[go: up one dir, main page]

WO2025163204A1 - Source de glutamine destinée à être utilisée dans des méthodes et des compositions pour réduire ou prévenir des adhérences ou une fibrose articulaires synoviales - Google Patents

Source de glutamine destinée à être utilisée dans des méthodes et des compositions pour réduire ou prévenir des adhérences ou une fibrose articulaires synoviales

Info

Publication number
WO2025163204A1
WO2025163204A1 PCT/EP2025/052712 EP2025052712W WO2025163204A1 WO 2025163204 A1 WO2025163204 A1 WO 2025163204A1 EP 2025052712 W EP2025052712 W EP 2025052712W WO 2025163204 A1 WO2025163204 A1 WO 2025163204A1
Authority
WO
WIPO (PCT)
Prior art keywords
glutamine
source
joint
synovial
poly
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/052712
Other languages
English (en)
Inventor
Sanjeev Singh
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Temple Therapeutics Bv
Original Assignee
Temple Therapeutics Bv
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Temple Therapeutics Bv filed Critical Temple Therapeutics Bv
Publication of WO2025163204A1 publication Critical patent/WO2025163204A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • Described herein are methods and compositions for preventing or reducing adhesions or fibrosis in synovial joints.
  • the methods described herein include administering a suitable source of glutamine to synovial joints or areas surrounding such joints of subjects with synovial joint adhesion or fibrosis or are at risk for developing synovial joint adhesion or fibrosis.
  • the musculoskeletal system of mammals articulates through the function of multicomponentjoints.
  • Each joint is a synovial capsule which includes synovial tissue with synovial fluid for lubrication of proximal articulating members.
  • Any trauma to the joint space resulting from injury or commonly from surgery, can produce fibrosis or fibrous adhesions within the joint that degrade the synovial tissues and can interfere with healing after surgery or injury or with the proper functioning of the joint.
  • the formation of fibrous adhesion post- surgery or trauma is a major problem in the field of orthopedics.
  • Synovial j oint fibrosis and adhesion formation can occur under various pathological conditions that disrupt normal joint homeostasis, create hypoxic conditions, and trigger aberrant wound healing responses, including but not limited to: traumatic injury, inflammatory conditions, post-surgical states, immobilization, infection, autoimmune responses, and metabolic disturbances. These pathological processes can result in fibrosis, formation of adhesions, reduced joint space volume, restricted range of motion, altered joint biomechanics, chronic pain and dysfunction, and / or progressive joint degeneration.
  • Lumbar decompression is one of the most common surgical procedures for the treatment of spinal disorders in patients.
  • Recurrence of pain after spine decompression is common and includes recurrent pain, recurrent disc herniation and recurrent stenosis.
  • Dense epidural fibrosis may adhere to the dura and nerve roots, causing nerve root irritation, entrapment and direct dural compression. Many of these patients undergo repeat surgical procedures in an attempt to alleviate their symptoms.
  • Epidural fibrosis complicates revision procedures and results in increased surgical risk due to difficult dissection through fibrotic tissue with risk of dural tear, nerve injury and bleeding. Those undergoing secondary procedures have increased complication rates and poorer outcomes.
  • the methods include the administration of a therapeutically effective amount of a source of glutamine to a synovial joint or one or more tissues surrounding the synovial joint.
  • the administration provides for an extended residence time of the source of glutamine within the joint or the surrounding tissue. Extended residence time may further prevent or reduce adhesion formation.
  • One embodiment described herein is a method of reducing the incidence or severity of adhesion in one or more susceptible synovial joints of a subject comprising administering to the one or more synovial joints or one or more tissues surrounding the synovial joint an effective amount of a source of glutamine.
  • the source of glutamine is administered prior to, during or after a surgery involving the one or more synovial joints.
  • Another embodiment described herein is a method of reducing the incidence or severity of fibrosis in one or more susceptible synovial joints of a subject comprising administering to the one or more synovial joints or one or more tissues surrounding the synovial joint an effective amount of a source of glutamine.
  • the source of glutamine is administered prior to, during or after a surgery involving the one or more synovial joints.
  • One embodiment described herein is a method of preventing adhesion or fibrosis in one or more susceptible synovial joints of a subject comprising administering to the one or more synovial joints or one or more tissues surrounding the synovial joint an effective amount of a source of glutamine.
  • Another embodiment described herein is a method of reducing adhesion or fibrosis in one or more susceptible synovial joints of a subject comprising administering to the one or more synovial joints or one or more tissues surrounding the synovial joint an effective amount of a source of glutamine.
  • Another embodiment described herein is a method of protecting one or more synovial joints of a subject from adhesion comprising administering to the one or more synovial joints or one or more tissues surrounding the synovial joint an effective amount of a source of glutamine.
  • Another embodiment described herein is a method of prophylactically treating adhesion or reducing the incidence of fibrosis in the spine in a subject having a surgical spinal procedure comprising administering an effective amount of a source of glutamine to one or more synovial joints of the spine or one or more tissues surrounding the synovial joint of the spine.
  • Another embodiment described herein is a method of prophylactically treating or reducing the incidence of adhesive capsulitis in a subject having shoulder surgery comprising administering an effective amount of a source of glutamine to one or more shoulder synovial joints or one or more tissues surrounding the shoulder.
  • Another embodiment described herein is a method of treating or reducing the incidence of a pathological condition of one or more synovial joints comprising administering to the one or more synovial joints or one or more tissues surrounding the synovial joint an effective amount of a source of glutamine, wherein the pathological condition comprises arthritis, joint inflammation, bursitis, gout, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, and septic arthritis.
  • Another embodiment described herein is a method of reducing the recovery time of a subject following a surgical intervention involving one or more synovial joints comprising administering an effective amount of a source of glutamine, wherein the administration reduces or prevents adhesion or fibrosis in the one or more synovial joints.
  • Another embodiment described herein is a method of treating or reducing the incidence of adhesion or fibrosis stemming from a pathological condition comprising administering to a relatively low-vascularized cavity or tissue an effective amount of a source of glutamine, wherein the pathological condition comprises arthritis, joint inflammation, bursitis, gout, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, and septic arthritis.
  • Another embodiment described herein is a pharmaceutical composition
  • a pharmaceutical composition comprising a source of glutamine and a means for delivering the source of glutamine to one or more synovial joints, wherein the source of glutamine is effective in treating or reducing adhesion or fibrosis in the one or more synovial joints.
  • kits for the treatment or reduction of synovial joint adhesion or fibrosis in a subject comprising an effective amount of a source of glutamine, wherein the source of glutamine is formulated as a dosage form selected from the group consisting of a surgical implantable film, an injectable, a topical cream or dosage form suitable for iontophoresis.
