EP1670486A1 - Treatment of a condition in a mammal with adminisration of aminosugar and uses thereof - Google Patents
Treatment of a condition in a mammal with adminisration of aminosugar and uses thereofInfo
- Publication number
- EP1670486A1 EP1670486A1 EP04789289A EP04789289A EP1670486A1 EP 1670486 A1 EP1670486 A1 EP 1670486A1 EP 04789289 A EP04789289 A EP 04789289A EP 04789289 A EP04789289 A EP 04789289A EP 1670486 A1 EP1670486 A1 EP 1670486A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- aminosugar
- intra
- group
- glcnac
- joint
- 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.)
- Withdrawn
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Classifications
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- a joint related condition or disease can include, but is not limited to physical injury to the joint, osteoarthritis (OA) and rheumatoid arthritis.
- the associated pathological markers can include synovitis, subchondral bone edema, and progressive cartilage degradation, although numerous others do exist.
- GlcN glucosamine
- GlcN is cytotoxic for chondrocytes at low millimolar concentrations, making treatment with high concentrations of GlcN undesireable.
- GlcNAc N-acetylglucosamine
- the present invention relates to treating joint related conditions in mammals by administering an aminosugar, and wherein said treatment specifically prevents, lessens or reverses pathologies associated with the joint condition, said pathologies being selected from the group consisting of synovitis, subchondral bone edema, and cartilage degradation.
- a preferred embodiment of the present invention relates to methods of preventing, lessening or reversing the severity pathologies associated with joint conditions by administering to a mammal a therapeutically effective amount of an aminosugar including, but not limited to N-acetylglucosamine, glucosamine, galactosamine, N-acetylgalactosamine, iminocyclitol, and pharmaceutically acceptable salts thereof.
- a joint condition is evaluated for specific pathological markers, and if said markers are present, a therapeutically effective amount of an aminosugar is administered.
- joint conditions know in the art to have these pathological markers associated therewith are treated using a therapeutically effective amount of an aminosugar.
- the therapeutically effective amount of an aminosugar is intra-articularly administered to a mammal.
- that aminosugar is GlcNAc and more preferably that aminosugar is GlcNAc contained in a matrix as a controlled release formulation.
- GlcNAc is intra- articularly administered to a mammal having a joint condition to treat cartilage degeneration, subchondral bone edema and synovitis.
- the treatment affects are seen at the macroscopic level and the microscopic level.
- the treatment effects are particularly the retardation of cartilage degeneration, the reduction of hypercellularity in marrow of subchondral bone edema and the reduction of membrane inflammation for synovitis .
- Another preferred embodiment of the present invention is methods for administering to a mammal a composition comprising a therapeutically effective amount of an aminosugar, preferably GlcNAc, either alone or in combination with an existing anti-inflammatory drug or a hexoaminidase inhibitor.
- methods for administering formulations of the present invention include, but are not limited to, intra-articular, topical, and intra-muscular methods. More preferably, controlled release formulations of the aminosugar are intra-articularly administered to mammals in need of such treatment.
- the current invention provides methods for specifically treating joint conditions having one or more of the pathological markers that respond favorably to aminosugar therapy.
- the current invention also provides new uses for aminosugars in the targeted treatment of joint conditions having one or more of the pathological markers.
- the current invention furthermore provides compounds and pharmaceutical formulations thereof that are useful for the targeted treatment of joint conditions having one or more of the pathological markers.
- BRIEF DESCRIPTION OF THE DRAWINGS Figure 1A shows the gross morphological grading of femoral condyles in rabbits with bilateral anterior cruciate ligament transection (ACLT) and treated with intra-muscular GlcNAc or normal saline.
- Figure IB shows the gross morphological grading of tibial plateau in rabbits with bilateral anterior cruciate ligament (ACL) transection and treated with intramuscular GlcNAc or normal saline.
- Figure 2 shows the gross morphological grading of femoral condyles in rabbits with unilateral ACL transection and treated with intra-articular GlcNAc, Sodium hyaluronate or saline.
- Figure 3 shows the gross morphological grading of tibial plateaus in rabbits with unilateral ACL transection and treated with intra-articular GlcNAc, Sodium hyaluronate or saline.
- Figure 4 illustrates the gross morphological assessment of joint swelling in rabbits with unilateral ACL transection and treated with intra-articular GlcNAc, Sodium hyaluronate or saline.
- Figure 5 illustrates DNA content in synovial tissue from rabbits with unilateral ACL transection and treated with intra-articular GlcNAc, Sodium hyaluronate or saline.
- Figure 6 shows the digital image analysis of the lesion size in femoral condyles (Fig. 6A) and tibial plateaus (Fig. 6B) from rabbits with unilateral ACL transection and treated with intra-articular GlcNAc or Sodium hyaluronate.
