is therefore advantageous.
  • the crosslinking ratio may influence the rheology and injectability of the hydrogel formulation.
  • An embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the ratio between HA and crosslinking agent is in the range of about 12: 1 % (w/w) to about 18: 1 % (w/w), such as about 14: 1 % (w/w) to about 18: 1 % (w/w), such as about 16: 1 % (w/w) to about 18: 1 % (w/w), preferably about 17: 1 % (w/w).
  • a further embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the ratio between HA and crosslinking agent is about 10: 1 % (w/w).
  • Crosslinking of hyaluronic acid changes the form of the raw HA material and facilitates the transformation into non-dissolvable hydrogels that may absorb large amounts of water without losing a defined structure.
  • the principle of the crosslinking reaction of HA is that the polymer chains are covalently linked by reaction with a crosslinking agent, which can be selected from a number of different chemical compounds, including, but not limited to, divinyl sulfone (DVS), 1,4-butanediol diglycidyl ether (BDDE), and polyethylene glycol (PEG).
  • an embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the crosslinking agent is selected from the group consisting of divinyl sulfone (DVS), 1,4-butanediol diglycidyl ether (BDDE), poly(lactic acid) (PLA), poly(ethylene glycol) (PEG), poly(ethylene glycol) bis(amine), polyethylene glycol diacrylate (PEGDA), poly(ethylene glycol)-dimethacrylate (PEGDM), poly(ethylene glycol) -diacrylamide (PEGDAA) and polyethylene glycol)- dimethacrylamide (PEGDMA), carboxymethylcellulose (CMC), dextran acrylate, dextran methacrylate, dextran glycidyl methacrylate, glycerol dimethacrylate, glycerol 1,3-diglycerolate diacrylate, sorbitol acrylate, and derivatives thereof.
  • the crosslinking agent is selected from the group consisting of diviny
  • a preferred crosslinking agent is divinyl sulfone (DVS).
  • VVS divinyl sulfone
  • the crosslinking reaction takes place between the primary hydroxyl group of N-acetyl-D- glucosamine, which reacts by a nucleophilic addition at the vinylic carbon atom at the DVS molecule.
  • DVS contains two vinyl groups and is very reactive towards nucleophilic addition, which results in a ratio of two mole HA-disaccharide (N-acetyl-D- glucosamine) to one mole of DVS. Since DVS crosslinking does not involve the biologically reactive functional groups (carboxylate and acetamide) on the HA molecule, the gels largely preserve HA's natural polyanionic character, physiochemical and biological properties.
  • DVS is very reactive under aqueous alkaline conditions and is thus instantaneous fully reacted.
  • the resulting bond between HA and DVS is a sulfonyl bis-ethyl ether linkage, which is known to be very stable towards hydrolysis (degradation) and stable towards basic treatment.
  • a preferred embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the crosslinking agent is divinyl sulfone (DVS).
  • DVD divinyl sulfone
  • the size of the HA polymers can be varied to influence the structure of the polymeric network of the hydrogel.
  • the size (molecular weight) of the HA polymers can be determined by measuring the intrinsic viscosity using the Mark Houwink Kuhn Sakurada (MHKS) equation or size exclusion chromatography coupled with multi angle laser light scattering (SEC-MALLS).
  • An embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the molecular weight of the HA of said first component and/or second component is the range of about 500 kDa to about 1500 kDa, such as about 750 kDa to about 1250 kDa, preferably about 1000 kDa.
  • Another embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the molecular weight of the HA of said first component and second component is the same.
  • the HA utilized in the hydrogel may in principle be any type of HA including, but not limited to, HA salified with organic or inorganic bases, HA esters with alcohols, HA amides, O-sulphated derivates of HA, deacetylated derivatives of HA, and percarboxylated derivatives of HA.
  • HA ester may be with alcohols of the aliphatic, araliphatic, cycloaliphatic, aromatic, cyclic and heterocyclic series.
  • HA amides may be with amine of the aliphatic, araliphatic, cycloaliphatic, aromatic, cyclic and heterocyclic series.
  • the HA is provided as an inorganic salt.
  • an embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the HA is provided as an inorganic salt selected from the group consisting of sodium hyaluronate, potassium hyaluronate, ammonium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, and cobalt hyaluronate, preferably sodium hyaluronate.
  • an embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the HA is provided as an inorganic salt which does not comprise calcium.
  • Another embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the hydrogel formulation comprises less than 300 ppm calcium ions, such as less than 250 ppm, such as less than 200 ppm.
  • a preferred embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the HA is provided as sodium hyaluronate.
  • the polymeric nature of the HA hydrogel of the first component makes the hydrogel, and there with the hydrogel formulation, very viscous and structurally inhomogeneous. This texture works well for use as medical device which is implanted surgically or as dermal fillers wherein large needle sizes may not be prohibitive for its utilization. However, for use with smaller needle sizes or even sprays, it is required that the hydrogel formulation is very homogenous. This may be accomplished by micronizing the first component comprising the hydrogel prior to mixing with the second component comprising non-crosslinked HA.
  • an embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the mean particle size of the first component is less than about 1500 pun, such as less than about 1250 pirn, such as less than about 1000 pirn, such as less than about 750 pirn, such as less than about 500 pirn.
  • Another embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the mean particle size of the first component is in the range of about 50 pirn to about 1500 pirn, such as about 100 pirn to about 1250 pirn, such as about 150 pirn to about 1000 pirn, such as about 200 pirn to about 750 pirn, such as about 300 pirn to about 500 pirn.
  • the hydrogel formulation comprises a solvent into which the mix of the first component and second component is dispersed.
  • the solvent may be any aqueous solvent which is compatible with the HA hydrogel and biocompatible for administration to a subject.
  • aqueous buffers including, but not limited to, PBS buffer.
  • the buffer is preferably adjusted to a pH value suitable for accommodating the active compound and in a range acceptable for administration to a subject.
  • the pH value is selected to avoid any degradation of hyaluronic acid, such as in the range of pH 6.5- 8.5.
  • an embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the solvent of the hydrogel formulation is aqueous.
  • pH of the hydrogel formulation is in the range of about pH 6.5 to about pH 8.5, such as about pH 7 to about pH 8.
  • the concentration of dexamethasone or salts thereof in the hydrogel formulation can be adjusted so that levels within the therapeutic window is maintained over a prolonged period of time.
  • hydrogel formulation with relative higher content of first component to second component may be loaded with higher concentration of dexamethasone without reaching toxic levels because dexamethasone is released slower compared to a hydrogel formulation with less relative content of the first component.
  • the hydrogel formulations can be utilized with a range of different concentrations of dexamethasone.