  • the kit comprises a pre-filled syringe (single or multi-compartment) comprising the source of glutamine and a biologically acceptable carrier.
  • the kit comprises a film or gel impregnated with the source of glutamine.
  • the kit comprises a dosage form, wherein a drug load of the dosage form is about I 0% to about 50%.
  • FIGURE I Depiction of spinal sectioning technique. Sections were taken 2.5 mm cephalad and caudad to the laminectomy site, marked by a non-dissolvable suture.
  • FIGURE 3 Average operative time per animal in animals having a laminectomy in saline and L- alanyl-L-glutamine treatment groups.
  • FIGURE 4 Chart depicting intraoperative and postoperative complications during study in saline and L-alanyl-L-glutamine treatment groups.
  • FIGURE 5 Histological grade of epidural fibrosis in saline and L-alanyl-L- glutamine treatment groups
  • FIGURE 6 Histological grade of epidural fibrosis in 'low grade' and 'high grade' subsets in saline and L-alanyl-L-glutamine treatment groups
  • FIGURE 7 Average daily body weight (g)
  • FIGURE 8 Percent change in daily body weight compared to day 0
  • FIGURE 9 Average body weight (0-28 days) from laminectomized rates;*** indicates statistical significance
  • FIGURE 11 Serum TGF-pi estimation TGF-pi levels (ng/ml) in serum from Laminectomy study animals
  • FIGURE 12 Sirius red fibrosis scoring of vertebrae, Epidural fibrosis scoring;
  • Described herein are methods and compositions for preventing or reducing adhesion or fibrosis in one or more susceptible synovial joints of a subject comprising administering to the one or more synovial joints or one or more tissues surrounding the synovial joint an effective amount of a source of glutamine.
  • a susceptible joint is a joint that has experienced or is experiencing one or more of hypoxia, traumatic injury, inflammation, surgery, immobilization, infection, autoimmune response, or metabolic disturbance.
  • the present description encompasses the various conditions and mechanisms that may contribute to synovial joint fibrosis and adhesions, enabling the development of targeted therapeutic interventions for prevention and treatment.
  • the glutamine source is formulated for administration or is administered in a manner that extends the retention time of the glutamine source in the joint area (e.g. contact with joint tissues and fluids) compared to a single injection (e.g. immediate release) of the glutamine source into the same area.
  • an effective amount the glutamine source is initially released into the synovial joint area followed by extended release for a period of at least about 12 hours, 24 hours/1 day, 36 hours, 48 hours/2 days, 60 hours, 72 hours/3 days, 5 days, 7 days, 10 days, or 14 days.
  • the glutamine source is provided in two or more doses.
  • the two or more doses are provided in two or more different dosage forms.
  • the two or more dosage forms have different release profiles.
  • the administering comprises providing at least a first dose and a second dose of the glutamine source, wherein the first dose has a release profile that is faster than a release profile of the second dose.
  • the first dose comprises a rapid release or substantially immediate release of the glutamine source. Rapid release may, for example, mean that at least about 85% of the glutamine source (e.g. as intact dipeptide) is released within about 30 minutes, 20 minutes, 15 minutes, or even less, under physiologic conditions in the joint area. Substantially immediate release may mean, for example, that at least about 90% of the glutamine source is released within about 15 minutes, 10 minutes, 5 minutes, 1 minute, or even less, under physiologic conditions in the joint area.
  • a therapeutic amount of the glutamine source is released within about 15 minutes , about 10 minutes, about 5 minutes, about 1 minute (e.g. about 0-5, 1-5, 5-10, 1- 15, 5-15, 10-15 minutes) under physiologic conditions.
  • the glutamine source is formulated in an immediate release dosage form. Examples of an immediate release dosage form include but are not limited to a solution, suspension, dispersion, emulsion, coating, or combination thereof.
  • the solution is an aqueous solution as known in the art.
  • the first dose is administered via injection, infusion, instillation or direct application to the susceptible joint or joint tissue or area.
  • the release profile of the first and/or second dose is sustained release or delayed release.
  • the glutamine source may be formulated in a sustained-release drug delivery system that provides extended release of the glutamine source over a period of up to/at least 24 hours, 48 hours, 72 hours, 3 days, 4, days, 5 days, 6 days, 7 days, 10 days, 15 days.
  • Sustained release may mean, for example, that at least 85% of the glutamine source is released over the extended release period.
  • the sustained release may be continuous or may have phases with different rates of release. With a delayed release delivery system, the release is delayed by a certain time after administration. Numerous delayed and sustained release delivery systems are known in the art.
  • one or more additional doses and/or dosage forms are administered following the initial treatment protocol, e.g. one or more additional doses or dosage forms over the next 7, 15, or 21 days.
  • the sustained-release drug delivery system is selected from the group consisting of: a biodegradable film, a gel matrix, a hydrogel, microspheres, nanoparticles, rods and combinations thereof.
  • the sustained-release drug delivery system comprises: (a) a biodegradable polymer; and (b) a glutamine source dispersed within and/or coated on said biodegradable polymer.
  • the sustained-release drug delivery system comprises a biodegradable polymer matrix or film loaded with the glutamine source, wherein said polymer matrix or film controls the release rate of the glutamine source.
  • the sustained-release drug delivery system is in the form of a film having a thickness of between about 0.1 mm and about 2 mm, e.g. from about 0.1 mm to 1 mm, about 0.25 mm to about 0.75 mm, about 0.5 mm (500 pm).
  • the sustained-release drug delivery system is in the form of a gel that solidifies or increases in viscosity upon contact with physiological fluids or conditions.
  • the sustained-release drug delivery system is in the form of microparticles, nanoparticles or spheres as known in the art.
  • the method comprises: (a) administering an initial dose (e.g. bolus dose/loading dose) of a glutamine source to one or more susceptible synovial joints or one or more tissues surrounding the one or more susceptible synovial joints; and (b) administering a sustained-release drug delivery system comprising a glutamine source to the one or more susceptible synovial joints or one or more tissues surrounding the one or more susceptible synovial joints, wherein the bolus dose provides an immediate release of the glutamine source and the sustained-release drug delivery system provides extended release of the glutamine source.
  • an initial dose e.g. bolus dose/loading dose
  • a sustained-release drug delivery system comprising a glutamine source to the one or more susceptible synovial joints or one or more tissues surrounding the one or more susceptible synovial joints
  • the sustained-release drug delivery system is selected from the group consisting of a biodegradable film, a non-biodegradable film, a gel matrix, a hydrogel, microspheres, nanoparticles, and combinations thereof.
  • the sustained-release drug delivery system is in the form of a film having a thickness of between about 0.1 mm and about 2 mm.
  • the sustained-release drug delivery system is in the form of a gel that solidifies or increases in viscosity upon contact with physiological fluids or conditions.
  • the joint has experienced or is undergoing a surgery.
  • Surgeries involvingone or more synovial joints include but are not limited to arthroplasty, arthroscopic surgery, osteotomy, synovectomy, joint replacement, injury repair, or laminectomy or a combination thereof.
  • the subject being administered a source of glutamine has one or more pathological conditions that render a joint susceptible to fibrosis or adhesions, including but not limited to arthritis, osteoarthritis, an autoimmune disease, a metabolic disturbance, rheumatoid arthritis, psoriatic arthritis, or a combination thereof.
