US20130266555A1 - Therapeutic agent for disc herniation - Google Patents

Therapeutic agent for disc herniation Download PDF

Info

Publication number
US20130266555A1
US20130266555A1 US13/993,919 US201113993919A US2013266555A1 US 20130266555 A1 US20130266555 A1 US 20130266555A1 US 201113993919 A US201113993919 A US 201113993919A US 2013266555 A1 US2013266555 A1 US 2013266555A1
Authority
US
United States
Prior art keywords
chondroitinase abc
units
administration
disc
disc herniation
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.)
Abandoned
Application number
US13/993,919
Other languages
English (en)
Inventor
Taiichi Sirogane
Takao Murayama
Masafumi Yaguchi
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.)
Seikagaku Corp
Original Assignee
Seikagaku Corp
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 Seikagaku Corp filed Critical Seikagaku Corp
Assigned to SEIKAGAKU CORPORATION reassignment SEIKAGAKU CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MURAYAMA, TAKAO, SIROGANE, TAIICHI, YAGUCHI, MASAFUMI
Publication of US20130266555A1 publication Critical patent/US20130266555A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/51—Lyases (4)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0085—Brain, e.g. brain implants; Spinal cord
    • 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
    • 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
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y402/00—Carbon-oxygen lyases (4.2)
    • C12Y402/02—Carbon-oxygen lyases (4.2) acting on polysaccharides (4.2.2)
    • C12Y402/02004—Chondroitin ABC lyase (4.2.2.4), i.e. chondroitinase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y402/00—Carbon-oxygen lyases (4.2)
    • C12Y402/02—Carbon-oxygen lyases (4.2) acting on polysaccharides (4.2.2)
    • C12Y402/0202—Chondroitin-sulfate-ABC endolyase (4.2.2.20)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y402/00—Carbon-oxygen lyases (4.2)
    • C12Y402/02—Carbon-oxygen lyases (4.2) acting on polysaccharides (4.2.2)
    • C12Y402/02021—Chondroitin-sulfate-ABC exolyase (4.2.2.21)