  • a preferred concentration of dexamethasone is about 1 mg/g. Therefore, an embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the concentration of dexamethasone or a salt thereof is in the range of about 0.2 mg/g to about 5 mg/g with respect to the total weight of the hydrogel formulation, such as about 0.5 mg/g to about 4 mg/g, such as about 0.75 mg/g to about 2 mg/g, preferably about 1 mg/g.
  • dexamethasone sodium phosphate is a water-soluble inorganic ester (9-Fluoro-llB, 17,21- trihydroxy-16o-methylpregna-l, 4-diene-3, 20-dione 21-(dihydrogen phosphate) disodium salt).
  • a preferred embodiment of the present invention relates to the hydrogel formulation as described herein, wherein said dexamethasone or a salt thereof is dexamethasone sodium phosphate.
  • the hydrogel formulation may further comprise one or more conventional ingredients added to improve physical and/or chemical characteristics of the formulation. These may improve e.g. stability, appearance, and/or effect of the hydrogel formulation.
  • an embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the hydrogel formulation further comprises one or more additives.
  • Another embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the one or more additives are selected from the group consisting of osmolality adjusters, pH adjusters, thickening agents, gelling agents, preservatives, stabilizers, solubilizers, emulsifying agents, anti-oxidants, electrolytes, radical scavengers, vitamins, scents, coloring agents, pigments, melanin, light protection filters, waxes, resins, oils, esters, alcohols, and polyols.
  • the one or more additives are selected from the group consisting of osmolality adjusters, pH adjusters, thickening agents, gelling agents, preservatives, stabilizers, solubilizers, emulsifying agents, anti-oxidants, electrolytes, radical scavengers, vitamins, scents, coloring agents, pigments, melanin, light protection filters, waxes, resins, oils, esters, alcohols, and polyols.
  • a further embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the hydrogel formulation further comprises a preservative.
  • a still further embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the preservative is selected from the group consisting of methyl paraben, ethyl paraben, propyl paraben, butyl paraben, benzyl alcohol, chlorobutanol, phenol, meta cresol, chloro cresol, benzoic acid, sorbic acid, thiomersal, phenylmercuric nitrate, bronopol, propylene glycol, benzalkonium chloride, benzethonium chloride.
  • the preservative is selected from the group consisting of methyl paraben, ethyl paraben, propyl paraben, butyl paraben, benzyl alcohol, chlorobutanol, phenol, meta cresol, chloro cresol, benzoic acid, sorbic acid, thiomersal, phenylmercuric nitrate, bronopol, propylene glycol, benzal
  • hydrogel formulation may be produced under sterile conditions, a preservative may for some variants of the hydrogel formulation not be necessary. This may for example be, but is not limited to, one-time use hydrogel formulations.
  • an embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the hydrogel formulation does not comprise a preservative.
  • hydrogel formulation as described herein, wherein the hydrogel formulation further comprises a pharmaceutically acceptable carrier, excipient or diluent.
  • the viscosity of medical formulations plays a crucial role in how they can be administered to a subject. If the formulation is too viscous it limits significantly how a treatment may be administered to a subject, e.g., because it can no longer be injected with a syringe through a needle or would entail undesirable and unacceptable discomfort for the recipient of the formulation.
  • the hydrogel formulation described herein comprises a fraction of non-crosslinked to reduce the viscosity of the more dense hydrogel. If the relative content of crosslinked HA becomes too high, the formulation might become unsuitable e.g. for injection. Importantly, increasing the fraction of linear HA promotes the shear thinning properties of the hydrogel formulation and improves injectability as force is applied to the syringe.
  • the storage modulus is one parameter that can be used to describe the viscoelastic properties of the hydrogel formulation.
  • High crosslinking degree of the first component will result in high storage modulus. While high storage modulus typically leads to prolonged release profiles, too high storage modulus can cause the hydrogel to behave as a crystalline-like material into which loading of active compound becomes inefficient. Moreover, such type of inhomogeneous material is not suitable for injection. Accordingly, depending on the application of the hydrogel formulation, it is preferred to obtain a storage modulus that fits the desired viscoelastic properties of the specific application, e.g. to provide a hydrogel formulation with a desired cushioning effect.
  • a storage modulus of about 20-200 Pa is suitable (see T.C Laurent (1998), "The Chemistry, Biology and Medical Applications of Hyaluronan and its Derivatives", p. 243- 253).
  • storage modulus of knee synovial fluid is approx. 117 Pa, and it is therefore desirable to mimic this number as closely as possible to ensure high compatibility with the local tissue subject to the injection.
  • an embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the storage modulus of the hydrogel formulation is in the range of about 20 Pa to about 200 Pa, such as about 50 Pa to about 150 Pa, such as about 75 Pa to about 125 Pa.
  • a preferred embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the storage modulus G' of the hydrogel formulation is in the range of about 110 Pa to about 130 Pa.
  • Another embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the storage modulus of the hydrogel formulation is about 100 Pa.
  • an embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the loss modulus G" of the hydrogel formulation is in the range of about 10 Pa to about 80 Pa, such as about 10 Pa to about 50 Pa, such as about 15 Pa to about 70 Pa, such as about 20 Pa to about 60 Pa, preferably about 25 Pa to about 50 Pa.
  • the hydrogel formulation is designed for injection into the tissue (e.g. joint) in need of the anti-inflammatory infect of dexamethasone and the cushioning effect of the hydrogel.
  • An integral part of the design of the hydrogel formulation is therefore its ability to be injected (or injectability).
  • the force required to inject the hydrogel formulation into the target tissue should not be too high as it will cause unacceptable discomfort for the recipient of the injection.
  • injectability may be quantified by the injection force required to dispense the hydrogel formulation through a needle.
  • An acceptable force for intraarticular administration is less than 15 N.
  • the injection force will logically also depend on the size of the needle and consequently the orifice the hydrogel formulation is pushed through.
  • Typical needles sizes used in osteoarthritis treatment typically ranges from 18 to 22 gauge (Birmingham gauge, G).
  • an embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the hydrogel formulation is injectable from a 1 mL syringe through a needle with a gauge (Birmingham gauge) in the range of about 18 G to about 22 G, such as about 20 G to about 22 G, preferably about 22 G.
  • a gauge Billermingham gauge
  • a further embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the hydrogel formulation is injectable at an injection speed of about 2 ml/min to about 6 mL/min, such as about 3 mL/min to about 5 mL/min, preferably about 4 mL/min.
  • a still further embodiment of the present invention relates to the hydrogel formulation as described herein, wherein the hydrogel formulation is injectable with an injection force of less than about 15 N.
  • dexamethasone is released to the surrounding environment. Over time all the content of the hydrogel formulation will be released, endpoint release time being dependent on the exact configuration of the hydrogel formulation.