  • the adhesion or fibrosis to be reduced or prevented may be a result of one or more of these pathological conditions.
  • the effective amount of glutamine is an amount of glutamine administered in one or more doses, which prevents or reduces adhesion in the synovial joint or one or more tissues adjacent to or surrounding the synovial joint, wherein the one or more tissues restrict a movement of the synovial joint in comparison to a subject having one or more synovial joints of the same type susceptible to adhesion that is not administered the effective amount of glutamine.
  • the effective amount of glutamine is an amount of glutamine administered in one or more doses, which prevents or reduces one or more pathological conditions of the one or more synovial joints or one or more tissues adjacent to or surrounding the synovial joint comprising inflammation, angiogenesis, immune cell infiltration, fibrosis, scarring, reduced joint flexibility, joint pain, or a combination of conditions thereof in comparison to a subject having one or more synovial joints of a same type with the same one or more pathological conditions of the synovial joint that is not administered the effective amount of glutamine.
  • the incidence or severity of adhesion is reduced or prevented in an amount greater than about 10% in comparison to subjects not administered the effective amount of glutamine.
  • the one or more pathological conditions is reduced in an amount greater than about 10% in comparison to a subject not administered the effective amount of glutamine.
  • the source of glutamine is formulated as a liquid, an injectable, injectable microparticle or microspheres, a depot, a surgical implant, a topical, a transdermal patch, or for iontophoretic delivery.
  • the effective amount of glutamine comprises one or more doses of a source of glutamine.
  • the source of glutamine is formulated as a surgical implant.
  • Surgical implants may include but are not limited to biomaterials, scaffolds, matrices, films, microspheres, microparticles, gels, hydrogels.
  • the surgical implant comprises a drug load of about 2% to about 80% of the source of glutamine. In some embodiments, the surgical implant comprises a drug load of about 25% to about 60% of the source of glutamine. In some embodiments, the surgical implant comprises a drug load of about 30% of the source of glutamine.
  • drug refers to a pharmaceutical agent, active ingredient, compound, or substance, compositions, or mixtures thereof, that provide a pharmacological, often beneficial, effect.
  • dose or “dose” or “dosage form” as used herein denote any form of the active ingredient formulation that contains an amount sufficient to produce a therapeutic effect with a single administration.
  • prevention of includes the meaning of reducing.
  • the amount of the reduction may be from about 0.01% to about 100%.
  • the term “effective amount” is an amount that achieves the desired effect.
  • the effective amount is an effective amount of a source of glutamine that prevents or reduces synovial joint adhesion.
  • the effective amount is the amount of glutamine administered after a single administration that reduces or prevents synovial joint adhesion.
  • drug load refers to the wt% of the active pharmaceutical ingredient relative to the total mass of the dosage form.
  • formulation refers to the drug in combination with pharmaceutically acceptable excipients.
  • extended release or “sustained release” as used herein refers to a composition that releases an active ingredient according to a desired profile over an extended period under physiological conditions or in an in vitro test.
  • the release profile is determined using a standard dissolution test apparatus under physiologically relevant conditions (e.g., 37°C, pH 6.8 phosphate buffer).
  • physiologically relevant conditions e.g. 37°C, pH 6.8 phosphate buffer.
  • the dissolution test may approximate the physiologically relevant conditions at a particular joint site, e.g. post surgery or injury (e.g. hypoxic / acidic conditions).
  • delayed release refers to a composition that releases an active ingredient after a period of time, for example minutes or hours, such that the active ingredient is not released initially.
  • a delayed release composition may provide, for example, the release of a drug or active ingredient from a dosage form, after a certain period, under physiological conditions or in an in vitro test.
  • treating refers to administering a therapy in an amount, manner, or mode effective (e.g., a therapeutic effect) to improve a condition, symptom, disorder, or parameter associated with a disorder, or a likelihood thereof.
  • treating refers to the treatment or of synovial joint adhesion.
  • prophylactically treating refers to administering to a subject a therapy in an amount prior to the subject incurring a condition, symptom, disorder, or parameter associated with a disorder, or likelihood thereof.
  • prophylactically treating refers to the prophylactic treatment of synovial joint adhesion or fibrosis to reduce or prevent synovial joint adhesion or fibrosis from occurring.
  • subject refers to any mammal.
  • the subject can be any mammal, including animals and humans.
  • the subject may be a medical patient in need of treatment.
  • preventing or “reducing” refers to preventing or reducing the progression of a disorder, such as joint adhesion, either to a statistically significant degree or to a degree detectable to one skilled in the art.
  • substantially means to a great or significant extent, but not completely.
  • Adhesions typically present as fibrous bands forming between tissues and organs. The formation of adhesions results in the connection of tissues that are not normally physiologically connected. Most commonly, adhesions form in the abdominal and intestinal areas, pelvis, pericardium, peritendinous area, synovial joints (e.g., adhesive capsulitis), and peridural areas of the spine. Of these areas, the successful treatment or prevention of adhesion in the synovial joints has remained elusive.
  • Glutamine is a conditionally essential amino acid that is well absorbed, enhances wound healing, and modulates the function of neutrophils, macrophages, and lymphocytes.
  • Glutamine is synthesized from glycine, glutamic acid and cysteine. During periods of catabolic stress (trauma, sepsis, burn), glutamine is released from muscle stores and serum, and intracellular levels of glutamine decrease. Previous work has demonstrated the efficacy of glutamine in preventing peritoneal adhesion formation (U.S. Patent No. 9,011,883).
  • glutamine administration may reduce symptoms resulting from inflammatory processes and by protecting against oxidative stress.
  • glutamine administration may further reduce inflammatory cytokine signaling molecules, such as TGF- p. It is thought that because of its anti-inflammatory effects, applying source of glutamine to the site of inflammation may further contribute to the reduced adhesion formation.
  • glutamine is safe, well absorbed, and has no documented side effects.
  • Glutamine is known to enhance wound healing.
  • Glutamine and its dipeptides have been used for parenteral and enteral supplementation components in critically ill patients and in other clinical settings.
  • the first uses of sources of glutamine have been employed either through enteral administration (e.g. in a food supplement) or parenteral administration through the intravenous route.
  • enteral administration e.g. in a food supplement
  • parenteral administration through the intravenous route.
  • At least one study described administration of glutamine to highly vascular areas, such as the peritoneum, where it is readily absorbed by the vasculature. At these locations, L-glutamine prevented the loss of vascularization due to peritoneal suturing that causes devascularization and adhesion formation.
  • glutamine may prevent fibrosis and adhesion formation by uptake of glutamine in the vasculature and preventing the loss of vascularization.
  • the application of a glutamine source to the synovial joint or tissues surrounding the synovial joint that is susceptible to undergoing adhesion significantly reduces fibrosis and associated adhesion. This result is unexpected and surprising since the tissues of the synovial joints and the areas of adhesion formation in and around these joints have substantially lower vasculature than the soft tissues of the peritoneum.