Definitions

  • the present invention relates to a therapeutic agent for disc herniation containing chondroitinase ABC as an active ingredient.
  • Disc herniation is a disease that causes leg pain, low back pain, and the like due to the pressure on nerves of spinal cords, and the like, attributed to protrusion of the disc tissue into the vertebral canal because the nucleus pulposus perforates the anulus fibrosus present therearound. It has been reported that the therapeutic principle is a conservative therapy and approximately 90% of cases have been cured by such a conservative therapy. As the conservative therapy, there have been performed various treatments, such as rest, bed rest, medication (non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, muscle relaxants), spinal orthosis (corset), traction therapy, thermotherapy, epidural block, nerve root block, and exercise therapy.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • corticosteroids corticosteroids
  • corset spinal orthosis
  • Chemonucleolysis is a method of injecting an enzyme into the disc to bring about the nucleolysis of nucleus pulposus and reduce the internal pressure of the disc so that the pressure on the spinal nerve roots is reduced.
  • Non-Patent Document 1 So far, a method of using chymopapain as an enzyme to be injected into the disc has been reported, and its effectiveness has been reported in 1964 (Non-Patent Document 1). However, chymopapain also acts on the surrounding tissue of the disc including not only the nucleus pulposus but also the spinal cord, and its sale as a medicine has been discontinued at present because severe neurological complications (paraplegia, transverse myelitis, cerebral hemorrhage, subarachnoid hemorrhage, quadriplegia, etc.) were found (Non-Patent Document 2).
  • chondroitinase ABC decomposes the glucosaminoglycan chains of proteoglycans present in the nucleus pulposus (such as chondroitin sulfate chains and hyaluronic acid chains) to reduce the intradiscal pressure due to the reduction in high water retention ability of proteoglycan, resulting in reduction of the pressure on the spinal nerve roots.
  • Non-Patent Document 5 Non-Patent Document 5
  • chondroitinase ABC is a heterologous protein that is not present in humans, it is necessary to succeed in a therapy in only a single dose rather than multiple doses, also from the viewpoint of prevention of anaphylactic shock or the like. Completion of the therapy in a single dose administration means that it is required to show a significant therapeutic effect in only a single dose administration and derive the optimal dose with few adverse side effects because multiple dose administration cannot be performed until a complete recovery.
  • Non-Patent Document 6 Non-Patent Document 6
  • Patent document 1 describes that disc herniation is treated by administering chondroitinase ABC into a disc so that the nucleus pulposus undergoes the nucleolysis and a therapeutic effect on disc herniation was obtained by administering chondroitinase ABC in an amount of 100 units per disk into a human disk.
  • chondroitinase ABC in an amount of 100 units per disk into a human disk.
  • its effective dose has not yet been determined because the effect is not sufficient and the investigation on the adverse side effects has not been made.
  • Non-Patent Document 3 describes that a therapeutic effect on disc herniation was obtained by administering chondroitinase ABC in an amount of 0.5 units per disk into a human disk.
  • Non-Patent Document 4 describes that chondroitinase ABC was administered into a dog disc in an amount of 0.5-1, 2.5-5, and 5-10 units per disk, but when this dose is converted into the dose for humans, it becomes to be about at least 35 units because the volume of human nucleus pulposus is approximately 70 times compared to that of dog nucleus pulposus.
  • chondroitinase ABC was administered into a dog disc in an amount of 0.5-1, 2.5-5, and 5-10 units per disk, but when this dose is converted into the dose for humans, it becomes to be about at least 35 units because the volume of human nucleus pulposus is approximately 70 times compared to that of dog nucleus pulposus.
  • a detailed study of adverse side effects after administration of chondroitinase ABC has not been carried out.
  • chondroitinase ABC is useful as an active ingredient of a medicine for chemonucleolysis, but chondroitinase ABC has not yet been put to practical use because serious adverse side effects caused by the excess dissolution of the nucleus pulposus is also concerned and it is unknown whether or not a reliable therapeutic effect can be exhibited in only a single dose and whether or not there is a dose with no adverse side effects.
  • the problem of the present invention is to provide a therapeutic agent for disc herniation, which has extremely few adverse side effects, can achieve a prolonged pain-ameliorating effect when administered in only a single dose, and can exhibit a high therapeutic effect and high safety in clinical applications.
  • the present invention relates to a therapeutic agent for disc herniation, containing chondroitinase ABC as an active ingredient and being administered into a human disk in an amount of 1-8 units per disk.
  • the present invention relates to a formulation for the treatment of disc herniation, which formulation is used for the administration of chondroitinase ABC into a human disk in an amount of 1-8 units per disk.
  • the present invention relates to a method for treating disc herniation, comprising administering a formulation containing, as an effective dose, 1-8 units of chondroitinase ABC to a patient with disc herniation.
  • the present invention is as follows.
  • a therapeutic agent for disc herniation which is characterized by containing chondroitinase ABC as an active ingredient and being administered in such a manner that the ingredient can be administered into a human disk in an amount of 1-8 units per disk.