  • an embodiment of the present invention relates to the hydrogel formulation as described herein, wherein said hydrogel formulation is adapted for releasing at least 90%, such as at least 95%, such as at least 99% of said dexamethasone or a salt thereof to a subject no earlier than after about 8 hours after administration, such as no earlier than after about 9 hours, such as no earlier than after about 10 hours, such as no earlier than after about 11 hours, such as no earlier than after about 12 hours.
  • Another embodiment of the present invention relates to the hydrogel formulation as described herein, wherein said hydrogel formulation is adapted for releasing at least 99% of the dexamethasone to a subject no earlier than after about 8 hours after administration.
  • the hydrogel formulation described herein is prepared by mixing a first component comprising a crosslinked HA hydrogel with a second component comprising noncrosslinked HA, and loading the obtained mixture with dexamethasone.
  • the first component is made through a series of steps, including crosslinking of HA with a crosslinking agent, curing and comminuting the obtained hydrogel, neutralization and micronization of the fragmented hydrogel.
  • an aspect of the present invention relates to a method for preparing a hydrogel formulation as described herein, said method comprising the following steps:
  • Crosslinking of HA by means of a crosslinking agent can be via covalent bonds with hydroxyl, carboxylate and/or acetamide functional groups of the hyaluronic acid polymer.
  • crosslinking may be achieved through the primary hydroxyl group of N-acetyl-D-glucosamine of HA under alkaline conditions.
  • the base can be NaOH.
  • the HA is dissolved in the alkaline solution by mixing with a turbine mixer. Extended mixing for up to 90 min at 600 rpm is preferred to ensure that all HA are dissolved. However, mixing could be extended for as long as 180 min.
  • an embodiment of the present invention relates to the method as described herein, wherein said solution is alkaline.
  • Another embodiment of the present invention relates to the method as described herein, wherein the pH of said solution is in the range of about pH 9 to about pH 12, such as about pH 10 to about pH 12.
  • a further embodiment of the present invention relates to the method as described herein, wherein said solution has a pH of at least 9.
  • a still further embodiment of the present invention relates to the method as described herein, wherein said solution comprises NaOH in a concentration between about 0.001 M to about 2.0 M, such as about 0.01 M to about 1.0 M, such as about 0.1 M to about 0.5 M, preferably about 0.2 M.
  • step (vii) Design of the hydrogel formulation is guided by the amount of HA added for the first component and second component, respectively. Since the second component is added without any further processing, the amount of HA added in step (vii) will reflect directly the amount of non-crosslinked HA in the formulation. In contrast, the HA of the first component is subjected to many processing steps and is therefore "diluted" as part of the process. Overall, the initial content of HA in the solution of step (i) is higher than in the first component of the final hydrogel.
  • an embodiment of the present invention relates to the method as described herein, wherein said solution comprises about 5-7 % (w/w), preferably about 6 % (w/w).
  • Another embodiment of the present invention relates to the method as described herein, wherein said first component comprises about 0.8-2 % (w/w) HA, such as about 1.0-1.5 % (w/w), such as about 1.2-1.4 % (w/w).
  • a further embodiment the present invention relates to the method as described herein, wherein said second component comprises about 1.5-4.5 % (w/w) non-crosslinked HA, such as about 2-4 % (w/w), preferably about 3 % (w/w).
  • the HA is mixed with a crosslinking agent and stirred intensely to ensure homogeneous distribution of the reactants. Mixing is preferably followed by an incubation period to cure the HA hydrogel before it is fragmented as part of the processing.
  • an embodiment of the present invention relates to the method as described herein, wherein said reaction is performed with a ratio between HA and crosslinking agent in the range of about 12: 1 % (w/w) to about 22: 1 % (w/w), such as about 15: 1 % (w/w) to about 20: 1 % (w/w), preferably about 17: 1 % (w/w).
  • Another embodiment of the present invention relates to the method as described herein, wherein said reaction is performed under agitation.
  • a further embodiment of the present invention relates to the method as described herein, wherein the crosslinking agent is selected from the group consisting of divinyl sulfone (DVS), 1,4-butanediol diglycidyl ether (BDDE), formaldehyde, glutaraldehyde, polyanhydrides, polyaldehydes, polyhydric alcohols, carbodiimides, carboxylic acid chlorides, sulfonic acid chlorides, celluloses, dextrans, epichlorohydrin, ethylene glycol, diglycidyl ethers, polyglycerol polyglycidyl ethers, and bis- or polyepoxides.
  • the crosslinking agent is selected from the group consisting of divinyl sulfone (DVS), 1,4-butanediol diglycidyl ether (BDDE), formaldehyde, glutaraldehyde, polyanhydrides, polyaldehydes, polyhydric alcohols,
  • a still further embodiment of the present invention relates to the method as described herein, wherein step (ii) is immediately followed by curing of said first hydrogel prior to comminution.
  • Yet another embodiment of the present invention relates to the method as described herein, wherein curing comprises heating at about 35°C to about 45°C, such as at 40°C, for at least 1 hour, preferably 2 hours.
  • the HA hydrogel is divided into smaller pieces to yield a fragmented hydrogel.
  • the hydrogel is broken down into chunks of 25x40 mm. It is to be understood that the chunks can be smaller or larger, such as down to about 10 mm or up to about 50 mm. This may be achieved by cutting the hydrogel on a plate of glass, plastic or metal.
  • the hydrogel can be fragmented by mechanically forcing it through a cutting mesh (also known as an extrusion screen).
  • the extrusion screen may have a mesh size of 25x25 mm.
  • an embodiment of the present invention relates to the method as described herein, wherein said comminution is performed by cutting.
  • Comminution of the hydrogel is followed by rinsing of the fragmented hydrogel in excess volumes of an aqueous solvent.
  • the solvent may be purified water or any type of suitable aqueous buffer with a pH in a range that serves to neutralize the fragmented hydrogel following the initial hydrogel formation in alkaline solution and wash out remaining unreacted crosslinking agent.
  • the HA hydrogel absorb the aqueous medium and swell to a saturated form.
  • the time required to saturate the fragmented HA hydrogel varies depending on the exact content and crosslinking degree of the hydrogel, but the neutralization and swelling is preferably performed for 19-25 hours.
  • an embodiment of the present invention relates to the method as described herein, wherein said comminution is immediately followed by rinsing of the fragmented hydrogel.
  • Another embodiment of the present invention relates to the method as described herein, wherein said rinsing is achieved by immersion of the fragmented hydrogel in ultrapure water and/or rinsing buffer, and optionally agitating the immersed fragmented hydrogel.
  • Yet another embodiment of the present invention relates to the method as described herein, wherein the buffer agent is a phosphate buffer or a saline buffer.
  • a further embodiment of the present invention relates to the method as described herein, wherein the buffer agent has a pH in the range of about 5.5 to about 9.
  • a still further embodiment of the present invention relates to the method as described herein, wherein the buffer agent has a pH in the range of about 5 to about 7.5, such as in the range of about 6 to about 7, preferable about 6.9.