  • the joint space is relatively small and delivery of large amounts of a glutamine source is difficult or nearly impossible.
  • the synovial joint that the glutamine source is administered to comprises one or more joints of a spine, upper limbs, elbows, head, neck, thorax, pelvis, perineum, or lower limb joints.
  • Suitable joints that may be targeted include those such as the joints of the spine, including zygapophyseal joints, upper limb joints, including acromioclavicular joint, finger carpometacarpal joint, thumb carpometacarpal joint, coracoclavicular joint, elbow joint, intermetacarpal joint, interphalangeal joint, metacarpophalangeal joint, midcarpal joint, wrist radiocarpal, distal radioulnar joint, intermediate radioulnar joint, proximal radioulnar joint, shoulder joint, sternoclavicular joint, and wristjoint; joints of the head and neck, including the temporomandibular joint; joints of the thorax including the sternocostal joints and xiphisternal joints; joints of the pelvis and perineum, including the lumbosacral joint and the sacroiliac joint; and the lower limb joints including the ankle joints, hip joints, interphalangeal joints, and knee joints.
  • Some embodiments described herein are methods of preventing or reducing adhesion in one or more susceptible synovial joints of a subject comprising administering to the one or more synovial joints or one or more tissues surrounding the synovial joint an effective amount of a source of glutamine.
  • the source of glutamine can be delivered to any tissue in close proximity to the synovial joint.
  • the source of glutamine may be delivered to one or more tissues including the articular capsule tissue, articular cartilage, fat pads (e.g. infrapatellar, articular), synovial membrane or within the joint cavity or epidural space within the spine.
  • the source of glutamine may be delivered to tissues external to the joint including but not limited to one or more ligaments, muscle, fat, connective tissues.
  • the source of glutamine maybe also delivered to the overlying subcutaneous tissue, dermis, and epidermis.
  • Some embodiments are methods of treating a medical patient having a synovial joint that is susceptible to adhesion or fibrosis.
  • Susceptible synovial joints for example, are joints which have incurred an injury, have a history of inflammation, or have been or will be surgically operated on.
  • the source of glutamine is administered to a subject prior to, at the same time, or following a surgery involving one or more synovial joints.
  • the prior administration results in the one or more synovial joints being protected from incurring fibrosis and eventual joint adhesion.
  • Prior administration of the source of glutamine in some cases may further reduce or treat joint inflammation and recovery time following surgery in a subject.
  • the source of glutamine is administered to a subject after having undergone a surgery that involves one or more synovial joints. Similarly, one or more of the synovial joints is protected from undergoing additional fibrosis and joint adhesion. It is further contemplated that the administration of a source of glutamine can reduce adhesion.
  • the source of glutamine is administered to a subject prior to (e.g. within about 190, 120, 90, 60, 30, 15, 10, 5, 1 minutes prior to), at the same time (e.g. within about 15 minutes before or after) , or following a surgery (e.g. within about 1, 5, 15, 30, 60, 90, 120, 190 minutes after) surgery.
  • a surgery may be any synovial joint surgery, including but not limited to arthroplasty, arthroscopic surgery, osteotomy, synovectomy, joint replacement, or laminectomy or a combination of surgical procedures thereof.
  • the source of glutamine is administered after the subject has sustained an injury to one or more synovial joints.
  • the injury to the synovial joints may include any orthopaedic injury stemming from a physical insult, such as playing sports, dancing, incurring a fall.
  • the injury may be incurred from the presence of an underlying disease or pathological condition, including but not limited to inflammation, autoimmune diseases, arthritis, and old age.
  • exemplary and non-limiting underlying diseases that affect the synovial joint include but are not limited to arthritis joint inflammation, bursitis, gout, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, and septic arthritis.
  • the underlying disease or condition may include any underlying joint adhesion condition, such as adhesive capsulitis, temporomandibular joint pain, or a pre-existing adhesion in any synivial joint.
  • the reduced amount of joint adhesion is less than the amount of joint adhesion in a subject undergoing the same surgical procedure on the same synovial joint without receiving administration of a source of glutamine.
  • the amount of reduced joint adhesion may be determined clinically by a suitable method.
  • clinically decreased adhesion may be measured by range of motion exercises which assess the articulation of the joint and any associated pain.
  • the range of motion may be quantified by the number of degrees of flexion, extension, abduction, adduction, external and internal rotation depending on the specific joint as is known in the medical arts.
  • the reduced amount of joint adhesion or fibrosis in a subject that has been administered a source of glutamine to one or more synovial joints that has had or will have a surgery or has incurred an injury is at least about 10% when compared to a subject having a surgery or injury to the same synovial joint.
  • the amount of reduction of joint adhesion or fibrosis determined by, for example increased range of motion is at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99%, or even 100%.
  • a subject has previously had a surgery or injury to one or more synovial joints and is administered a source of glutamine and has a reduction in the amount of fibrosis or synovial joint adhesion.
  • the amount of reduction of fibrosis or adhesion in the synovial joint of a subject is at least 10% in a subject following administration of the source of glutamine.
  • the amount of reduction of adhesion within the subject having a previous surgery or injury is at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99%, or even 100%.
  • one or more pathological conditions of one or more synovial joints or one or more tissues adjacent to or surrounding the synovial joint comprising fibrosis, inflammation, angiogenesis, immune cell infiltration, fibrosis, scarring, reduced joint flexibility, joint pain, or a combination of conditions thereof is reduced by an administration of a source of glutamine to one or more of the synovial joints of a subject.
  • a subject that has been administered a source of glutamine to one or more synovial joints of a subject that has a pathological condition is reduced by at least about 10% when compared to a subject having the same synovial joint with the same pathological condition not administered a source of glutamine.
  • the amount of reduction of one or more pathological condition of a synovial joint is decreased by at least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99%, or even 100%.
  • pathological conditions of the synovial joint may be assessed by clinical tests known in the art. For example, a tissue biopsy may be used followed by routine histological preparation and tissue histopathological analysis methods known in the art.
  • the source of glutamine is administered to one or more synovial joints in a manner to extend the residence time of glutamine at the synovial joint or one or more tissues surrounding the synovial joint.
  • glutamine intrinsically has a high turnover and is quickly absorbed by immune cells including lymphocytes and macrophages.
  • the source of glutamine is administered to one or more synovial joints in a single dose, wherein an effective amount of glutamine is retained at or near the administration site for at least about 30 minutes to about 96 hours, including e.g. about 30 minutes to about 72 hours, about 30 minutes to about 48 hours, about 30 minutes to about 24 hours.
  • glutamine may persist in the area until metabolized.