- Figure 7 shows the time dependant in vitro release of GlcNAc entrapped in injectable polymeric formulations according to one embodiment of the present inventions. DETAILED DESCRIPTION OF THE INVENTION
- ACL Anterior Cruciate Ligament
- GlcN glucosamine
- GAGs glycosaminoglycans
- GlcNAc N-Acetylglucosamine
- HA hyaluronic acid
- IL-1 ⁇ interleukin-l ⁇
- IL-6 interleukin-6
- NSAID nonsteroidal anti-inflammatory drug
- PBS phosphate-buffered saline
- PEG polyethylene glycol
- PMSF phenylmethylsulfonyl fluoride
- active ingredient refers to a therapeutically effective amount of drug or formulation thereof.
- active ingredients of the present invention are aminosugars, more preferably the aminosugars GlcNAc and GlcN; and most preferably is the aminosugar GlcNAc.
- therapeutically effective amount refers to the amount of an active ingredient necessary to induce one or more of the desired pharmacological effects of the current invention. The amount can vary greatly according to the effectiveness of a particular active substance; the age, weight, and response of the individual; as well as the nature and severity of the individual's symptoms. Accordingly, there is no upper or lower critical limitation with respect to the amount of the active substance.
- alginate gel refers to natural polysaccharide polymers comprising
- Alginate is capable of forming stable gels, particularly in the presence of certain divalent cations, such as calcium, barium, and strontium.
- divalent cations such as calcium, barium, and strontium.
- the term "aminosugar” refers to any synthetic or naturally occurring sugar wherein one or more carbon atoms are substituted with an amino group (- NH 2 ).
- arthritis refers to any particular disease characterized by joint inflammation, although the etiology of the inflammation may differ in various conditions.
- articular cartilage or “cartilage” refer to a substance that covers ends of bones and forms the joint surfaces. Cartilage can withstand compressive forces and creates a low friction surface upon which the joints can glide. Articular cartilage comprise chondrocytes and a substrate further comprising proteins and glycosaminoglycan polysaccharides.
- carbtilage degradation refers to degradation in the tissues comprising cartilage.
- chitin refers to (poly)GlcNAc linked in a ⁇ -1,4 fashion.
- Chitin is found throughout nature, for example in the exoskeletons of insects and Crustacea.
- chitosan refers to deacylated chitin or (poly)N-glucosamine linked in a ⁇ -1.4 fashion.
- chondrocyte refers to cells found within articular cartilage.
- Chondrocytes produce collagen, a gelatinous protein, and proteoglycans, which are glucosamine glycans linked to proteins (also called mucopolysaccharides).
- condition of the joint or “joint condition” means any disease affecting the joint of a mammal and which presents with one or more of the following pathological conditions: synovitis, subchondral bone edema, and cartilage degeneration.
- encapsulation efficiency refers to the amount of a compound or active ingredient encompassed, incorporated, loaded, associated, bound or otherwise entrapped within injectable polymeric gels, liposomes, microspheres, nanoparticles, or the like.
- yield is expressed as a percent encapsulation of the active ingredient.
- entrapped or encapsulated refers to any method of formulating an active ingredient, which confines, sequesters, or otherwise inhibits the free dissolution of the active ingredient in a matrix, such as a solution or solid phase.
- Preferred examples of entrapping or encapsulating active ingredients include, but are not limited to, formulations entrapped in a matrix wherein said matrix is selected from a particle, an implant, or a gel.
- matrix refers to a solid, gel or liquid composition capable to entrapping an aminosugar(s), and optional additional materials, such as an anti- inflammatory drug, therein.
- glycosaminoglycan refers to long heteropolysaccharide molecules containing repeating disaccharide units.
- the disaccharide units may comprise modified aminosugars: D-, N-acetylgalactosamine or D-GlcNAc and an uronic acid such as D-glucuronate or L-iduronate.
- GAGs serve as a lubricating fluid in the joints. Specific GAGs of physiological significance are hyaluronic acid, dermatan sulfate, chondroitin sulfate, heprin, heparan sulfate, and keratan sulfate.
- Hyaluronic acid refers to a naturally occurring mucopolysaccharide comprising alternating subunits of D-glucuronic acid and D-N- acetyl glucosamine.
- Hyaluronic acid is a linear polysaccharide (long-chain biological polymer) formed by repeating disaccharide units consisting of D- glucuronic acid ⁇ (l-3) N-acetyl-D-glucosamine linked by ⁇ (l-4) glycosidic linkages.
- Hyaluronic acid is commercially available in several molecular weight ranges spanning from about 50,000 Daltons to about 8 x 10. sup.6 Daltons.
- Hyaluronic acid is also available as a sodium salt and is a dried, highly purified substance.
- Sodium hyaluronate may be preserved with a variety of preservatives known in the art including, but not limited to, alkyl-substituted benzoic acid esters, alcohols, conjugates, blends, and mixtures thereof.