  • An even further embodiment of the present invention relates to the method as described herein, wherein the buffer agent is added in a volume of at least 3 times the volume of the fragmented hydrogel, such as at least 4 times the volume of the fragmented hydrogel, such as at least 5 times the volume of the fragmented hydrogel, such as at least 6 times the volume of the fragmented hydrogel, such as at least 10 times the volume of the fragmented hydrogel.
  • the neutralized (and swollen) hydrogel which is still fragmented, is separated from excess and non-absorbed buffer by use of a sieve.
  • the neutralized hydrogel is placed in the sieve and the non-absorbed liquid fraction is drained to provide a purified swollen hydrogel out of solution.
  • an embodiment of the present invention relates to the method as described herein, wherein the separation of said neutralized hydrogel from said buffer is achieved by placement of the neutralized hydrogel in a sieve followed by drainage of the liquid fraction.
  • the purified hydrogel is micronized to secure a homogeneous material that can administered without any difficulties, such as blocking of needles.
  • the hydrogel formulation described herein is readily injectable through various needle sizes, types or catheters (22G-30G) without the need for applying strong force. To obtain a smooth injection profile forces below 20N, but preferably below 15N, is recommended. Micronization can be achieved by extrusion or mixing.
  • the micronized hydrogel is introduced in the hydrogel formulation as the first component.
  • an embodiment of the present invention relates to the method as described herein, wherein the micronization of said purified hydrogel is performed by extrusion and/or mixing.
  • Another embodiment of the present invention relates to the method as described herein, wherein the micronization of said purified hydrogel is achieved by extrusion using an extrusion screen.
  • Yet another embodiment of the present invention relates to the method as described herein, wherein said extrusion screen has a mesh size in the range of 200-450 pm.
  • a further embodiment of the present invention relates to the method as described herein, wherein the micronization is achieved by mixing with a high shear mixer.
  • the micronized hydrogel may optionally be subjected to autoclaving prior to mixing with the second component comprising non-crosslinked HA. Autoclaving will sterilize the hydrogel. However, the optional step of autoclaving may also be used to adjust the rheology of the hydrogel slightly.
  • an embodiment of the present invention relates to the method as described herein, wherein said first component and/or second component are sterilized by autoclaving before addition of the second component.
  • Another embodiment of the present invention relates to the method as described herein, wherein said first component and/or second component are autoclaved for about 10 min to about 20 min at about 110°C to about 130°C.
  • the first component comprising the processed HA hydrogel is mixed with a second component comprising non-crosslinked HA to form a hydrogel composition.
  • the hydrogel composition is then loaded with dexamethasone to obtain the hydrogel formulation.
  • the method as described herein will produce hydrogel formulations which can extend the release of dexamethasone and thereby more efficiently exploit the therapeutic window over time.
  • an aspect of the present invention relates to a hydrogel formulation as described herein obtainable by a method as described herein.
  • hydrogel formulations described herein will improve efficiency of existing and future treatments by maximizing the therapeutic effect obtained from a given dosage of dexamethasone.
  • the ability to more accurately adjust the levels of dexamethasone further lessens the risk of adverse effects and reduces the number of administrations required in a treatment schedule.
  • an aspect of the present invention relates to a hydrogel formulation as described herein for use as a medicament.
  • the hydrogel formulation is a delivery system that facilitates a more efficient use of dexamethasone.
  • the hydrogel formulation is consequently not limited to any particular therapy but may be utilized for treatment of any disease that may be prevented, inhibited of alleviated by delivery of dexamethasone. These include, but are not limited to, musculoskeletal conditions, acute and chronic inflammatory arthritis, metabolic joint conditions, and gout.
  • another aspect of the present invention relates to a hydrogel formulation as described herein for use in the treatment, prevention or inhibition of one or more diseases or disorders selected from the group consisting of arthritis, tendonitis, synovitis, bursitis, metabolic joint conditions, gout, allergic disorders, dermatological diseases, endocrine disorders, gastrointestinal diseases, hematological disorders, neoplastic diseases, nervous diseases, ophthalmic diseases, renal diseases, respiratory diseases skin diseases, and pain, preferably arthritis.
  • diseases or disorders selected from the group consisting of arthritis, tendonitis, synovitis, bursitis, metabolic joint conditions, gout, allergic disorders, dermatological diseases, endocrine disorders, gastrointestinal diseases, hematological disorders, neoplastic diseases, nervous diseases, ophthalmic diseases, renal diseases, respiratory diseases skin diseases, and pain, preferably arthritis.
  • An embodiment of the present invention relates to the hydrogel formulation for use as described herein, wherein said arthritis is selected from the group consisting of osteoarthritis, acute or chronic inflammatory arthritis, such as psoriatic arthritis, rheumatoid arthritis, and juvenile arthritis.
  • a preferred embodiment of the present invention relates to the hydrogel formulation as described herein for use in the treatment, prevention or inhibition of osteoarthritis.
  • hydrogel formulations may improve current therapies relating to inflammatory musculoskeletal conditions. These conditions include, but are not limited to, tendonitis, bursitis, fasciitis, neuropathies and myositis.
  • an embodiment of the present invention relates to the hydrogel formulation as described herein for use in the treatment, prevention or inhibition of one or more inflammatory musculoskeletal conditions.
  • Another embodiment of the present invention relates to the hydrogel formulation for use as described herein, wherein the inflammatory musculoskeletal conditions are selected from the group consisting of tendonitis, bursitis, fasciitis, neuropathies and myositis.
  • a further embodiment of the present invention relates to the hydrogel formulation for use as described herein, wherein the hydrogel formulation is administered to a subject.
  • a still further embodiment of the present invention relates to the hydrogel formulation for use as described herein, wherein said subject is a mammal, such as a domestic animal, a livestock animal or a human, preferably a human.
  • Administration of the hydrogel formulation is preferably directed to the site of pain or disease, e.g. a joint in pain.
  • the preferred route of administration is joint injection (intraarticular).
  • the injection is performed with a hypodermic needle which is injected directly into the affected joint.
  • an embodiment of the present invention relates to the hydrogel formulation for use as described herein, wherein the route of administration is intraarticular.
  • the hydrogel formulation may be administered either as a single injection treatment or as a treatment requiring repeated injections.
  • the treatment is suitable for an ambulatory/outpatient care setting.
  • an embodiment of the present invention relates to the hydrogel formulation for use as described herein, wherein the intraarticular administration is performed as a single administration or as multiple administrations.
  • Another embodiment of the present invention relates to the hydrogel formulation for use as described herein, wherein the intraarticular administration is an injection in a joint selected from the group consisting of hip, knee, shoulders, wrists, ankles, hands, and fingers, preferably hip or knee.