  • an effective amount of glutamine following a single administration is retained at or near the administration site for at least about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 28 hours, about 32 hours, about 36 hours, about 40 hours, about 44 hours, 48 hours, or 72 hours.
  • the effective amount of a source of glutamine to reduce adhesion or fibrosis or one or more pathological conditions of the synovial joint described herein is administered in a single dosage.
  • the amount of a source of glutamine administered in a single dosage form ranges from about 0.0001 g/kg to about 5 g/kg of a subject's body weight.
  • the amount of a source of glutamine administered in a single dosage form is about 0.0001 g/kg, about 0.001 g/kg, about 0.01 g/kg, about 0.05 g/kg, about 1 g/kg, about 1.5 g/kg, about 2 g/kg, about 2.5 g/kg, about 3 g/kg, about 3.5 g/kg, about 4 g/kg, about 4.5 g/kg, about 5 g/kg, about 0.1 g/kg to about 5 g/kg, about 0.5g/kg to about 3 g/kg, about 0.01 g/kg to about 2 g/kg, about 1 g /kg to about 3 g/kg, about 0.5 g/kg to about 1.5 g/kg .
  • the total amount of glutamine source to be administered in a single dose ranges from about 0.007 grams to about 500 g, from about 0.5 grams to about 100 g, from about 10 grams to about 300 g, from about 50 g to about 150 g.
  • Some embodiments described herein are pharmaceutical dosage forms for reducing synovial joint adhesions in a subject. Some embodiments are methods of treating subject in need thereof with the pharmaceutical dosage forms described herein. Suitable pharmaceutical dosage forms include a source of glutamine and other pharmaceutically acceptable carriers and excipients for administration to the synovial tissues or tissues surrounding the synovial joint. Assistive devices such as vials, syringes and injectors may be used for administration. In some embodiments, the composition comprising the glutamine source is formulated as a lyophilized powder for reconstitution prior to administration.
  • the glutamine source includes glutamine or any pharmaceutically acceptable salt thereof.
  • the source of glutamine includes L-glutamine or is L-glutamine. It is known that L-glutamine has a relatively low water solubility (i.e., about 40 g/L at room temperature) and low stability during storage.
  • the source of glutamine may also include further carrier amino acids or glutamine can be incorporated as part of an oligopeptide, which may increase one or both of the solubility of the L-glutamine and stability.
  • the oligopeptide may include any naturally occurring or non-naturally occurring amino acid.
  • Suitable oligopeptides comprise L- glutamine and are capable of being metabolized to provide L-glutamine.
  • such peptides will exhibit increased aqueous solubility and increased stability of L-glutamine.
  • such peptides will also exhibit increased resistance to breakdown during sterilization and storage.
  • the oligopeptide comprising L-glutamine may further include cleavable linker peptide moieties known in the art (see, Bohme and Sickinger., J. Pept Sci. 21, pp. 186-200 (2015). These cleavable linkers may be utilized for attachment to various scaffolds and implants and for the administration methods described herein.
  • the source of glutamine is L-glutamine incorporated as part of a dipeptide.
  • Two such peptides that may be used are dipeptides comprising L-glutamine and either L-alanine or glycine.
  • the dipeptide alanyl-glutamine (glutamine residue at the C- terminal position) has high solubility in water (568 g/L).
  • Glycyl-glutamine (glutamine at the C-terminal position) also shows enhanced solubility in water as compared to glutamine (154 g/L).
  • Each of the latter dipeptides is sufficiently stable during heat sterilization and prolonged storage that they have been previously employed in total parenteral nutrition formulations for intravenous injection.
  • the source of glutamine comprises L-alanyl- L-glutamine.
  • the source of glutamine is provided as part of an oligopeptide comprising glutamine, wherein an aqueous solubility and an aqueous stability of the source of glutamine is higher than glutamine alone.
  • the glutamine source is a glutamine conjugate wherein at least one glutamine residue is bound to a compound via an amino ester bond. Examples of such glutamine sources include, but are not limited to, dichloroacetylglutamine, acetylglutamine, butryrlglutamine, pyruvylglutamine, and glutamine conjugated to any other suitable organic acid via an amino ester bond.
  • L-glutamine and L-glutamine containing peptides are commercially available.
  • L-glutamine containing peptides for use in the methods described herein may also be synthesized according to known methodology and purified and sterilized for pharmaceutical use.
  • the source of glutamine is administered with one or more additional active pharmaceutical ingredients.
  • the additional active pharmaceutical ingredient may be administered in the same way as the source of glutamine or by a different suitable parenteral method or enteral method.
  • the additional one or more active pharmaceutical ingredients is administered with the source of glutamine by the same route of administration prior to, at the same time, or following the administration of the source of glutamine.
  • the additional one or more active pharmaceutical ingredients are administered with the source of glutamine by a different route of administration prior to, at the same time, or following the administration of the source of glutamine.
  • Suitable pharmaceutically active ingredients include any drug or agent that is used for treating joint pain, inflammation, or adhesion.
  • Non-steroidal antiinflammatory drugs include non-steroidal antiinflammatory drugs (NS AID) aceclofenac, acemetacin, amoxiprin, aspirin, azapropazone, benorilate, bromfenac, carprofen, celecoxib, choline magnesium salicylate, diclofenac, diflunisal, etodolac, etoricoxib, chloramine, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, meloxicam, meclofenamic acid, mefenamic acid, meloxicam, metamizole, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salicyl salicy
  • the source of glutamine may further be administered with an anti- autoimmune disease drugs such as disease modifying anti-rheumatic drugs (DMARDs) including but not limited to anti-folates, methotrexate, leflunomide, mycophenolate mofetil, sulfasalazine, apremilast, tofacitinib; biologies, such as tocilizumab, certolizumab, etanercept, adalimumab, anakinra, abatacept, infliximab, and rituximab.
  • DMARDs disease modifying anti-rheumatic drugs
  • the source of glutamine is administered by intra-articular injection, infrapatellar fat pad injection, articular fat pad injection, topical administration, transdermal administration, by iontophoresis, or surgically.
  • the source of glutamine is administered by implanting a surgical implant, comprising the source of glutamine, within the synovial joint or one or more tissues in proximity to the one or more synovial joints.
  • the source of glutamine is formulated for delivery to a synovial joint or tissue surrounding the synovial joint by injection comprising an intraarticular injection method known in the art.
  • the glutamine source e.g., L- alanyl-L-glutamine
  • the glutamine source can be formulated as part of an aqueous solution with a pharmaceutically acceptable carrier such as sterile distilled water, sterile isotonic solutions, sterile physiological 1 saline solutions or dry buffer and/or salt mixes or concentrations which when diluted form such a solution.
  • the source of glutamine is formulated into an intra- articluar injectable formulation comprising biocompatible, resorbable polymer microparticles or microspheres.
  • an intra- articluar injectable formulation comprising biocompatible, resorbable polymer microparticles or microspheres.
  • biocompatible, resorbable polymer microparticles or microspheres See, for example, PCT International Application Publication No WO/2015154924A1.
  • suitable biocompatible resorbable polymers for creating the microparticles or microspheres are similar to those listed for formation of implantable film and are given below.
  • the Formulations may be a liquid, paste, or gel comprising a glutamine source dissolved in an aqueous phase. Compositions described herein may be such formulations or may be compositions intended to produce such a formulation when hydrated.