- hyaluronan refers to a polymer of repeating molecules of N- acetylglucosamine and glucuronic acid.
- IL-1 ⁇ refers to interleukin-l ⁇ , an immunomodulator that mediates a wide range of immune and inflammatory responses, including the activation of B- and T-cells.
- injectable formulation refers to a sterile, injectable composition prepared as a liquid solution or suspension. Solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection may also be prepared. The preparation may also be emulsified or the active ingredient entrapped. An injectable formulation may also comprise a variety of preservatives known in the art, including, but not limited to, alkyl-substituted benzoic acid esters, alcohols, conjugates, blends, and mixtures thereof.
- injectable polymer gel refers to a polymeric matrix carrier used to entrap or encapsulate active ingredients of the invention. Polymer-based injectable formulations allow drug dosage and timing to be tailored through the choice and formulation of various active ingredient/polymer combinations.
- the total dose of medication and the kinetics of release are variables that can be adjusted. For example, by varying the solvent content, copolymer ratio and molecular weight, and polymer solvent polarity drug delivery parameters can be optimized. Polymer- based systems may also increase the life span of active ingredients. The use of polymeric systems comprising poly lactide and lactide-glycolide copolymers in formulations offers certain advantages such as biocompatability and biodegradability. Injectable polymer gels may be prepared, e.g., processed, mixed, filtered, heated, or sterilized according to processes known in the art.
- microsphere refers to a polymeric matrix carrier used to entrap or encapsulate active ingredients of the invention.
- Microsphere-based formulations allow drug dosage and timing to be tailored through the choice and formulation of various active ingredient/polymer combinations.
- the total dose of medication and the kinetics of release are variables that can be adjusted. For example, by varying the copolymer ratio and copolymer molecular weight, drug delivery parameters can be optimized.
- Microsphere-based systems may also increase the life span of active ingredients.
- the use of microspheres comprising lactide-glycolide copolymers in formulations offers certain advantages such as biocompatability and biodegradability.
- Microspheres may be prepared, e.g., processed, machined, milled, ground, or extruded according to processes known in the art.
- Intra-articular refers to a method of delivering a drug directly to a joint.
- Traditional routes of drug delivery such as for example, oral, intravenous or intramuscular administration, depend upon vascular perfusion of the synovium to carry the drug to the joint. This is inefficient because transynovial transfer of small molecules from the synovial capillaries to the joint space generally occurs by passive diffusion, which becomes less efficient with increasing size of the target molecule.
- the access of directing molecules, for example, GlcN to the joint space is substantially restricted.
- Intra-articular injection or perfusion of drugs circumvents those limitations.
- polymeric refers to hyaluronic acid, polyethylene glycol, copolymers of polyethylene glycol and poly(lactic/glycolic acid), polymers of lactic acid, and copolymers of poly (ethylene glycol-y- (DL-lactic acid-co-glycolic acid), alginate gels, chitosans, or pharmaceutically acceptable salts thereof.
- sustained release refers to the time period during which a drug is released for availability, or otherwise becomes available for physiological uptake. Periods of sustained release may be preceded by an induction period, during which little or no drug is released, or may be biphasic, comprising an initial time period during which some drug is released, and a second time period during which additional drug is released.
- the term “continuous release” is used solely to describe a release profile that appears to be monophasic, having a smooth-curved time profile of release. Those of skill in the art will appreciate that the release profile may actually correspond to an exponential or logarithmic time-release profile.
- the term “synovitis” means inflammation of the joint lining (synovium). Synovitis is present in a variety of joint related conditions, including, but not limited to osteoarthritis, physical or traumatic injury, rheumatoid arthritis and other autoimmune disorders . It is discovered that aminosugars lessen, prevent and reverse the pathologies associated with joint conditions. This discovery, therefore, provides for the specific treatment of any condition of the joint wherein one or more of these pathologies are present.
- This newly discovered method of treating joint conditions having one or more of said pathological markers is a targeted approach, wherein the newly discovered affects of aminosugars allow for treatment of joint conditions that would otherwise have not received aminosugar therapy.
- pathology refers to synovitis, subchondral bone edema, and cartilage degradation.
- the present invention relates to treating joint related conditions in mammals by administering an aminosugar, and wherein said treatment specifically prevents, lessens or reverses pathologies associated with the joint condition, said pathologies being selected from the group consisting of synovitis, subchondral bone edema, and cartilage degradation.
- a preferred embodiment of the present invention relates to methods of preventing, lessening or reversing the severity pathologies associated with joint conditions by administering to a mammal a therapeutically effective amount of an aminosugar including, but not limited to N-acetylglucosamine, glucosamine, galactosamine, N-acetylgalactosamine, iminocyclitol, and pharmaceutically acceptable salts thereof.