  • Yet another embodiment of the present invention relates to the hydrogel formulation for use as described herein, wherein said hydrogel formulation is used as a supplementary treatment given to a subject receiving physiotherapy, rehabilitation and/or have undergone joint or musculoskeletal/orthopaedic surgery.
  • a further embodiment of the present invention relates to the hydrogel formulation for use as described herein, wherein at least 90%, such as at least 95%, such as least 99% of said dexamethasone or a salt thereof is released from said hydrogel formulation no earlier than after about 8 hours after administration, such as no earlier than after about 9 hours, such as no earlier than after about 10 hours, such as no earlier than after about 11 hours, such as no earlier than after about 12 hours.
  • the hydrogel formulation may conveniently be provided in a kit comprising also relevant information on how to administer the formulation.
  • the hydrogel formulation may be included preloaded in one or more syringes for easy use.
  • an aspect of the present invention relates to a kit comprising:
  • Another embodiment of the present invention relates to a kit as described herein, wherein said hydrogel formulation is provided in a syringe.
  • a hydrogel formulation comprising:
  • hydrogel formulation according to item XI wherein the ratio between HA and crosslinking agent is in the range of about 12: 1 % (w/w) to about 18: 1 % (w/w), such as about 14: 1 % (w/w) to about 18: 1 % (w/w), such as about 16: 1 % (w/w) to about 18: 1 % (w/w).
  • hydrogel formulation according to any one of items XI or X2, wherein the ratio between HA and crosslinking agent is about 17: 1 % (w/w).
  • X5 The hydrogel formulation according to any one of the preceding items, wherein the ratio between said first component and said second component is about 90: 10 % (w/w).
  • hydrogel formulation according to any one of the preceding items, wherein the ratio between HA and crosslinking agent is about 17: 1 % (w/w), and the ratio between said first component and said second component is about 90: 10 % (w/w).
  • hydrogel formulation according to any one of the preceding items, wherein the first component comprises a hydrogel comprising about 0.5-3% (w/w) of hyaluronic acid (HA).
  • HA hyaluronic acid
  • hydrogel formulation according to any one of the preceding items, wherein the second component comprises about 1-6% (w/w) non-crosslinked HA.
  • a hydrogel formulation comprising:
  • a first component comprising a hydrogel comprising about 0.5-3% (w/w) of hyaluronic acid (HA) crosslinked with a crosslinking agent, wherein the ratio between HA and crosslinking agent is in the range of about 10: 1 % (w/w) to about 25: 1 % (w/w),
  • a second component comprising about 1-6% (w/w) non-crosslinked HA
  • hydrogel formulation according to item X9 wherein ratio between said first component and said second component is in the range of about 85: 15 % (w/w) to about 95:5 % (w/w), such as about 88: 12 % (w/w) to about 92:8 % (w/w), preferably about 90: 10 % (w/w).
  • XI 1 The hydrogel formulation according to any one of items X9 or X10, wherein the ratio between HA and crosslinking agent is in the range of about 12: 1 % (w/w) to about 22: 1 % (w/w), such as about 15: 1 % (w/w) to about 20: 1 % (w/w), preferably about 17: 1 % (w/w).
  • hydrogel formulation according to any one of the preceding items, wherein the concentration of crosslinked HA is in the range of about 0.2% (w/w) to about 2 % (w/w), such as about 0.4 % (w/w) to about 1.8 % (w/w), such as about 0.6 % (w/w) to about 1.6 % (w/w), such as about 0.8 % (w/w) to about 1.4 % (w/w), such as about 1.0 % (w/w) to about 1.2 % (w/w), based on the total weight of the hydrogel formulation.
  • hydrogel formulation according to any one of the preceding items, wherein the first component comprises about 0.8-2 % (w/w) HA, such as about 1.0-1.5 % (w/w), such as about 1.2-1.4 % (w/w).
  • hydrogel formulation according to any one of the preceding items, wherein the second component comprises about 1.5-4.5 % (w/w) non-crosslinked HA, such as about 2-4 % (w/w), preferably about 3 % (w/w).
  • hydrogel formulation according to any one of the preceding items, wherein the crosslinking agent is selected from the group consisting of divinyl sulfone (DVS), 1,4-butanediol diglycidyl ether (BDDE), poly(lactic acid) (PLA), poly(ethylene glycol) (PEG), poly(ethylene glycol) bis(amine), polyethylene glycol diacrylate (PEGDA), poly(ethylene glycol)-dimethacrylate (PEGDM), poly(ethylene glycol) -diacrylamide (PEGDAA) and polyethylene glycol)-dimethacrylamide (PEGDMA), carboxymethylcellulose (CMC), dextran acrylate, dextran methacrylate, dextran glycidyl methacrylate, glycerol dimethacrylate, glycerol 1,3-diglycerolate diacrylate, sorbitol acrylate, and derivatives thereof.
  • the crosslinking agent is selected from the group consisting of divinyl sulf
  • hydrogel formulation according to any one of the preceding items, wherein the total concentration of HA is in the range of about 10 mg/g to about 25 mg/g, such as about 12 mg/g to about 20 mg/g.
  • hydrogel formulation according to any one of the preceding items, wherein the molecular weight of the HA of said first component and/or second component is the range of about 500 kDa to about 1500 kDa, such as about 750 kDa to about 1250 kDa, preferably about 1000 kDa.
  • X19 The hydrogel formulation according to any one of the preceding items, wherein the molecular weight of the HA of said first component and second component is the same.
  • X20 The hydrogel formulation according to any one of the preceding items, wherein the HA is provided as an inorganic salt selected from the group consisting of sodium hyaluronate, potassium hyaluronate, ammonium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, and cobalt hyaluronate, preferably sodium hyaluronate.
  • hydrogel formulation according to any one of the preceding items, wherein the hydrogel formulation comprises less than 300 ppm calcium ions, such as less than 250 ppm, such as less than 200 ppm.
  • hydrogel formulation according to any one of the preceding items, wherein the solvent of the hydrogel formulation is aqueous.
  • hydrogel formulation according to any one of the preceding items, wherein pH of the hydrogel formulation is in the range of about pH 6.5 to about pH 8.5, such as about pH 7 to about pH 8.
  • hydrogel formulation according to any one of the preceding items, wherein the concentration of dexamethasone or a salt thereof is in the range of about 0.2 mg/g to about 5 mg/g with respect to the total weight of the hydrogel formulation, such as about 0.5 mg/g to about 4 mg/g, such as about 0.75 mg/g to about 2 mg/g, preferably about 1 mg/g.
  • hydrogel formulation according to item X28 wherein the preservative is selected from the group consisting of methyl paraben, ethyl paraben, propyl paraben, butyl paraben, benzyl alcohol, chlorobutanol, phenol, meta cresol, chloro cresol, benzoic acid, sorbic acid, thiomersal, phenylmercuric nitrate, bronopol, propylene glycol, benzalkonium chloride, benzethonium chloride.