  • a method for treating disc herniation comprising administering chondroitinase ABC to a human disk of a patient with disc herniation in an effective amount of 1-8 units per disk.
  • Chondroitinase ABC for use as a therapeutic agent for disc herniation, which is characterized by being used in such a manner that it can be administered into a human disk in an amount of 1-8 units per disk.
  • a therapeutic agent for disc herniation which has fewer adverse side effects, is able to complete the therapy of disc herniation in only a single dose, is safe, has a high therapeutic effect and a high clinical usefulness, and is highly practical.
  • the present invention is intended to clarify for the first time the existence of a dose that is safe and has a high therapeutic effect as well as a clinical usefulness in chemonucleolysis with chondroitinase ABC and also clarify for the first time the limited range of the dose including 1-8 units, preferably 1-5 units, contributing much to a practical use of chemonucleolysis by the administration of chondroitinase ABC.
  • FIG. 1 is a graph showing the transition of leg pain at the worst time (VAS) after administration of a therapeutic agent.
  • FIG. 2 is a graph showing the incidence rate of adverse side effects per administration group of each unit.
  • FIG. 3 is a graph showing the average reduction rate for the disc height per administration group of each unit.
  • Chondroitinase ABC used as an active ingredient for the therapeutic agent of the present invention is not particularly limited as long as it is an enzyme having an action of chondroitinase ABC. Although its origin is also not particularly limited, chondroitinase ABC is preferably derived from microorganisms and preferably derived from Proteus vulgaris.
  • chondroitinase ABC is also not particularly limited, and chondroitinase ABC may be manufactured, for example, by culturing a microorganism such as Proteus vulgaris and the like or by genetic engineering techniques using a DNA encoding the chondroitinase ABC.
  • Chondroitinase ABC as such is preferably an enzyme which is purified to the extent that can be used as a medicine and does not contain any medically unacceptable contaminants.
  • chondroitinase ABC has an enzymatic activity of 270 units/mg protein or more and contains endotoxin, nucleic acid, and protease in amounts not more than the respective detection limits.
  • Such chondroitinase ABC can be obtained by, for example, the method as described in JP 6-153947-A.
  • “1 unit” of chondroitinase ABC is referred to as the amount of enzyme liberating 1 micromole (pi) of unsaturated disaccharide per minute when the enzyme was allowed to react with chondroitin sulfate C as a substrate at pH 8.0 and 37° C.
  • proteoglycan at the targeted site can be appropriately degraded without affecting tissues around the targeted site by administering it to a living body as an injectable pharmaceutical preparation.
  • the enzyme can be a safe and effective medicine.
  • Target disease of the therapeutic agent of the present invention is not limited as long as it is disc herniation, and such a target disease is preferably a lumbar disc herniation, and especially preferably, among these, a lumbar disc herniation occurring in the disc between the fourth lumbar vertebra and the fifth lumbar vertebra, or in the disc between the fifth lumbar vertebra and the first sacrum.
  • the therapeutic agent of the present invention is used to inject into the nucleus pulposus present within the disc where disc herniation occurs.
  • the frequency of the injection is once.
  • Chondroitinase ABC that is the active ingredient of the therapeutic agent of the present invention is administered at a dose of 1-8 units per disk.
  • 1-6 units are preferably administered, 1-5 units are more preferably administered, 1-3 units are more preferably administered, 1-2.5 units or 1.25-3 units are further preferably administered, 1.25-2.5 units are especially preferably administered, and 1.25 units or 2.5 units are most preferably administered.
  • the therapeutic effect is almost the same (see FIG. 1 ), and the incidence rate (%) of adverse side effects is minimal at a dose of 2.5 units (see FIG. 2 ).
  • 1-5 units preferably 1-3 units are required in order to ensure the effective therapeutic effect and safety in only a single dose.
  • the therapeutic agent of the present invention can be provided in a dosage form that is usually employed as an injection.
  • the dosage form may be any of a solution form, a frozen form, and a freeze-dried form.
  • An injection can be prepared by filling this into an appropriate container such as ampoules, vials, syringes for injections, etc. and sealing the container.
  • the container when filling or sealing the therapeutic agent of the present invention in a suitable container, such as ampoules, vials, and syringes for injection, in order to prevent a chemical reaction of the therapeutic agent of the present invention, especially oxidation, the container may be filled or sealed together with an inert gas such as nitrogen gas and rare gas.
  • an inert gas such as nitrogen gas and rare gas.
  • the material of the container such as ampoules, vials, and syringes for injections, which is able to fill and seal the therapeutic agent of the present invention, is not particularly limited as long as it does not affect the therapeutic agent of the present invention and is a pharmaceutically acceptable material.
  • Chondroitinase ABC was produced by culturing Proteus vulgaris and purifying the culture supernatant according to the method described in JP 6-153947-A.
  • chondroitinase ABC The respective enzyme activities of chondroitinase ABC produced were all in the range of 270-480 units/mg protein. In addition, the contents of endotoxin, nucleic acid, and protease in chondroitinase ABC were all equal to or below the detection limit.
  • Polyethylene glycol 3350 10 mg (Note: Polyethylene glycol 3350 corresponds to macrogol 4000 listed in the Japanese Pharmacopoeia.)