- an aminosugar including, but not limited to N-acetylglucosamine, glucosamine, galactosamine, N-acetylgalactosamine, iminocyclitol, and pharmaceutically acceptable salts thereof.
- a joint condition is evaluated for specific pathological markers, and if said markers are present, a therapeutically effective amount of an aminosugar is administered.
- joint conditions know in the art to have these pathological markers associated therewith are treated using a therapeutically effective amount of an aminosugar.
- the therapeutically effective amount of an aminosugar is intra-articularly administered to a mammal.
- that aminosugar is GlcNAc and more preferably that aminosugar is GlcNAc contained in a matrix as a controlled release formulation.
- GlcNAc is intra- articularly administered to a mammal having a joint condition to treat cartilage degeneration, subchondral bone edema and synovitis.
- the treatment affects are seen at the macroscopic level and the microscopic level.
- the treatment effects are particularly the retardation of cartilage degeneration, the reduction of hypercellularity in marrow of subchondral bone edema and the reduction of membrane inflammation for synovitis.
- Another preferred embodiment of the present invention is methods for , administering to a mammal a composition comprising a therapeutically effective amount of an aminosugar, preferably GlcNAc, either alone or in combination with an existing anti-inflammatory drug or a hexoaminidase inhibitor.
- methods for administering formulations of the present invention include, but are not limited to, intra-articular, topical, and intra-muscular methods. More preferably, controlled release formulations of the aminosugar are intra-articularly administered to mammals in need of such treatment.
- the current invention provides methods for specifically treating joint conditions having one or more of the pathological markers that respond favorably to aminosugar therapy.
- the current invention also provides new uses for aminosugars in the targeted treatment of joint conditions having one or more of the pathological markers.
- the current invention furthermore provides compounds and pharmaceutical formulations thereof that are useful for the targeted treatment of joint conditions having one or more of the pathological markers.
- ACLT anterior cruciate ligament transection
- Osteoarthritis is only one of many joint conditions that presents with one or more of the following pathologies, synovitis, subchondral bone edema and cartilage degradation. Other joint conditions include, but are not limited to physical or traumatic injury and rheumatoid arthritis. As used herein below, and in conjunction with the discussion of the ACLT model, the term “experimental OA” does not limit the current invention to osteoarthritis. Rather, “experimental OA” is merely common nomenclature in the art. The invention is useful for the full range of joint conditions associated with the above mentioned pathologies. In order to study the effects aminosugars have on the pathological markers associated with joint conditions, experimental OA was induced in the knee of rabbits by ACLT.
- GlcNAc was purchased from Sigma (St. Louis, MO). GlcNAc was dissolved in normal saline and sterilized by filtration through 0.22 micrometer filter (Corning, Acton, MA). Sterile solution of GlcNAc was stored at 4oC.
- HyalganTM Sodium hyaluronate
- PLAD Poly Lactic Acid Depot
- PLGA RG 502-H, Boehringer Ingelheim (BI) Chemicals, Inc. Wallingford, CT, USA
- USP/NF grade solvents NMP, DMSO, benzyl alcohol, benzyl benzoate, ethanol
- the injectable gel formulations were sterilized as aqueous solutions by terminal filtration through a 0.22 micron filter then dried aseptically.
- the sterile polymer solution and sterile GlcNAc powder were mixed using aseptic techniques at the point of use.
- the identity, purity, potency, sterility, and loading of each formulation were recorded in production batch records.
- HPLC or FT-IR were used to measure identity, purity, potency, and loading.
- Sterility was determined using a modified USP sterility test. Briefly, the sample was dissolved in an appropriate solvent (usually DMSO) then serially diluted with sterile water to level where any solvents present were no longer bacteriostatic.
- ACLT was performed using a medial arthrotomy technique (Yoshioka et. al. Osteoarthritis Cartilage 1996; 4:87-98). After dislocating the patella laterally, the ACL was transected with a sharp blade. Complete transection was confirmed by a manual anterior drawer test. The knee joints were irrigated with sterile saline and closed in layers with sutures. All animals were maintained individually with ad libitum activity. The animals were sacrificed 8 weeks after the surgery. Previously published data demonstrated that the majority of rabbits with ACLT develop cartilage degeneration at this time point (Sah et. al. J Orthop Res 1997 Mar; 15: 197-203). Intra-muscular injections of GlcNAc.
- Intra-muscular injections of GlcNAc were performed three times per week starting one week postoperatively for a period of seven weeks.
- the dose of GlcNAc was 200 mg/kg per injection.
- the control group of received the same number of intra-muscular injections of normal saline.
- Intra-articular injections of GlcNAc Intra-articular injections of GlcNAc started one week post-operatively for a period of seven weeks. Rabbits were injected twice per week with GlcNAc in a volume of 0.3 ml per knee joint. The single dose of GlcNAc per injection was 80 mg. Control animals were injected twice per week intra-articularly with normal saline (0.3 ml per joint).