  • the preservative is selected from the group consisting of methyl paraben, ethyl paraben, propyl paraben, butyl paraben, benzyl alcohol, chlorobutanol, phenol, meta cresol, chloro cresol, benzoic acid, sorbic acid, thiomersal, phenylmercuric nitrate, bronopol, propylene glycol, benzalkonium chloride, benzethonium
  • hydrogel formulation according to any one of the preceding items, wherein the storage modulus of the hydrogel formulation is in the range of about 20 Pa to about 200 Pa, such as about 50 Pa to about 150 Pa, such as about 75 Pa to about 125 Pa.
  • hydrogel formulation according to any one of the preceding items, wherein the storage modulus G' of the hydrogel formulation is in the range of about 50 Pa to about 200 Pa, such as about 75 Pa to about 175 Pa, such as about 100 Pa to about 150 Pa, preferably about 110 Pa to about 130 Pa.
  • hydrogel formulation according to any one of the preceding items, wherein the loss modulus G" of the hydrogel formulation is in the range of about 10 Pa to about 80 Pa, such as about 10 Pa to about 50 Pa, such as about 15 Pa to about 70 Pa, such as about 20 Pa to about 60 Pa, preferably about 25 Pa to about 50 Pa.
  • hydrogel formulation according to any one of the preceding items, wherein the hydrogel formulation is injectable from a 1 mL syringe through a needle with a gauge (Birmingham gauge) in the range of about 22 G to about 30 G, such as about 22 G to about 28 G, such as about 24 G to about 27 G, preferably about 27 G.
  • gauge Billermingham gauge
  • hydrogel formulation according to any one of the preceding items, wherein the hydrogel formulation is injectable from a 1 mL syringe through a needle with a gauge (Birmingham gauge) in the range of about 18 G to about 22 G, such as about 20 G to about 22 G, preferably about 22 G.
  • hydrogel formulation according to any one of the preceding items, wherein the hydrogel formulation is injectable from a 1 mL syringe through a needle with a gauge (Birmingham gauge) of about 22 G.
  • X36 The hydrogel formulation according to any one of items X33-X35, wherein the hydrogel formulation is injectable at an injection speed of about 2 ml/min to about 6 mL/min, such as about 3 mL/min to about 5 mL/min, preferably about 4 mL/min.
  • hydrogel formulation according to any one of items X33-X36, wherein the hydrogel formulation is injectable with an injection force of less than about 15 N.
  • hydrogel formulation according to any one of items X33-X37, wherein the hydrogel formulation is injectable with an injection force of less than about 15 N, such as less than about 14 N, such as less than about 13 N, such as less than about 12 N, such as less than about U N, preferably less than about 10 N.
  • hydrogel formulation according to any one of the preceding items, wherein the hydrogel formulation is injectable from a 1 mL syringe through a needle with a gauge (Birmingham gauge) of about 22 G using an injection force of less than about 15 N, such as less than about 14 N, such as less than about 13 N, such as less than about 12 N, such as less than about 11 N, preferably less than about 10 N.
  • hydrogel formulation according to any one of the preceding items, wherein the hydrogel formulation further comprises a pharmaceutically acceptable carrier, excipient or diluent.
  • hydrogel formulation according to any one of the preceding items, wherein said hydrogel formulation is adapted for releasing at least 90%, such as at least 95%, such as at least 99% of said dexamethasone or a salt thereof to a subject no earlier than after about 8 hours after administration, such as no earlier than after about 9 hours, such as no earlier than after about 10 hours, such as no earlier than after about 11 hours, such as no earlier than after about 12 hours.
  • Y9 The method according to any one of items Y1-Y8, wherein said reaction is performed with a ratio between HA and crosslinking agent in the range of about 12: 1 % (w/w) to about 22: 1 % (w/w), such as about 15: 1 % (w/w) to about 20: 1 % (w/w), preferably about 17: 1 % (w/w).
  • a ratio between HA and crosslinking agent in the range of about 12: 1 % (w/w) to about 22: 1 % (w/w), such as about 15: 1 % (w/w) to about 20: 1 % (w/w), preferably about 17: 1 % (w/w).
  • hydrogel formulation according to any one of items Y1-Y8, wherein the ratio between HA and crosslinking agent is in the range of about 10: 1 % (w/w) to about 18: 1 % (w/w), such as about 12: 1 % (w/w) to about 18: 1 % (w/w), such as about 14: 1 % (w/w) to about 18: 1 % (w/w), such as about 16: 1 % (w/w) to about 18: 1 % (w/w).
  • crosslinking agent is selected from the group consisting of divinyl sulfone (DVS), 1,4-butanediol diglycidyl ether (BDDE), formaldehyde, glutaraldehyde, polyanhydrides, polyaldehydes, polyhydric alcohols, carbodiimides, carboxylic acid chlorides, sulfonic acid chlorides, celluloses, dextrans, epichlorohydrin, ethylene glycol, diglycidyl ethers, polyglycerol polyglycidyl ethers, and bis- or polyepoxides, preferably divinyl sulfone (DVS).
  • DVDDE 1,4-butanediol diglycidyl ether
  • formaldehyde glutaraldehyde
  • polyanhydrides polyaldehydes
  • polyhydric alcohols carbodiimides
  • carboxylic acid chlorides sulfonic acid chlorides
  • celluloses dextrans
  • step (ii) is immediately followed by curing of said first hydrogel prior to comminution.
  • Y19 The method according to any one of items Y1-Y18, wherein the buffer agent has a pH in the range of about 5.5 to about 9. Y20.
  • the buffer agent is added in a volume of at least 3 times the volume of the fragmented hydrogel, such as at least 4 times the volume of the fragmented hydrogel, such as at least 5 times the volume of the fragmented hydrogel, such as at least 6 times the volume of the fragmented hydrogel, such as at least 10 times the volume of the fragmented hydrogel.
  • diseases or disorders selected from the group consisting of arthritis, tendonitis, synovitis, bursitis, metabolic joint conditions, gout, allergic disorders, dermatological diseases, endocrine disorders, gastrointestinal diseases, hematological disorders, neoplastic diseases, nervous diseases, ophthalmic diseases, renal diseases, respiratory diseases skin diseases, and pain, preferably arthritis.
  • hydrogel formulation for use according to any one of items W1-W4, wherein the hydrogel formulation is administered to a subject.
  • hydrogel formulation for use according to item W5 wherein said subject is a mammal, such as a domestic animal, a livestock animal or a human, preferably a human.
  • a kit comprising:
  • Hydrogel formulations were prepared by a custom designed process to evaluate the potential of the resulting formulations for providing controlled release of dexamethasone.