  • a freeze-dried injectable formulation containing only the formulation ingredients (not containing chondroitinase ABC) prepared in the same manner was used as a placebo.
  • a ready-to-use solution (4 mL) having the following composition was added to each formulation of (A) to (C) (including a placebo) described above before use, so that the formulations were dissolved to prepare a formulation of 1.25 units/mL for administration, a formulation of 2.5 units/mL for administration, and a formulation of 5 units/mL for administration, respectively.
  • a placebo formulation was prepared in the same manner.
  • the above subjects were divided into each group of a placebo administration group (47 subjects), an administration group of 1.25 units of chondroitinase ABC (49 subjects), an administration group of 2.5 units of chondroitinase ABC (49 subjects) and an administration group of 5 units of chondroitinase ABC (49 subjects), and corresponding formulations as described above were administered respectively.
  • the amount of the enzyme which is to be administered is 1.25 units/mL in the case of the formulation for the administration of 1.25 units, 2.5 units/mL in the case of the formulation for the administration of 2.5 units, and 5 units/mL in the case of the formulation for the administration of 5 units.
  • VAS evaluation the worst leg pain during the past 24-hour period
  • the VAS evaluation by the subject was performed before bedtime. On a 100 mm straight line of “a pain evaluation sheet” in which “no pain” is described on the left end of the straight line and “biggest pain felt in the past” is described on the right end, the degree of pain was marked with a point by the subject oneself.
  • the distance (mm) of from the left end of the same straight line to the point where the subject had marked was measured to evaluate the degree of pain.
  • the results of this evaluation were analyzed by a Dunnett type multiple comparison test using a placebo group as a control.
  • rate of change in pain was evaluated.
  • the rate of change in VAS was determined by obtaining a VAS variation by subtracting the VAS value at 13 weeks after administration of the formulation from the VAS value before administration of the formulation, and dividing the VAS variation by the VAS value before administration of the formulation.
  • a covariance analysis (p ⁇ 0.05) was performed for this VAS variation, using a placebo group as a control.
  • SLR test A straight leg raising test (SLR test) was performed at week 13 after administration of the formulation, in order to examine the nerve stimulation caused by disc herniation.
  • the SLR test is one of the neurological examinations of lumbar disc herniation, and when the lower limbs were stretched, the case where the straight leg raising angle is 70 degrees or less is determined to be “positive” and the case where the straight leg raising angle exceeds 70 degrees is determined to be “negative”. Before administration of the formulation in this study, all subjects were positive.
  • the frequency of the positive and negative cases in the SLR test for each group was summed up, and the ratio of negative cases in the SLR test was examined by a Steel-type multiple comparison using a placebo group as a control.
  • a safety evaluation was carried out in 194 cases of the target subjects.
  • the number of appearance and the incidence rate of adverse side effects were determined. The evaluation was carried out until 13 weeks after administration of the formulation. However, among the adverse side effects, the following items of (a) and (b) were evaluated until 52 weeks after the administration;
  • the safety evaluation of the item (b), such that the vertebral posterior angle of the vertebral body should be equivalent to or more than 5 degrees, is an index related to the instability of the disc, which is established by The U.S. Food and Drug Administration (FDA).
  • the average reduction rate of the disc height in an administration group receiving each unit was determined 13 weeks after the administration of the formulation.
  • FIG. 1 shows transition of the worst leg pain (VAS) after administration of the formulation.
  • VAS worst leg pain
  • the horizontal axis of FIG. 1 shows the time (weeks) after the administration, and the vertical axis shows the value (mm) of VAS.
  • the rhomboid mark ( ⁇ ) in the graph shows the results of the placebo group
  • the black circle mark ( ⁇ ) shows the results of an administration group of 1.25 units of chondroitinase ABC
  • the square mark ( ⁇ ) shows the results of an administration group of 2.5 units of chondroitinase ABC
  • the black triangle mark ( ⁇ ) shows the results of an administration group of 5 units of chondroitinase ABC.
  • a pain-inhibitory effect was observed from the first week in any of the administration groups of the formulations.
  • a significant pain-inhibitory effect (p ⁇ 0.05) was observed from the first week in the administration group of the formulation of 1.25 units of chondroitinase ABC, and the administration group of the formulation of 5 units of chondroitinase ABC, compared to the placebo group.
  • a significant pain-inhibitory effect (p ⁇ 0.01 or p ⁇ 0.001) was shown in all the administration groups, compared to the placebo group.
  • the pain-inhibitory effects are substantially equal in the administration group of 1.25 units, the administration group of 2.5 units, and the administration group of 5 units, and it was shown that such inhibitory effect was effective over a one year (52 weeks). As a result, it was demonstrated that a single administration of the formulation showed a significant pain-inhibitory effect.
  • the rate of change in VAS at week 13 after the administration was 66% in the administration group of 1.25 units of chondroitinase ABC, 61% in the administration group of 2.5 units of chondroitinase ABC, and 69% in the administration group of 5 units of chondroitinase ABC, and a significant reduction in the rate of change in VAS was confirmed in any of the administration groups of the above units, compared to that (45%) of the placebo administration group.