- the third group of rabbits received intra-articular injections of hyaluronan (0.3 ml per joint) twice per week for seven weeks starting one week after the ACL transection.
- Synovial fluid analysis was performed in 3 animals that developed gross synovial effusions (2 animals in the control group and 1 animal in the hyaluronan group). In all three animals synovial fluid was culture negative.
- Gross morphological assessment of the knee joints included assessment of joint swelling, synovial effusion, macroscopic articular cartilage morphology of tibial plateaus and femoral condyles, and assessment of the menisci.
- grade 0 normal
- Grade 1 mild inflammation and/or proliferation of the joint capsule
- Grade 2 moderate swelling
- Grade 3 severe swelling
- the following grading system was used to assess synovial effusions: Grade 0 - normal; Grade 1 (mild effusion) - effusion is greater than normal, but does not fill the knee joint; Grade 2 (moderate effusion) - effusion fills the knee joint, but does not pour out of the capsule as it is opened; Grade 3 (severe effusion) - effusion expands the knee joint and pours out as the capsule is opened.
- Grade morphological assessment of the articular cartilage The distal femur and proximal tibia were harvested keeping a 3.5cm to 4cm shaft of the bones.
- Grade 1 intact surface
- Grade 2 minimal fibrillation
- Grade 3 overt fibrillation
- Grade 4 erosion
- An image (resolution: 60 pixels per mm; onscreen magnification: 20x) of the femoral condyles was obtained using a Canon EOS D30 digital camera with a 100 mm macro lens at a distance of approximately 12 cm. A millimeter scale was included in the photograph to accurately scale the image. The scaled image was then projected onto a 3D model of the femoral condyles. The 3D surface area of the lesion was measured by interactively plotting the margins of the lesion. A digital image of articular surface of the tibia was obtained as described above. No 3D projection was used since the tibial surface was relatively flat and 2D measurements do not vary significantly from 3D measurements. Histological grading of the knee joints.
- Distal femur and proximal tibia from the rabbit knee joints were fixed in 10%) buffered formalin, decalcified in TBD-2 decalcifier (ThermoShandon, Pittsburg, CA) and embedded in paraffin blocks. Sagittal sections of lateral and medial femoral condyles, and coronal sections of tibial plateaus were used for further histological analysis. The assessment of sulfated glycosaminoglycan (SGAG) content was performed after staining of the tissue sections with Safranin O / Fast Green.
- SGAG sulfated glycosaminoglycan
- the following grading system was used for assessing SG ⁇ A content: Grade 1 - Less than 25% loss of Safranin O staining; Grade 2 - 25-50% loss of Safranin O staining; Grade 3 - More than 50% loss of Safranin O staining;
- the following grading system was used for assessing cartilage integrity: Grade 1 - Intact cartilage surface; Grade 2 - Presence of fibrillations; Grade 3 - Full thickness cartilage defect.
- all tissue samples were analyzed for the presence of chondrocyte proliferation or cloning.
- synovium Histological assessment of synovium was based on the presence of synovial proliferation and synovial neoangiogenesis, and it was performed separately for the synovium attached to the tibial plateaus, lateral, and medial femoral condyles. Microscopic assessment of bone marrow was based on the presence of subchondral bone marrow hypercellularity and increased vascularization as shown in Table 3. Measurement of DNA content in synovial tissue. Synovial tissue cellularity was assessed by quantitating the tissue concentration of DNA (Amiel et. al. J Orthop Res 1986; 4:162-172). Briefly, washed and lyophilized synovial tissue was solubilized by incubation for 2 hours in 1 N NaOH at 65°C.
- Group A was treated with saline (negative control group); Group B was treated with 1.5 M GlcNAc group; Group C was treated with 0.5 M GlcNAc group; Group D was treated with 0.15 M GlcNAc group; Group E was treated with 0.05 M GlcNAc group. All compounds were continuously delivered to the joints by Alzet mini pumps. The delivery rate for this pump was 2.5 ⁇ l/hour. All the rabbits received ACLT surgery on the right knee and GlcNAc was delivered to the right knee. GlcNAc was administered to the right knee by alzet pump for 8 weeks starting immediately following ACLT procedure. The pumps were replaced at the end of week 4. Pump and delivery tube were checked twice a week to make sure that the delivery tube remained in place at the joint.
- Intra-articular injection of GlcNAc shows improvement in the condition of the tibial plateaus and femoral condyles.
- FIG. 4 morphological analysis of the tibial plateaus revealed remarkable chondroprotective activity of GlcNAc in that only 1 of 7 treatment rabbits developed a cartilage lesion compared to 6 of 7 in the control group developing such lesions (p ⁇ 0.003).