  • a formulation for use in this invention will consist of a glutamine source dissolved in a sterile aqueous liquid vehicle, suitable for instilling within a synovial joint during surgery or for interarticular injection performed thereafter.
  • the formulation may be instilled through a port created for laparoscopic surgery or during laminectomy.
  • the source of glutamine is formulated as part of a gel or hydrogel.
  • Hydrogel formulations allow for an extended delivery of suitable drugs including for example, L-glutamine or di- or tri -peptides containing at least one glutamine residue. Hydrogels typically form a depot, which further allows for a concentrated application of a drug.
  • the hydrogel comprising a source of glutamine may be generated prior to administration and impregnated with the source of glutamine for further implantation.
  • hydrogels that form in situ after change environment, including pH and temperature may be utilized for intra-articular injection.
  • Various physical and chemical cross-linking polymers for in situ hydrogel formation are known in the art.
  • Exemplary and non-limiting hydrogels may include co-polymers comprising blocks of poly ethylene oxide (PEO) propylene oxide (PPO), poly(lactide-co-glycolic acid) (PLGA), poly (N-isopropylacrylamide), poly(propy lene fumarate), poly (caprolactone) and the like (see, for example, Hoare and Kohane., Polymer. 49, pp. 1993-2007 (2008)).
  • Suitable hydrogels may also be generated from naturally occuring proteins and peptides, see, for example Jonker et al., Chem Mater. 24, pp. 759-773 (2011) article)
  • the particular hydrogel formulation can be determined by the application site or the specific joint being treated.
  • the source of glutamine is formulated as part of an implantable film containing the source of glutamine.
  • the glutamine source may be applied to or impregnated in the surgical implantable film or other surgical implant.
  • the source of glutamine may be formulated as part of a gel and adhered to the exterior of an implant.
  • Implants composed of a material such as woven resorbable cellulose commercially available as INTERCEED® from Ethicon may be impregnated with a liquid or gel formulation of this invention.
  • Other films contemplated comprise biocompatbile resorbable polymers.
  • biocompatible resorbable polymers are poly(ortho esters), poly(anhydrides), poly(D,L-lactic acid), poly (L-lactic acid), poly(glycolic acid), copolymers of poly(lactic) and glycolic acid, poly(L-lactide), poly(D,L-lactide), poly(glycolide), poly(D,L-lactide-co-glycolide), poly(L-lactide-co-glycolide), poly(phospho esters), poly(trimethylene carbonate), poly(oxa-esters), poly(oxa-amides), poly(ethylene carbonate), polypropylene carbonate), poly(phosphoesters), poly(phosphazenes), poly(tyrosine derived carbonates), poly(tyrosine derived arylates), poly(tyrosine derived iminocarbonates), copolymers of these polymers with poly(ethylene glycol) (PEG), or combinations thereof.
  • PEG poly(ethylene glycol)
  • the films comprise polyesteramide (PEA) (see, for example, PCT International Application Publication No. WO/2014053542A1 and WO/2012175746A1).
  • PET polyesteramide
  • the source of glutamine is formulated for topical, transdermal, or for iontophoretic administration.
  • the drug load of the source of glutamine within the dosage form is about 2% to about 90%, including each integer within the specified range. In some embodiments, the drug load is about 10% to about 80%. In some embodiments, the drug load is about 20% to about 60%. In some embodiments, the drug load is about 20% to about 50%. In some embodiments, the drug load is about 20% to about 40%. In some embodiments, the drug load is about 1%, about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%.
  • the drug is impregnated into an implantable film.
  • the drug load in the implantable film is about 2% to about 90%, including each integer within the specified range.
  • the drug load in the implantable film is about 10% to about 80%.
  • the drug load in the implantable film is about 20% to about 60%.
  • the drug load in the implantable film is about 20% to about 50%.
  • the drug load in the implantable film is about 20% to about 40%.
  • the drug load in the implantable film is about 1%, about 2%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, or about 90%.
  • the drug load in the implantable film is about 30%. In another embodiment the drug load in the implantable film is about 50%.
  • the dosage form comprising a source of glutamine is stable for months or years.
  • the pharmaceutical dosage forms of a source of glutamine described herein are stable at 25 °C and 60% relative humidity (RH) for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 9 months, about 10 months, about 11 months, about 12 months, or even longer.
  • kits for preventing or reducing synovial joint adhesion in a subject include a source of glutamine (e.g., L- alanyl-L-glutamine) in a suitable dosage form described herein.
  • the kits described herein further include instructions and suitable administration schedules depending on the synovial joint being treated.
  • the kit comprises a dosage form that is provided as an injectable.
  • the dosage form comprises a dosage form that is a film impregnated with the source of glutamine.
  • the kit comprises a dosage form that is a topical cream.
  • the kit comprises a dosage form that is suitable for iontophoretic delivery.
  • the kit comprises multiple dosage forms for administration to a subject in need thereof.
  • PEA III Ac Bz and PEA III X 25 are polyesteramides (PEAs), synthesized by first reacting a diol with an amino acid forming bis-amino-acid diol monomers. The monomers are reacted in a one-step condensation reaction with a di-acid to form a random copolymer amino acid based poly(esteramide).
  • PEA III Ac Bz is poly 8- ⁇ [(L-Leu- DAS)_ ⁇ 0.45 ⁇ (L-Leu-6)_ ⁇ 0.3 ⁇ -[L-Lys(Bz)]_ ⁇ 0.25 ⁇ .
  • the pfractions indicate overall fractions of the monomers in the synthesis.
  • 25% of L-Lys is in the unprotected, free COOH form.
  • Polymer Drug films containing L-Alanyl-L-Glutamate in PEA where prepared by firstly melt extrusion of a mixture of polymer (PEA) and L-Alanyl-L-Glutamate followed by melt pressing into films. Weight ratio of L-Alanyl-L-Glutamate to PEA polymer where 30% and 50wt% with respect to drug.
  • Extrusion PEA III Ac Bz formulations were homogenized by extrusion using DSM Xplore Pharma extruder. Temperature settings were 120°C (Top), 130°C (Middle) and 140°C (Bottom).
  • Melt pressing was performed using Fontijne Grotnes TP600 Table Press. Typical conditions involved temperature setting of 90-140°C and pressure of lOOkN. Aluminum spacer molds were used to assure desired thickness of 500pm. Teflon sheets were used to prevent adherence of samples to aluminum molds.
  • Anesthesia was induced with inhalational isoflurane 2% at 5 liters/min, and animals were maintained under anesthesia using inhalational isoflurane 2% at 2-3 liters/min.
  • Preoperative analgesia was provided with subcutaneous buprenorphine 0.05 mg/kg.
  • Each rat was marked with an identifying ear tag. The rat was placed in the prone position, and the operative area shaved and sterilized with Hibitane and 70% ethanol. Standard sterile surgical techniques were used. Using anatomic landmarks, a dorsal midline incision was made from LS to S2. The paraspinal muscles were dissected away from the spinous processes.
  • the spinous processes of SI was identified and removed with a rongeur. Using a dissecting microscope, a bilateral total laminectomy of SI was completed laterally to the level of the pedicle. The ligamentum flavum and epidural fat was removed to expose the dura mater. Normal saline irrigation and compression with surgical pads were used for hemostasis.
  • 6 animals underwent no procedure and were used as histological controls.
  • the test L- alanyl-L-glutamine treatment group received L-alanyl-L-glutamine 1 g/kg applied to the peridural space after laminectomy.
  • the surgical control group underwent laminectomy with instillation of normal saline. Treatment substances were instilled into the laminectomy site just prior to wound closure.
  • fascia at the laminectomy site was marked with a non- dissolvable suture to facilitate harvest of pathological specimens.