  • Sodium Hyaluronate (1 MDa) were dissolved in a 0.2M NaOH solution under mechanical stirring by an Ika-mixer with a turbine mixer to prepare a 6% (w/w) HA solution.
  • the solution was stirred until no HA lumps were present in the solution.
  • Divinyl sulfone (DVS) was added to the solution in an amount to reach the desired HA to DVS ratio (10: 1, 17: 1 or 20: 1) followed by mixing until completely dispersed in the solution.
  • the HA: DVS mix was then transferred to a plastic tray in an even layer with a thickness of approximately 25-40 mm, and cured at 40°C for 2 hours while covering the tray with a lid. Subsequent to curing, the crosslinked hydrogel was placed at ambient temperature for 10 min and thereafter cut in pieces (approx. 25x40 mm) with a cutting wheel. The fragmented hydrogel was transferred to a beaker containing 12 mM PBS (137 mM NaCI, 2.7 mM KCI, 10.2 mM Na 2 HPO 4 , 2.0 mM KH2PO4) pH 6.9 and swollen for up to 25 hours.
  • 12 mM PBS 137 mM NaCI, 2.7 mM KCI, 10.2 mM Na 2 HPO 4 , 2.0 mM KH2PO4
  • the swelling and neutralization are done to neutralize the pH of the gel and wash out remaining DVS and possible DVS adducts.
  • the total swelling time for the fragmented hydrogel is set to be 19-25 hours, depending on the crosslinking degree. All gels of a higher crosslinking degree than 10: 1 should be neutralized for at least 24 hours, whereas fragmented hydrogels of a lower crosslinking degree than 10: 1 should be neutralized for 19 hours.
  • the neutralized hydrogel (pH 6.9-7.3) was separated from the buffer in a mesh.
  • the hydrogel was left in the mesh for 10 min to let all buffer seep out.
  • the remaining hydrogel was weighed and, if necessary, mass corrected by buffer if needed to reach a specific HA concentration in the bulk purified hydrogel.
  • the bulk purified hydrogel was then micronized by either high shear mixing or extrusion.
  • Micronization by high shear mixing was performed by using a Silverson mixer attached with a Ultramixer workhead.
  • Micronization by extrusion was performed by passing the hydrogel through an extrusion screen with a mesh size of 200-450 pm.
  • a support screen with a mesh size of 1.5 mm may be placed on each side of the extrusion screen for support.
  • the hydrogel can be treated with 20 strokes (10 in each direction) at a pressure of approx. 6 bars.
  • the mean particle size of the micronized hydrogel particles was measured in a buffer with 0.9% NaCI using a Malvern Mastersizer 2000 coupled with a Hydro2000 dispersion unit. Measurements were performed assuming spherical particles and in the interval 0.02 - 2000 pm.
  • the micronized hydrogel particles were autoclaved at 121 °C for 15 min to provide the first component of the hydrogel formulation.
  • a second component of non-crosslinked (linear) HA (3 % (w/w)) in 12 mM PBS (137 mM NaCI, 2.7 mM KCI, 10.2 mM Na 2 HPO 4 , 2.0 mM KH 2 PO 4 ) pH 6.9 was added to reach a desired ratio between first and second components, and the hydrogel composition was autoclaved at 121 °C for 15 min.
  • Hydrogel formulations for two types of studies were prepared. One study aimed at evaluating varying crosslinking degree (/.e. HA to crosslinking agent) and another study aimed at evaluating ratios of hydrogel component with non-crosslinked HA.
  • the first component of the hydrogel formulation samples was named as follows: PAT (or DX1)-XXX-YZZZ, wherein "XXX” is the crosslinker, Y is the added % (w/w) HA in the first component, and ZZZ is the crosslinking degree.
  • PAT-DVS-6101 is a sample wherein 6% HA is crosslinked with DVS in a ratio of 10: 1. It is to be understood that the 6% is the initial concentration of HA, and not the concentration of HA in the first component.
  • the rheology of the hydrogel formulations was measured on a Malvern, Bohlin CV-100- 901 rheometer. The samples were tested at the following conditions: Frequency sweep from 0.01-10 Hz, strain 0.005, 21 points, Gap 1000 pm and running temperature of 25°C, Geometry is plate-plate 20mm. Read-out in Pa was at 2.5 Hz as stated in the information for SynVisc. The storage modulus was measured without loading of DSP to the hydrogel formulation to enable direct comparison with the SynVisc product.
  • the Synvisc product had a storage modulus G' of 133 Pa and a viscous modulus G" of 22 Pa ( Figure 1).
  • the hydrogel formulation had a storage modulus G' of 98 Pa and a viscous modulus G" of 23 Pa ( Figure 1).
  • the numbers are similar, suggesting that the hydrogel formulation are suitable for use in treatment of e.g. osteoarthritis, which is the indication for which SynVisc is used.
  • hydrogel formulation have visco-elastic properties that are suitable for use in treatment of rheumatic disorders, such as osteoarthritis.
  • Example 2 Effect of hydrogel formulation on release profile of dexamethasone The release of dexamethasone from the hydrogel formulations was measured to evaluate how efficiently the dexamethasone was retained and gradually released over time.
  • Hydrogel formulations were prepared as described in Example 1.
  • DSP Dexamethasone sodium phosphate
  • a reference sample of DSP in 1.5% (w/w) linear HA dissolved in 12 mM PBS (137 mM NaCI, 2.7 mM KCI, 10.2 mM Na?HPO4, 2.0 mM KH2PO4) pH 6.9 was prepared in concentrations of 1 mg/g DSP.
  • Release profiles of dexamethasone from the hydrogel formulations were measured using a Sotax USP 4 dissolution system (Figure 2A-C).
  • the system consists of a piston pump (CP7), a dissolution unit (SOTAX CE7), a UV spectrophotometer (Shimadzu UV- 1800), and controlling software (WinSOTAX+).
  • DSP dexamethasone sodium phosphate
  • the release profile of DSP was delayed when incorporated in the hydrogel formulation (samples 3-8) compared to formulation with pure linear HA (sample 2). By increasing the crosslinking degree, the release could be further prolonged (samples 3-5). Interestingly, a visual inspection of the dialysis cells showed that the hydrogel formulation was still present after a 100% release of the drug, which means there is also a mechanical/physiological effect of the hydrogel in i.e. osteoarthritis or similar applications.
  • hydrogel formulations described herein can be used for extended and controlled release of dexamethasone sodium phosphate (DSP).
  • DSP dexamethasone sodium phosphate
  • the hydrogel formulation may therefore serve the dual purpose of providing a cushioning effect to the site of treatment and ensuring a controlled release of DSP to the site of treatment for a prolonged period of time.
  • Visco-elastic properties of the hydrogel formulation were tested for different ratios between the first and second components ("formulation ratio”) and different ratios between HA and crosslinking agent (“crosslinking ratio”).