- Figures 4 and 5 show that intra-articular administration GlcNAc does not significantly affect joint swelling, synovial effusions or DNA content in synovial tissue.
- intra-muscular injection of GlcNAc does not demonstrate chondroprotective effects, but does show a trend towards reduction of synovitis.
- Intra-articular administration of GlcNAc does show a significant reduction of cartilage degradation at both the macroscopic and microscopic levels.
- FIGS. 6a and 6b There is no significant difference in synovial effucion between the GlcNAc group and the Hyaluronan group (figure 4); however, DNA content assessment reveals a significant reduction in synovial hyperplasia and cellularity (p ⁇ 0.05) for the GlcNAc group over the hyaluronan group (figure 5).
- a histological analysis of experimental rabbits receiving either GlcNAc treatment or saline was performed and the results from each population were compared. As is seen in table 1 below, there is a similar loss of SGAG in the medial femoral condyles for both the treatment population and the control population.
- intra-articular GlcNAc demonstrated significant retardation of cartilage degeneration on both macroscopic and microscopic levels.
- intra-articular GlcNAc is superior to visco-supplementation therapy with hyaluronan in regard to their chondroprotective efficacy.
- intra-articular therapy of experimental OA rabbits with GlcNAc unexpectedly reduced cartilage degradation with a macroscopic reduction in lesion size in mammals, significantly suppressed synovitis, and reduced the bone marrow hypercellularity of subchondral bone edema.
- an aminosugar most preferably, GlcNAc, as the active ingredient
- a pharmacological composition comprising active ingredients dissolved or dispersed therein need not be limited based on formulation.
- Such compositions may be prepared as injectable liquid solutions or suspensions.
- solid forms suitable for dissolution, or resuspension, in liquid prior to use can also be prepared.
- the preparation can also be emulsified.
- the composition is held within a container, which includes a label stating to the effect that the composition is approved by the FDA in the United States (or other equivalent labels in other countries) for treating a disease or condition described herein.
- a container will provide therapeutically effective amount of the active ingredient to be administered to a host.
- the particular aminosugars that affect the conditions of interest can be administered to a mammal either by alone or in pharmaceutical compositions where it is mixed with suitable carrier(s) or excipient(s).
- a therapeutically effective amount of an agent or agents, such as GlcNAc is administered.
- the active ingredient can be mixed with excipients that are pharmaceutically acceptable and compatible with said active ingredient and in amounts suitable for use in the therapeutic methods described herein.
- Pharmaceutically acceptable salts can be prepared by standard techniques.
- the free base form of the compound is first dissolved in a suitable solvent such as an aqueous or aqueous-alcohol solution, containing the appropriate acid.
- a suitable solvent such as an aqueous or aqueous-alcohol solution, containing the appropriate acid.
- the salt is then isolated by evaporating the solution.
- the salt is prepared by reacting the free base and acid in an organic solvent.
- Carriers or excipients can be used to facilitate administration of the compound, for example, to increase the solubility of the compound.
- carriers and excipients include calcium carbonate, calcium phosphate, various sugars or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, water, saline, dextrose, glycerol, ethanol and physiologically compatible solvents.
- compositions of the present invention can include pharmaceutically acceptable salts of the components therein.
- Pharmaceutically acceptable salts include acid addition salts (formed with any free amino groups of the aminosugars) that are formed with inorganic acids such as, for example, hydrochloric or phosphoric, sulfuric acids, etc., or such organic acids as acetic, tartaric, mandelic and the like. Salts formed with the free carboxyl groups of the aminosugars can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-an ⁇ inoethanol, histidine, procaine and the like.
- Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
- the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
- Compounds which exhibit large therapeutic indices are preferred.
- the data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
- the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
- the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
- the therapeutically effective dose can be estimated initially from cell culture assays.
- a dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 as determined in cell culture (i.e., the concentration of the test compound which achieves a half-maximal disruption of the protein complex, or a half-maximal inhibition of the cellular level and/or activity of a complex component).
- IC50 as determined in cell culture
- levels in plasma may be measured, for example, by HPLC.
- Another preferred embodiment of the present invention relates to an improved formulation for the active ingredient, GlcNAc.
- GlcNAc is entrapped in a matrix. More preferably, GlcNAc in entrapped in a matrix selected from the groups consisting of a particle, an implant, or a gel.
- the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the mammal's condition. (See e.g. Fingl et al., in The Pharmacological Basis of Therapeutics, 1975, Ch. 1 p. 1).
- the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity, or to organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity).
- the magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual mammal. A program comparable to that discussed above may be used in veterinary medicine. Depending on the specific conditions being treated, such agents may be formulated and administered systemically or locally.
- the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
- physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
- Use of pharmaceutically acceptable carriers to formulate the compounds herein disclosed for the practice of the invention into dosages suitable for systemic administration is within the scope of the invention.