  • Wounds were closed by approximating the paraspinal muscles, fascia and subcutaneous tissues using 3-0 vicryl. The skin was closed using staples.
  • Post- operative analgesia involved a tapering dose of subcutaneous buprenorphine every 12 hours for three days.
  • Each section was examined under a light microscope (Olympus 2x and 4x/0. 1 0 objective, 20x and 40x total magnification). Two digital microphotographs (12.Sx and 20x magnification) were taken for each slide. The extent and maturity of epidural fibrosis was graded ( Figure 2). Grade 0 represented no fibrosis; Grade 1 represented minimal, immature fibrosis; Grade 2 represented moderate fibrosis with immature and mature areas; Grade 3 represented dense, mature fibrosis; Grade 4 represented dense, mature fibrosis occasionally disrupting tissue architecture. Each section was evaluated at two separate time points by an anatomic veterinary pathologist, as well as at two different time points by less experienced student. Both evaluators were blinded to treatment groups.
  • the average surgical time was 26 minutes.
  • the average operating time in the surgical control group was 31 minutes, and in the L-alanyl-L-glutamine treatment group 26 minutes ( Figure 3).
  • Intraoperative and postoperative complications There were no intraoperative deaths. Intraoperative and postoperative complications are tabulated in Figure 4. There were no significant differences between the groups.
  • Nonsurgical control rats demonstrated no fibrosis.
  • Rats who underwent laminectomy demonstrated exuberant fibrosis in the epidural, deep and superficial epaxial layers. Fibroblastic tissue formed over the laminectomy defect, and extended to adhere to the dura and nerve roots. In some cases, fibrosis was so severe that canal and nerve roots were indistinguishable from the surrounding fibrotic tissue.
  • the intraobserver correlation coefficient values for first and second pathological grading of the epidural layer was 0.68.
  • Laminectomy is widely accepted across the medical community as the treatment of choice in lumbosacral disorders.
  • FBSS failed back surgery syndrome
  • Epidural fibrosis (EF) is main factor for FBSS.
  • the markers of fibrosis like TGF beta and Hematoxylin and eosin (H&E) and Masson's tri-chrome or Sirius red staining were used to evaluate epidural fibrosis & extent of inflammation.
  • the treatment was started by local application (control film or drug impregnated film and/or bolus injection) (table 2).
  • Bolus injection was given at the dose of Ig/kg (-0.8 to 0.9ml/rat) based on the body weight of individual animals. All the rats were sacrificed four weeks after the treatment (day 28).
  • Path control (group I) - induced epidural fibrosis by laminectomy alone.
  • Film control (group 2) - induced epidural fibrosis by laminectomy and control films were implanted.
  • Bolus drug control (group 5) - induced epidural fibrosis by laminectomy and control films were implanted along with bolus administration of L-alanine-L-glutamine, locally at the site of implantation.
  • TGF-pi levels in serum samples were determined using the R&D systems ELISA kit (Catalog No.SMBIOOB) as per the manufacturer's instructions. Samples were activated with IN HCL followed by neutralization in O.SM HEPES/1 ,2N NaOH to convert latent TGF-pi to its active form and analyzed. Histopathology
  • fibrosis was scored only in the epidural area and fibrosis noticed in the muscles and vertebral foramen (if any) was not included in the scoring criterion.
  • complete removal of the spinous process along with the vertebral arch was attained thus ensuring uniformity in the subsequent fibrosis observed in the epidural area where the bone has been resected.
  • the scoring for fibrosis was done in Sirius red stained slides. Sirius red specifically captures fibrosis by staining collagen dark red. The degree of fibrosis was scored based on the intensity and area of fibrosis (dark red stained area) in the epidural space alone.
  • Body Weight There was a trend of increased body weight in all the treatment groups, when compared to pathological control group rats. However, the increase in mean body weight for 28 days (day 0 to day 28) was statistically significant in “30% drug film+ bolus” group and “control film+ bolus” groups when compared to pathological control group( p ⁇ 0.001 ;Student' s t test); Figures 7-9 and Table 3.
  • Drug film (30%) showed around 14% reduction in serum TGF-pi levels when compared to pathological control; though the inhibition was not statistically significant.
  • “Drug film (30%) + bolus” treatment group showed 20% decrease in TGF-pi levels as compared to pathological control rats; which was statistically significant by t-test. However we don't see significant reduction in TGF-pi levels when we compared the combined group (“Drug film” and “Drug film+ bolus”) with the pathological control group (Student’s t test). Also, there was no significant difference in TGF-pi levels between the treatment groups and pathological control group when One way ANOVA followed by Dunnett's posttest was applied.
  • Body weight Increase in body weight was observed in all the treatment groups during the course of study, when compared to pathological control group rats. However, the increase in mean body weight for 28 days (day Oto day 28) was statistically significant in “30% drug film+ bolus” group and “control film + bolus” groups when compared to pathological control group ( p ⁇ 0.001 ;Student' s t test).
  • TGF-pi The TGF-pi levels in “Control film” & “Control film + bolus” were similar to Pathological control group. “Drug film (30%)” showed around 14% reduction in serum TGF-pi levels when compared to pathological control; though the inhibition was not statistically significant. “Drug film (30%) + bolus” treatment group showed 20% decrease in TGF-pi levels as compared to pathological control rats; which was statistically significant. However we don't see significant reduction in TGF-pi levels when we compared the combined group (“Drug film” and “Drug film + bolus”) with the pathological control group (Student’s t test).
  • TGF-pi levels There was no significant difference in TGF-pi levels between the treatment groups and pathological control group when One way ANOVA followed by Dunnett's posttest was applied. “Drug film (50%)” and “Drug film (50%) + Bolus” groups did not show significant reduction in TGF-pi levelsp-0[gcdpvi (-2 & -4% respectively) when compared to path control group by Student's t test /One way ANOVA followed by Dunnett’s posttest. TGF pi levels vary at different stages of fibrosis and/or inflammation. For the purpose of this study, differences in TGF 01 levels were measured at the end of the study but are not necessarily directly related to the levels of the fibrosis or adhesions detected at that timepoint.
  • a glutamine source into one or more susceptible synovial joints of a subject may be sufficient to reduce / prevent adhesions and fibrosis if amount and retention time is sufficient, the beneficial effects may be more pronounced when administered in a manner that achieves a substantially immediate release of the glutamine source into the joint area followed by release of the glutamine source in the area for an extended period of time.
  • subjects may benefit from an initial dose of a glutamine source to counteract hypoxia/injury/assault combined with an extended/delayed release of the glutamine source over time in the area to counteract downstream events and/or restore homeostasis.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des méthodes et des compositions pour inhiber l'adhérence ou la fibrose dans des articulations synoviales. Les méthodes de l'invention comprennent l'administration d'une source appropriée de glutamine au niveau d'articulations synoviales de sujets présentant une adhérence et une fibrose articulaires synoviales ou risquant de développer une fibrose et une adhérence articulaires synoviales.
PCT/EP2025/052712 2024-02-01 2025-02-03 Source de glutamine destinée à être utilisée dans des méthodes et des compositions pour réduire ou prévenir des adhérences ou une fibrose articulaires synoviales Pending WO2025163204A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202463548676P 2024-02-01 2024-02-01
US63/548,676 2024-02-01