  • the negative rate in the placebo group was about 50%, but the negative rates in the administration groups were all 60% or more.
  • the negative rate in the administration group of 1.25 units of chondroitinase ABC has reached 80% or more.
  • the incidence rate of adverse side effects is shown in FIG. 2 .
  • the horizontal axis in FIG. 2 shows each administration group, and the vertical axis shows the incidence rate (%) of adverse side effects.
  • the incidence rate of adverse side effects in the administration group of 5 units of chondroitinase ABC was 61.2%, 44.9% in the administration group of 2.5 units of chondroitinase ABC, and 46.9% in the administration group of 1.25 units of chondroitinase ABC. From this, it was shown that the minimum value of the incidence rate of adverse side effects was in the vicinity of 2.5 units per disk for the administration group and the presence of a dose being able to cause minimal adverse side effects was clarified.
  • FIG. 3 shows the average reduction rate of the disc height in the administration groups of each unit.
  • the horizontal axis in FIG. 3 shows each administration group, and the vertical axis shows the reduction rate (%) of the disc height.
  • Chondroitinase ABC of 10 units per disk was administered to patients (6 persons) with lumbar disc herniation in the same way as above.
  • (a) the reduction rate in the disc height at week 12 after the administration and (b) the case with the number and incidence rate of vertebral posterior angle of the vertebral body being equivalent to or more than 5 degrees were determined.
  • the reduction rate in the disc height at week 12 after the administration is shown in FIG. 3 .
  • the average reduction rate in the disc height was 45.4% which was significantly greater than the value (30%) that might produce a problem in safety.
  • the results of the vertebral posterior angle of the vertebral body being equivalent to or more than 5 degrees were also shown in Table 1.
  • Table 1 33.3% of the patients who showed the vertebral posterior angle of the vertebral body being equivalent to or more than 5 degrees were observed in the administration group of 10 units of chondroitinase ABC. From these results, it is considered that the administration group of 10 units has a high risk related to the instability of the spine.
  • the volume of the nucleus pulposus in humans and dogs was measured by MRI in order to estimate a dose of chondroitinase ABC effective to humans from the dose of chondroitinase ABC in dogs as described in the Non-Patent Document 4.
  • T2 weighted images were obtained by MRI imaging of the disc between the fourth lumbar vertebra and the fifth lumbar vertebra in 9 healthy volunteers (6 males, 3 females) and resected specimens of dogs (6 animals), and the minor axis, major axis, and area of coronal image of the nucleus pulposus, and the minor axis of sagittal image of the nucleus pulposus were measured.
  • the volume of the nucleus pulposus was calculated (coronal cross-sectional area ⁇ sagittal cross-sectional minor axis). The results are shown in Table 2 below.
  • the incidence rate of showing the vertebral posterior angle of the vertebral body being equivalent to or more than 5 degrees was 33.3% when 10 units of chondroitinase ABC were administered, whereas it was found that such an incidence rate could be significantly reduced to 2% when a half dose, i.e. 5 units were administered.
  • Non-Patent Document 3 describes that when 0.5 unit of chondroitinase ABC per disk was administered into the human disk, a rapid amelioration in leg pain did not occur, indicating that 0.5 unit was a less dose, but detailed studies on the adverse side effects were not performed and the clinically effective dose was unknown.
  • chondroitinase ABC in a range of 1-8 units per disk, preferably 1-5 units per disk in accordance with the present invention, it is possible to reduce the adverse side effects while exhibiting a significant amelioration in pain in only a single dose. Further, it was found that by selecting an administration of chondroitinase ABC in the range of 1-3 units, the adverse side effects could be further reduced while exhibiting a similar effect in ameliorating pain to a higher dose of 5 units.
  • Non-Patent Document 4 describes that even when 0.5-1 unit of chondroitinase ABC per disk was administered into a dog disc, rapid reduction of the nucleus pulposus did not occur, indicating that the dose was too small.
  • Non-Patent Document 6 describes that the setting of scaling is necessary in the analysis of the experimental results in animal models because the behavior of the disc depends on the size of the disc. Then, from the above reference example, it was confirmed that the volume of human nucleus pulposus was 70 times as large as that of dog nucleus pulposus.
  • the dose for humans estimated from the experimental results in dogs as described in the Non-Patent Document 4 is quite different from the dose that was found in the present invention, and it was extremely difficult to predict an effective dose for humans.
  • the present invention can provide a therapeutic agent for disc herniation, which has extremely few adverse side effects, can achieve a prolonged pain-ameliorating effect when administered in only a single dose, and can exhibit a high therapeutic effect and high safety in clinical applications.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Genetics & Genomics (AREA)
  • General Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Neurology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Psychology (AREA)
  • Dermatology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Rheumatology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US13/993,919 2010-12-13 2011-12-13 Therapeutic agent for disc herniation Abandoned US20130266555A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2010277490 2010-12-13
JP2010-277490 2010-12-13
PCT/JP2011/006938 WO2012081227A1 (ja) 2010-12-13 2011-12-13 椎間板ヘルニア治療剤