- the compositions of the present invention in particular, those formulated as solutions, may be administered parenterally, such as by intravenous injection.
- compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
- these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
- the pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levitating, emulsifying, encapsulating, entrapping or lyophilizing processes.
- compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Dragee cores are provided with suitable coatings.
- concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
- Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
- the inventions illustratively described herein can suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc. shall be read expansively and without limitation.
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US50771603P | 2003-10-01 | 2003-10-01 | |
PCT/US2004/032048 WO2005034961A1 (en) | 2003-10-01 | 2004-09-30 | Treatment of a condition in a mammal with adminisration of aminosugar and uses thereof |
Publications (2)
Publication Number | Publication Date |
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EP1670486A1 true EP1670486A1 (en) | 2006-06-21 |
EP1670486A4 EP1670486A4 (en) | 2009-04-01 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP04789289A Withdrawn EP1670486A4 (en) | 2003-10-01 | 2004-09-30 | Treatment of a condition in a mammal with adminisration of aminosugar and uses thereof |
Country Status (5)
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EP (1) | EP1670486A4 (en) |
JP (1) | JP2007507516A (en) |
CN (1) | CN1909911A (en) |
CA (1) | CA2540586A1 (en) |
WO (1) | WO2005034961A1 (en) |
Families Citing this family (8)
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---|---|---|---|---|
US20120225033A1 (en) * | 2010-11-24 | 2012-09-06 | Durect Corporation | Biodegradable Drug Delivery Composition |
JP2007518814A (en) * | 2004-01-20 | 2007-07-12 | ザ・スクリップス・リサーチ・インスティテュート | Treatment of degenerative chondrosis in mammals with glycosidase inhibitors |
CA2731201C (en) * | 2008-07-18 | 2018-10-16 | Genis Ehf. | Composition for treating autoimmune disorders |
KR101098581B1 (en) | 2009-01-09 | 2011-12-26 | 서울대학교산학협력단 | Composition for Improving Inflammatory Disorder Using ABH Antigen |
CN102614111B (en) * | 2012-04-05 | 2013-11-06 | 苏州豫源生物医药有限公司 | Glucosamine gel and preparation method thereof |
CN105884720A (en) * | 2016-04-23 | 2016-08-24 | 陈斌 | Buspirone hydrochloride pharmaceutical composition and medical application thereof |
WO2020104833A1 (en) * | 2018-11-19 | 2020-05-28 | 4P-Pharma | Composition and methods for regulating chondrocyte proliferation and increasing of cartilage matrix production |
CN112169713A (en) * | 2020-09-09 | 2021-01-05 | 江南大学 | N-alkyl lactosamine surfactant micromolecule alcogel and preparation method thereof |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0379753A1 (en) * | 1989-01-26 | 1990-08-01 | Steigerwald Arzneimittelwerk Gmbh | N-acetyl glucosamine preparations for buccal use |
WO1997021434A1 (en) * | 1995-12-11 | 1997-06-19 | Inholtra, Inc. | Dietary regimen of nutritional supplements for relief of symptoms of arthritis |
WO1998025631A1 (en) * | 1996-12-13 | 1998-06-18 | Lescarden, Inc. | Treatment of osteoarthritis by administering poly-n-acetyl-d-glucosamine |
US6346519B1 (en) * | 1998-09-09 | 2002-02-12 | Advanced Medical Instruments | Method and composition for treating arthritis |
US6378527B1 (en) * | 1998-04-08 | 2002-04-30 | Chondros, Inc. | Cell-culture and polymer constructs |
WO2002078445A1 (en) * | 2001-03-29 | 2002-10-10 | The Scripps Research Institute | Formulations comprising entrapped active ingredients and uses thereof |
WO2003026677A1 (en) * | 2001-09-26 | 2003-04-03 | Primex Ehf. | Pharmaceutical composition comprising chito-oligomers |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AUPM666894A0 (en) * | 1994-07-07 | 1994-07-28 | University Of Melbourne, The | Diagnostic methods and compositions |
US5840715A (en) * | 1995-12-11 | 1998-11-24 | Inholtra Investment Holdings & Trading, N.V. | Dietary regimen of nutritional supplements for relief of symptoms of arthritis |