Publications (1)

Publication Number Publication Date
WO2025163204A1 true WO2025163204A1 (fr) 2025-08-07

Family

ID=94481183

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2025/052712 Pending WO2025163204A1 (fr) 2024-02-01 2025-02-03 Source de glutamine destinée à être utilisée dans des méthodes et des compositions pour réduire ou prévenir des adhérences ou une fibrose articulaires synoviales

Country Status (1)

Country Link
WO (1) WO2025163204A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012175746A1 (fr) 2011-06-23 2012-12-27 Dsm Ip Assets B.V. Nouveaux copolymères biodégradables de polyesteramide destinés à l'administration de médicaments
WO2014053542A1 (fr) 2012-10-02 2014-04-10 Dsm Ip Assets B.V. Composition de délivrance de médicament comprenant des protéines et des polyesteramides biodégradables
US9011883B2 (en) 2005-08-11 2015-04-21 Ade Therapeutics Inc. Reducing post-operative adhesion formation with intraperitoneal glutamine
WO2015154924A1 (fr) 2014-04-08 2015-10-15 Dsm Ip Assets B.V. Polyesteramide biodégradable utilisé pour le traitement de troubles arthritiques
CN113768912A (zh) * 2021-09-07 2021-12-10 安徽医科大学第二附属医院 L-谷氨酰胺在治疗骨关节炎中的应用
WO2022234489A1 (fr) * 2021-05-07 2022-11-10 Temple Therapeutics BV Procédés de traitement de la fibrose et de lésions associées à l'hypoxie à des nerfs périphériques

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9011883B2 (en) 2005-08-11 2015-04-21 Ade Therapeutics Inc. Reducing post-operative adhesion formation with intraperitoneal glutamine
WO2012175746A1 (fr) 2011-06-23 2012-12-27 Dsm Ip Assets B.V. Nouveaux copolymères biodégradables de polyesteramide destinés à l'administration de médicaments
WO2014053542A1 (fr) 2012-10-02 2014-04-10 Dsm Ip Assets B.V. Composition de délivrance de médicament comprenant des protéines et des polyesteramides biodégradables
WO2015154924A1 (fr) 2014-04-08 2015-10-15 Dsm Ip Assets B.V. Polyesteramide biodégradable utilisé pour le traitement de troubles arthritiques
WO2022234489A1 (fr) * 2021-05-07 2022-11-10 Temple Therapeutics BV Procédés de traitement de la fibrose et de lésions associées à l'hypoxie à des nerfs périphériques
CN113768912A (zh) * 2021-09-07 2021-12-10 安徽医科大学第二附属医院 L-谷氨酰胺在治疗骨关节炎中的应用

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
BOHMESICKINGER, J. PEPT SCI., vol. 21, 2015, pages 186 - 200
HOAREKOHANE, POLYMER, vol. 49, 2008, pages 1993 - 2007
JONKER ET AL., CHEM MATER., vol. 24, 2011, pages 759 - 773
KATSARAVA ET AL., JOURNAL OF POLYMER SCIENCE: PART A: POLYMER CHEMISTRY, vol. 37, 1999, pages 391 - 407
LI ET AL., EXP THER MED, vol. 6, 2013, pages 1507 - 1511
LI FENGFENG: "Celecoxib effectively inhibits the formation of joint adhesions", EXPERIMENTAL AND THERAPEUTIC MEDICINE, vol. 13, no. 6, 1 December 2013 (2013-12-01), GR, pages 1507 - 1511, XP093266719, ISSN: 1792-0981, DOI: 10.3892/etm.2013.1336 *
ROBERTSON LYNNE M. ET AL: "Evitar (l-Alanyl-l-Glutamine) Regulates Key Signaling Molecules in the Pathogenesis of Postoperative Tissue Fibrosis", REPRODUCTIVE SCIENCES, vol. 26, no. 6, 5 September 2018 (2018-09-05), US, pages 724 - 733, XP055942405, ISSN: 1933-7191, Retrieved from the Internet <URL:https://link.springer.com/article/10.1177/1933719118789511> DOI: 10.1177/1933719118789511 *

Similar Documents

Publication Publication Date Title
AU2008265576B2 (en) Composition and method for treating connective tissue damage
US6037331A (en) Compositions for prevention of inflammation and adhesion formation uses thereof
US5866554A (en) Compositions for prevention of inflammation and adhesion formation and uses thereof
JP2011105741A (ja) 骨関節症を治療するための、ヒアルロン酸ナトリウムとコンドロイチン硫酸との混合物の使用
US7803787B2 (en) Composition and method for treating connective tissue damage by transmucosal administration
CN103002903B (zh) 瘢痕疙瘩治疗法
US10471129B2 (en) Hyaluronic acid containing compositions for prevention of the formation of post-surgical scars and post-surgical adhesions
CN103189078A (zh) 含有透明质酸和l-精氨酸的抗粘连剂
EP2465513A2 (fr) Procédé permettant d&#39;augmenter l&#39;efficacité de compositions anti-adhésives pour lutter contre les inflammations et la douleur et utilisation des dites compositions
KR0131330B1 (ko) 피브린 침착 또는 유착을 방지하기 위한 방법 및 치료 조성물
JP5194207B2 (ja) 腹腔内グルタミンによる術後癒着形成の減少
CN102405050B (zh) 抑制细胞增殖和手术粘连的方法和组合物
US20080003258A1 (en) Composition and Method for Treating Rheumatoid Arthritis
WO2025163204A1 (fr) Source de glutamine destinée à être utilisée dans des méthodes et des compositions pour réduire ou prévenir des adhérences ou une fibrose articulaires synoviales
JP2021529837A (ja) 低酸素関連組織損傷を治療するための投薬レジメン
US9474767B2 (en) Compositions and methods for inhibiting bone growth
WO2005020955A1 (fr) Compositions pour prevenir les cicatrices et les fibroses apres blessure ou chirurgie
CN103948617A (zh) 一种治疗和预防腹部手术后粘连的药物组合物
KR20210034956A (ko) 히알루론산을 포함하는 활액보충용 조성물
HK1183626B (en) Keloid treatment

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25703498

Country of ref document: EP

Kind code of ref document: A1