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2011/006938 A-371-Of-International WO2012081227A1 (ja) 2010-12-13 2011-12-13 椎間板ヘルニア治療剤

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US14/491,792 Division US9463225B2 (en) 2010-12-13 2014-09-19 Therapeutic agent for disc herniation

Publications (1)

Publication Number Publication Date
US20130266555A1 true US20130266555A1 (en) 2013-10-10

Family

ID=46244346

Family Applications (5)

Application Number Title Priority Date Filing Date
US13/993,919 Abandoned US20130266555A1 (en) 2010-12-13 2011-12-13 Therapeutic agent for disc herniation
US14/491,792 Active US9463225B2 (en) 2010-12-13 2014-09-19 Therapeutic agent for disc herniation
US15/260,286 Active 2032-03-04 US10286046B2 (en) 2010-12-13 2016-09-08 Therapeutic agent for disc herniation
US16/368,159 Active 2032-02-05 US11266725B2 (en) 2010-12-13 2019-03-28 Therapeutic agent for disc herniation
US17/589,162 Active 2032-04-02 US11944670B2 (en) 2010-12-13 2022-01-31 Therapeutic agent for disc herniation

Family Applications After (4)

Application Number Title Priority Date Filing Date
US14/491,792 Active US9463225B2 (en) 2010-12-13 2014-09-19 Therapeutic agent for disc herniation
US15/260,286 Active 2032-03-04 US10286046B2 (en) 2010-12-13 2016-09-08 Therapeutic agent for disc herniation
US16/368,159 Active 2032-02-05 US11266725B2 (en) 2010-12-13 2019-03-28 Therapeutic agent for disc herniation
US17/589,162 Active 2032-04-02 US11944670B2 (en) 2010-12-13 2022-01-31 Therapeutic agent for disc herniation

Country Status (16)

Country Link
US (5) US20130266555A1 (ru)
EP (1) EP2653168B1 (ru)
JP (1) JP5465791B2 (ru)
KR (2) KR101692517B1 (ru)
CN (5) CN110101852A (ru)
BR (1) BR112013014584B1 (ru)
CA (1) CA2821244C (ru)
DK (1) DK2653168T3 (ru)
ES (1) ES2536982T3 (ru)
HK (1) HK1190073A1 (ru)
PL (1) PL2653168T3 (ru)
PT (1) PT2653168E (ru)
RU (2) RU2690185C2 (ru)
TW (1) TWI488641B (ru)
WO (1) WO2012081227A1 (ru)
ZA (1) ZA201304924B (ru)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109415714A (zh) * 2016-04-29 2019-03-01 艾诺奥医药品有限公司 体内使用软骨素酶和/或透明质酸酶以增强药剂的递送
US11266725B2 (en) 2010-12-13 2022-03-08 Seikagaku Corporation Therapeutic agent for disc herniation
US11648299B2 (en) 2018-02-28 2023-05-16 Seikagaku Corporation Pharmaceutical composition, package and method for producing the same

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190111178A1 (en) * 2016-04-04 2019-04-18 Gu Ventures Ab Methods and compositions for the treatment of intervertebral disc herniation
US9796970B1 (en) 2017-04-24 2017-10-24 Advantek Serum Laboratories Ltd. Production of high purity chondroitinase ABC
TW201940190A (zh) 2018-02-28 2019-10-16 日商生化學工業股份有限公司 包裝體及其製造方法
KR102270354B1 (ko) * 2018-10-08 2021-06-30 한국과학기술연구원 단결정 이종 2차원 물질의 애피택셜 성장 방법 및 적층 구조체
JP2022151423A (ja) * 2021-03-25 2022-10-07 均 石井 椎間板ヘルニア治療薬。