  • formulation ratio the ratios between the first and second components
  • crosslinking ratio the ratios between HA and crosslinking agent
  • Example 2 Two sets of hydrogel formulations were prepared according to Example 1; a first wherein the crosslinking ratio was kept constant at 17: 1 (formulation ratios of 10:90, 50:50, 80:20, 85: 15, 90: 10, 95:5, 99: 1 and 100:0) and a second wherein the formulation ratio was kept constant at 90: 10 (crosslinking ratios of 5: 1, 17: 1, 20: 1 and 25: 1).
  • the rheology of the hydrogel formulations was measured on an Anton Paar RheoCompassTM rheometer. The samples were tested at the following conditions: Frequency sweep from 0.01-10 Hz, strain 0.005, 19 points, Gap 1000 pm and running temperature of 25°C, Geometry is plate-plate 25mm (PP25). Read-out in Pa was at 2.5 Hz as stated in the information for SynVisc. The storage modulus was measured without loading of DSP to the hydrogel formulation to enable direct comparison with the SynVisc product.
  • the storage and loss modulus compared over the different formulation ratio are displayed in Table 3.
  • the hydrogel formulations FRIO, FR50 and FR100 fell outside the acceptable range G' and G" values.
  • the crosslinking ratio was varied it was apparent that high amounts of crosslinker (CR5) caused an increase of the storage modulus G' (Table 4) so that the hydrogel formulation did not fulfil the requirement of an acceptable visco-elastic supplement.
  • many of the tested hydrogel formulations (FR.80, FR.85, FR.90, FR.95, FR.99) showed excellent visco-elastic properties that fell inside the desired range.
  • Table 3 Storage modulus G' and loss modulus G" of hydrogel formulations with different formulation ratios.
  • Table 4 Storage modulus G' and loss modulus G" of hydrogel formulations with different crosslinking ratios.
  • hydrogel formulations presented herein have great viscoelastic properties if the formulation ratio and crosslinking ratio are carefully selected.
  • a second component of non-crosslinked HA is necessary to yield good visco-elastic properties.
  • the recommended needle size typically ranges from 18 to 22 gauge (e.g. SynVisc products). This range helps optimize fluid dynamics, making the injection process smoother and more comfortable for the patient. To facilitate a comfortable injection for the patient, the injection force should be no more than 15N.
  • hydrogel formulations were prepared to get an idea of the limitations of the formulations.
  • the formulations were prepared according to Example 1 with the formulation ratio being kept constant at 90: 10 (crosslinking ratios of 5: 1, 17: 1, 20: 1 and 25: 1). These formulations were stress tested by dispensing with needles of small size (25Gl 1 /2" and G27l 1 /2") and recording injection force.
  • a second set of hydrogel formulations were prepared according to Example 1 wherein the crosslinking ratio was kept constant at 17: 1 (formulation ratios of 50:50, 85: 15, 90: 10, 95:5, 99: 1 and 100:0). These formulations were dispensed with needles of small size (25Gl 1 /2") and regular size used in osteoarthritis treatment (22Gl 1 /2”) and injection force were recorded.
  • the injectability of the hydrogel formulations was measured on a Texture analyser from Micro Stable System. The samples were tested at the following conditions: Pre-test speed 10.2 mm/min, Test speed 57.0 mm/min, Trigger Force IN. Measured value is Force (N) and data collected over 0.7 minutes and read-out of average force in time range 0.30 - 0.40 minutes.
  • the hydrogel formulations were tested in 2.25 mL HY-PAK BD glass syringes with needles sizes of 22G l 1 /2", 25G l 1 /2" and 27Gl 1 /2". A syringe containing water attached with a 27G V2" needle size has in this test set up an injection force of 2.6N and used as minimum relevant force.
  • the identified advantageous crosslinking ratio enhances the thixotropic (or shear thinning) properties of the hydrogel formulation.
  • the hydrogel formulation becomes more rigid and therefore requires a high injection force.
  • the hydrogel formulation may become disorganised, as the internal structure of the hyaluronic acid polymers are less interconnected, to an extent that a larger force is required to align the polymeric material for dispensing through the restricted volume of the needle.

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Abstract

La présente invention concerne une formulation d'hydrogel facilitant la libération contrôlée de dexaméthasone ou d'un sel de celle-ci sur une période de temps prolongée. En particulier, la formulation d'hydrogel contient un composant d'acide hyaluronique réticulé formulé avec un composant d'acide hyaluronique non réticulé.
PCT/EP2024/076871 2023-09-25 2024-09-25 Système d'administration de dexaméthasone Pending WO2025068242A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR100E (fr) 1901-10-14 1902-10-24 Legrand Sa Un appareil dénommé "marquette manille"
US8680073B2 (en) * 2009-09-10 2014-03-25 Genzyme Corporation Stable hyaluronan/steroid formulation
EP2664334B1 (fr) * 2004-12-30 2015-03-04 Genzyme Corporation Schémas posologiques pour viscosupplémentation intra-articulaire
TWI808303B (zh) * 2020-02-05 2023-07-11 和康生物科技股份有限公司 用於治療肌腱炎的醫藥組成物及其用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR100E (fr) 1901-10-14 1902-10-24 Legrand Sa Un appareil dénommé "marquette manille"
EP2664334B1 (fr) * 2004-12-30 2015-03-04 Genzyme Corporation Schémas posologiques pour viscosupplémentation intra-articulaire
US8680073B2 (en) * 2009-09-10 2014-03-25 Genzyme Corporation Stable hyaluronan/steroid formulation
TWI808303B (zh) * 2020-02-05 2023-07-11 和康生物科技股份有限公司 用於治療肌腱炎的醫藥組成物及其用途

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Title
SMITH CHRISTOPHER ET AL: "Combined intra-articular injection of corticosteroid and hyaluronic acid reduces pain compared to hyaluronic acid alone in the treatment of knee osteoarthritis", KNEE SURGERY, SPORTS TRAUMATOLOGY, ARTHROSCOPY, vol. 27, no. 6, 25 July 2018 (2018-07-25), DE, pages 1974 - 1983, XP093231264, ISSN: 0942-2056, DOI: 10.1007/s00167-018-5071-7 *
T.C LAURENT, THE CHEMISTRY, BIOLOGY AND MEDICAL APPLICATIONS OF HYALURONAN AND ITS DERIVATIVES, 1998, pages 243 - 253, ISBN: 1855781190
ZHANG ZHIWEI ET AL: "Intra-Articular Injection of Cross-Linked Hyaluronic Acid-Dexamethasone Hydrogel Attenuates Osteoarthritis: An Experimental Study in a Rat Model of Osteoarthritis", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 17, no. 4, 15 April 2016 (2016-04-15), pages 411, XP093099267, DOI: 10.3390/ijms17040411 *

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