US6514983B1 (en) * | 1997-09-03 | 2003-02-04 | Guilford Pharmaceuticals Inc. | Compounds, methods and pharmaceutical compositions for treating neural or cardiovascular tissue damage |
US6514522B2 (en) * | 1998-04-08 | 2003-02-04 | Chondros, Inc. | Polymer constructs |
EP1077944A1 (en) * | 1998-05-15 | 2001-02-28 | Guilford Pharmaceuticals Inc. | Carboxamide compounds, compositions, and methods for inhibiting parp activity |
US6506785B2 (en) * | 1998-05-22 | 2003-01-14 | Pfizer, Inc. | Treating or preventing the early stages of degeneration of articular cartilage or subchondral bone in mammals using carprofen and derivatives |
US6656925B2 (en) * | 1998-09-09 | 2003-12-02 | Advanced Medical Instruments | Composition and method of treating arthritis |
US6662805B2 (en) * | 1999-03-24 | 2003-12-16 | The Johns Hopkins University | Method for composite cell-based implants |
MXPA01011542A (en) * | 2001-11-13 | 2003-05-22 | Alcon Inc | Regeneration of articular cartilage damaged by osteoarthritis i and ii, by means of intra-articular application of sodium hyaluronate and chondroitin sulphate in a gel carrier. |
JP2003225093A (en) * | 2001-11-30 | 2003-08-12 | Sumitomo Pharmaceut Co Ltd | Marker for cartilage disorder and use thereof |
KR100629380B1 (en) * | 2001-11-30 | 2006-09-29 | 화이자 인코포레이티드 | Controlled release polymeric compositions of bone growth promoting compounds |
-
2004
- 2004-09-30 CN CNA2004800323746A patent/CN1909911A/en active Pending
- 2004-09-30 WO PCT/US2004/032048 patent/WO2005034961A1/en active Application Filing
- 2004-09-30 CA CA002540586A patent/CA2540586A1/en not_active Abandoned
- 2004-09-30 EP EP04789289A patent/EP1670486A4/en not_active Withdrawn
- 2004-09-30 JP JP2006534068A patent/JP2007507516A/en active Pending
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0379753A1 (en) * | 1989-01-26 | 1990-08-01 | Steigerwald Arzneimittelwerk Gmbh | N-acetyl glucosamine preparations for buccal use |
WO1997021434A1 (en) * | 1995-12-11 | 1997-06-19 | Inholtra, Inc. | Dietary regimen of nutritional supplements for relief of symptoms of arthritis |
WO1998025631A1 (en) * | 1996-12-13 | 1998-06-18 | Lescarden, Inc. | Treatment of osteoarthritis by administering poly-n-acetyl-d-glucosamine |
US6117851A (en) * | 1996-12-13 | 2000-09-12 | Lescarden Inc. | Treatment of osteoarthritis by administering poly-N-acetyl-D-glucosamine |
US6378527B1 (en) * | 1998-04-08 | 2002-04-30 | Chondros, Inc. | Cell-culture and polymer constructs |
US6346519B1 (en) * | 1998-09-09 | 2002-02-12 | Advanced Medical Instruments | Method and composition for treating arthritis |
WO2002078445A1 (en) * | 2001-03-29 | 2002-10-10 | The Scripps Research Institute | Formulations comprising entrapped active ingredients and uses thereof |
WO2003026677A1 (en) * | 2001-09-26 | 2003-04-03 | Primex Ehf. | Pharmaceutical composition comprising chito-oligomers |
Non-Patent Citations (4)
Title |
---|
GREILING H ET AL: "DIE HEMMUNG LYSOSOMALER ENZYME DURCH EIN GLYKOSAMINOGLYKANPOLYSULFAT ZUR THERAPIE CHRONISCHER GELENKERKRANKUNGEN MIT ANTIDEGENERATIV WIRKSAMEN VERDINGUNGEN; EIN BEITRAG ZUR BIOCHEMIE" ARZNEIMITTEL FORSCHUNG. DRUG RESEARCH, ECV EDITIO CANTOR VERLAG, AULENDORF, DE, vol. 23, no. 4, 1 January 1973 (1973-01-01), pages 593-597, XP000990352 ISSN: 0004-4172 * |
LIU J ET AL: "Hexosaminidase inhibitors as new drug candidates for the therapy of osteoarthritis" CHEMISTRY AND BIOLOGY, CURRENT BIOLOGY, LONDON, GB, vol. 8, no. 7, 1 January 2001 (2001-01-01), pages 701-711, XP002444424 ISSN: 1074-5521 * |
See also references of WO2005034961A1 * |
SHIKHMAN A R ET AL: "N-acetylglucosamine prevents IL-1 beta-mediated activation of human chondrocytes" JOURNAL OF IMMUNOLOGY, AMERICAN ASSOCIATION OF IMMUNOLOGISTS, US, vol. 166, no. 8, 15 April 2001 (2001-04-15), pages 5155-5160, XP002505181 ISSN: 0022-1767 * |
Also Published As
Publication number | Publication date |
---|---|
EP1670486A4 (en) | 2009-04-01 |
CN1909911A (en) | 2007-02-07 |
CA2540586A1 (en) | 2005-04-21 |
JP2007507516A (en) | 2007-03-29 |
WO2005034961A1 (en) | 2005-04-21 |
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