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6007810A (en) * 1997-05-02 1999-12-28 Seikagaku Corporation Chondroitinase compositions
DE10308885A1 (de) * 2003-02-28 2004-09-23 Syha, Klaus, Dr. Verwendung glycosidasehaltiger Lösungen zur Behandlung von neuronalen Zellen
US20080145352A1 (en) * 2006-10-06 2008-06-19 Henrich Cheng Method for promoting axonal re-growth and behavior recovery in spinal cord injury
WO2009128446A1 (ja) * 2008-04-14 2009-10-22 国立大学法人名古屋大学 神経因性疼痛の改善剤

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4696816A (en) * 1985-11-07 1987-09-29 Brown Mark D Method for treating intervertebral disc displacement with enzymes
US5496718A (en) 1992-06-26 1996-03-05 Seikagaku Kogyo Kabushiki Kaisha (Seikagaku Corporation) Chondroitinase ABC isolated from proteus vulgaris ATCC 6896
JP3980657B2 (ja) 1992-06-26 2007-09-26 生化学工業株式会社 コンドロイチナーゼａｂｃ、その製造法及び医薬組成物
US6063378A (en) 1997-08-22 2000-05-16 Seikagaku Corporation Therapeutic agent for herniated intervertebral disc
JPH11193245A (ja) * 1997-12-26 1999-07-21 Seikagaku Kogyo Co Ltd コンドロイチナーゼａｂｃ組成物
ES2478257T3 (es) * 1998-10-06 2014-07-21 Stryker Corporation Composición que comprende una proteína osteogénica seleccionada del grupo que consiste en OP-2, OP-3, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-9, BMP-10, BMP-11 , BMP-15, BMP-3B, DPP, Vg-1, Vgr-1, proteína 60A, GDF-1, GDF-2, GDF-3, GDF-6, GDF-7, GDF-8, GDF-9, GDF-10, y GDF-11 para su uso en la reparación de defectos del cartílago no articular
JP3865364B2 (ja) * 2000-10-10 2007-01-10 生化学工業株式会社 コンドロイチナーゼ画分
JP4439396B2 (ja) * 2002-06-24 2010-03-24 田辺三菱製薬株式会社 神経系細胞の製造方法
EP2185165B1 (en) * 2007-08-06 2018-10-03 Mesoblast, Inc. STRO-1bright CELLS FOR USE IN TREATING CONNECTIVE TISSUE DISEASES
CN101406695A (zh) * 2007-10-08 2009-04-15 郑宏志 促进脊髓损伤中轴突再生和行为功能恢复的药物组合物
CA2821244C (en) 2010-12-13 2016-08-09 Seikagaku Corporation Chondroitinase abc for disk herniation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6007810A (en) * 1997-05-02 1999-12-28 Seikagaku Corporation Chondroitinase compositions
DE10308885A1 (de) * 2003-02-28 2004-09-23 Syha, Klaus, Dr. Verwendung glycosidasehaltiger Lösungen zur Behandlung von neuronalen Zellen
US20080145352A1 (en) * 2006-10-06 2008-06-19 Henrich Cheng Method for promoting axonal re-growth and behavior recovery in spinal cord injury
WO2009128446A1 (ja) * 2008-04-14 2009-10-22 国立大学法人名古屋大学 神経因性疼痛の改善剤

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AMS Biotechnology, "High Purity Reagents for Glycobiology & Glycoanalysis", 2008 Product & Services Catalog; AMS Biotechnology Ltd.: Oxon, UK. *
Manchikanti et al. "Comprehensive Review of Therapeutic Interventions in Managing Chronic Spinal Pain", Pain Physician 2009, Vol. 12, pages E123-E198. *
Tester, N.J. and Howland, D.R., "Chondroitinase ABC improves basic and skilled locomotion in spinal cord injured cats", Experimental Neurology 2008, Vol. 209, pages 483-496. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11266725B2 (en) 2010-12-13 2022-03-08 Seikagaku Corporation Therapeutic agent for disc herniation
US11944670B2 (en) 2010-12-13 2024-04-02 Seikagaku Corporation Therapeutic agent for disc herniation
CN109415714A (zh) * 2016-04-29 2019-03-01 艾诺奥医药品有限公司 体内使用软骨素酶和/或透明质酸酶以增强药剂的递送
US11648299B2 (en) 2018-02-28 2023-05-16 Seikagaku Corporation Pharmaceutical composition, package and method for producing the same

Also Published As

Publication number Publication date
US9463225B2 (en) 2016-10-11
JP5465791B2 (ja) 2014-04-09
US20170000863A1 (en) 2017-01-05
RU2015135843A3 (ru) 2019-03-26
PT2653168E (pt) 2015-04-01
WO2012081227A1 (ja) 2012-06-21
RU2015135843A (ru) 2018-12-25
US20190224289A1 (en) 2019-07-25
CN106975077A (zh) 2017-07-25
KR101692517B1 (ko) 2017-01-03
DK2653168T3 (da) 2015-04-20
US20150071896A1 (en) 2015-03-12
RU2564001C2 (ru) 2015-09-27
CN110101852A (zh) 2019-08-09
JPWO2012081227A1 (ja) 2014-05-22
CN103260636A (zh) 2013-08-21
RU2019116210A (ru) 2020-11-27
EP2653168A4 (en) 2014-06-25
US11266725B2 (en) 2022-03-08
CN111265472A (zh) 2020-06-12
TW201306860A (zh) 2013-02-16
ZA201304924B (en) 2014-09-25
HK1190073A1 (en) 2014-06-27
ES2536982T3 (es) 2015-06-01
EP2653168B1 (en) 2015-03-04
BR112013014584B1 (pt) 2020-12-01
EP2653168A1 (en) 2013-10-23
PL2653168T3 (pl) 2015-07-31
TWI488641B (zh) 2015-06-21
BR112013014584A2 (pt) 2016-09-20
CA2821244A1 (en) 2012-06-21
CN111420040A (zh) 2020-07-17
RU2013132566A (ru) 2015-01-20
US10286046B2 (en) 2019-05-14
CA2821244C (en) 2016-08-09
RU2690185C2 (ru) 2019-05-31
KR20170004032A (ko) 2017-01-10
KR20130139284A (ko) 2013-12-20
US20220160845A1 (en) 2022-05-26
US11944670B2 (en) 2024-04-02

Similar Documents

Publication Publication Date Title
US11944670B2 (en) Therapeutic agent for disc herniation
TWI234462B (en) Methods for treating pain
Toda Operative treatment of trigeminal neuralgia: review of current techniques
RU2733464C2 (ru) Препараты tpp1 и способы лечения заболевания cln2
EP1846022B1 (en) Methods for treating adhesive capsulitis
Chun-jing et al. The application of percutaneous lysis of epidural adhesions in patients with failed back surgery syndrome
Banno et al. Disc degeneration could be recovered after chemonucleolysis with condoliase.-1 year clinical outcome of condoliase therapy
Meadeb et al. Forceful sacrococcygeal injections in the treatment of postdiscectomy sciaticaA controlled study versus glucocorticoid injections
Banno et al. Condoliase therapy for lumbar disc herniation-2 year clinical outcome
RU2796540C2 (ru) Терапевтическое средство от грыжи межпозвоночного диска
Rodríguez-López et al. Multicenter clinical trial of epidural orgotein versus placebo in patients with chronic intractable spinal pain
Hedaoo Transforaminal epidural steroid injection in treatment of Sciatica: an outcome analysis
Graham BACK ACHE AND SCIATICA: A REPORT OF 90 PATIENTS TREATED BY INTRADISCAL INJECTION OF CHYMOPAPAIN (DISCASE)
Ingle et al. A Comparative study to evaluate the effectiveness of lumbar epidural local anaesthetic injection with or without corticosteroid in managing chronic low back pain
Zendejas et al. Botulinum Toxin Use in Complex Abdominal Wall Hernias
Ashrey et al. Epidural injection of methylprednisolone with levobupivacaine under CT guidance improve radicular pain in herniated disc versus spinal stenosis.
JPH11193245A (ja) コンドロイチナーゼａｂｃ組成物
Samoladas et al. Current Pharmaceutical & Clinical Research
Vles et al. Research article Percutaneous radiofrequency lesions adjacent to the dorsal root ganglion alleviate spasticity and pain in children with cerebral palsy: pilot study in 17 patients

Legal Events

Date Code Title Description
AS Assignment

Owner name: SEIKAGAKU CORPORATION, JAPAN

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SIROGANE, TAIICHI;MURAYAMA, TAKAO;YAGUCHI, MASAFUMI;REEL/FRAME:030607/0698

Effective date: 20130328

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION