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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • 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
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
• • 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
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P23/00—Anaesthetics
• • 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
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • 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
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • 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
  • A61P25/08—Antiepileptics; Anticonvulsants
• • 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
  • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

• RTX Resiniferatoxin
• the invention relates to the use of Resiniferatoxin (RTX) for the preparation of an agent for the treatment of joint pain according to the preamble of patent claim 1 and a method for applying this agent in the intracapsular space or in the joint lubricating bag of joints according to the preamble of claim 22 ,
• RTX Resiniferatoxin
• an analgesic substance for example, local anesthetics or morphine
• US Pat. No. 4,997,853 BERNSTEIN also discloses the use of capsaicin together with a superficial local anesthetic for the treatment of superficial pain syndromes.
• capsaicins without local anesthetics is known to be systemic (intraperitoneal, subcutaneous, intravenous, etc.) or regional (epidural, intrathecal, transcutaneous or regional selective nerve block), but always in combination with general anesthesia of the experimental animals.
• systemic intraperitoneal, subcutaneous, intravenous, etc.
• regional epidural, intrathecal, transcutaneous or regional selective nerve block
• the main disadvantage of a regional or systemic application is that not only the affected area is treated, but also asymptomatic, adjacent areas.
• capsaicins in the bladder is also known without local anesthetics, but here the agent is applied only superficially and not injected through a skin barrier.
• the invention aims to remedy this situation. It is an object of the present invention to provide a means for the treatment of joint pain according to the preamble of claim 1 and a method of inhibiting said agent which permanently damage the nerve endings responsible for nociception for prolonged analgesia, without removing the joints Endanger structures.
• RTX preferably at a specific concentration
• the same or better effect was surprisingly achieved than when using general anesthesia.
• RTX Resiniferatoxin
• RTX Resiniferatoxin
• a further surprising advantage of using without local or general anesthesia is that the injection gives a pleasant warm feeling, which decisively supports the fight against pain. In this way, a pain relief is achieved, which far exceeds that when combined with local anesthetics. This can also be explained by the antagonistic effect that the local anesthetics have on the vanilloid receptor agonists because they partially block the desired neurotoxic effect of vanilloids.
• the method according to the invention comprises locally injecting Resiniferatoxin (RTX) into a painful or diseased joint of the body in humans or animals.
• RTX Resiniferatoxin
• the RTX can either be left there or can be completely or partially withdrawn after a certain exposure time.
• the RTX now diffuses to the sensory nerve endings, which directly or indirectly innervate the area of the joint, inhibiting or damaging them predominantly and thus leads to a reduced perception of joint pain.
• the joint capsule or synovial bag is used to concentrate the effect of the RTX on the site of pain and thereby locally allow a higher concentration of RTX than without the protective joint capsule or synovial bag in the same Concentration and tolerability would be possible and at the same time to protect the vascular / nerve structures and other structures in the vicinity of the joint relatively.
• This method can be used both preventatively or therapeutically.
• RTX intra-articular injection of RTX for the analgesic therapy of joints leads to an extensive protection of the capsular ligament structures, the synovial and the cartilage bone structures and thus to maintain the physiological conditions.
• RTX does not depend on specific neuronal epitopes other than the TRPV1 receptor.
• the procedure can be performed with a thin, non-arthroscopic needle.
• the method results in local sensory denervation, i. an elimination of painful nerves.
• the use of Resiniferatoxin (RTX) - without the addition of other pharmacologically active substances - refers to the preparation of an agent for the treatment of local pain, in particular a) local wound pain after surgery in the form of a rinse solution for intraoperative use in a open or arthroscopic or endoscopic surgery or liposuction; b) Local treatment of joint pain by intraarticular injection
• Bone application eg after iliac crest osteotomy hallux-valgus correction d) treatment of bone pain by injection into the bone, especially in femoral head necrosis in the femoral head, in the vertebral body in osteochondrosis e) Local treatment of joint stiffness, especially in arthrofibrosis or frozen shoulder; e) Local treatment of muscle pain, by intramuscular injection, especially in torn muscle, soreness, or spasticity; f) Local injection into the painful meniscus at meniscal degeneration or meniscal tear; g) treatment of back pain by injection into the disc in case of disc degeneration or disc tear; h) injection around a painful nerve, especially in trigeminal neuralgia,
• RTX Resiniferatoxin
• Neuropathic joint pain Local treatment of bone pain after bone surgery by application to the bone, e.g. to
• Hallux valgus correction Treatment of bone pain by injection into the bone e.g. in femoral head necrosis into the femoral head in the vertebral body in osteochondrosis
• RTX concentration of RTX is expediently between 100 nM to 10 ⁇ M, preferably between 50OnM to 1 ⁇ M.
• the agent preferably contains no alcohol, especially no ethanol.
• Ethanol has the disadvantage that it causes a local inflammation and can lead to a painful neuritis.
• X-ray contrast agent preferably gadolinium-containing, iodine-containing or barium-containing
• Substances e.g. a barium supplement or an MRI contrast agent is used, so that an imaging control of the distribution of RTX in the intracapsular space is possible.
• a contrast agent e.g. a barium supplement or an MRI contrast agent is used, so that an imaging control of the distribution of RTX in the intracapsular space is possible.
• the following substances can be used as contrast agents:
• X-ray, CT iodine-containing substances, e.g. triiodinated benzoates or lopamidol, ideally 30 - 80g / 100ml or z.
• B 5-10% of another contrast agent, e.g. Barium.
• MRI e.g. Gadolinium, e.g. per 1 ml: 469.01 g Gadopentate dimeglumide,
• an antibiotic, disinfecting and / or sterilizing substance is added.
• a viscous additive e.g. Hyaluronic acid, preferably used at a concentration of 0.1-10.0 mg / ml solution for injection, which leads to a mechanical Gleitvertropicung of the joint.
• a vasoconstrictor in addition to RTX, is used, preferably preferably adrenaline, norepinephrine, phenylephrine or ornipressin, or other similar, preferably alpha-adrenergic vasoconstrictors.
• adrenaline the total dose of the neurotoxin (ie toxic for the peripheral nervous system) can be increased by a factor of about 2, as it reduces the systemic effect of decreased absorption.
• the adrenaline concentration can be 1:10 1 000 to 1: 80,000 to 1: 200,000.
• the Total adrenaline dose is ⁇ 0.25 mg.
• a 50 ml solution of 1: 200'000 epinephrine contains 0.25 mg adrenaline.
• glycerol is used as solvent in addition to RTX.
• Glycerol also has neurotoxic properties (but especially if injected intraneurally).
• glycerine has a lubricity for the joint, so that a physical effect occurs.
• the concentration of glycerol is preferably between 10 and 95%.
• water, saline, sodium bihalamate, lophendylate, ricin, poly-ethylene glycol or propylene glycol may also be used.
• the advantage of glycerol as a solvent is that it is hyperbaric and in itself a bit neurotoxic.
• a steroid in addition to the RTX, is used in order to control it in the event of an inflammatory reaction.
• it can be used to add a more causal treatment for painful, inflammatory joint disease that supports symptomatic neuroprolytic therapy.
• Betamethasone has proven to be particularly suitable; e.g. 5 mg betamethasone as diproprionate (crystalline suspension) and 2 mg betamethasone as disodium phosphate (solution in 1 ml, may be added to the total amount to be injected). This solution is equivalent to 45/23 mg prednisone / prednisolone.
• the agent is preferably used for denervation or neurolysis in degeneratively diseased joints.
• the agent may be dissolved in a carrier liquid, a pharmacologically acceptable vehicle, especially from the group consisting of sodium chloride injection solution, Ringier's injection solution, isotonic dextrose, sterile dextrose solution, Lactated Ringer's solution for injection, distilled water or mixtures thereof for local injection.
• the agent may additionally comprise a permeation enhancer, preferably dimethyl sulfoxide, ethoxyethylene diglycol, ethanol, phosphatidyl choline, propylene glycol! dipelargonate (DPPG), or glycosylated glyoxylated glycerides.
• the agent can also contain a substance which allows a delayed and prolonged release of the RTX, preferably glucosaminoglycans or hyaluronic acid.
• a pH varied at the site of action is produced, preferably by mixing RTX with a suitable buffered medium. If the pH is shifted, an altered profile of action can be generated. At a pH less than 7.4 the effect of RTX is enhanced, at a pH greater than 7.4 the painfulness of the injection is markedly reduced.
• the agent is conveniently dissolved in a buffer solution having a pH higher than 7.6, preferably higher than 8.5.
• the agent may be dissolved in a buffer solution having a pH lower than 7.2, preferably lower than 6.5.
• the pH is first set at application or injection higher than 7.4 and then decreases, preferably within minutes to hours below 7.4.
• suitable buffer media e.g. Powder or as implants such as bone substitute material
• the pH is first set at application or injection higher than 7.4 and then decreases, preferably within minutes to hours below 7.4.
• the solution medium water, saline, Sodiumiothalamate, lophendylat, ricin, poly-ethylene glycol or propylene glycol can be used instead of glycerol.
• glycerol as a solvent is that it is hyperbaric and in itself a bit neurotoxic.
• RTX calcium Ca 2+ or comparable ions in a concentration higher than physiologically present, used in the solvent and released simultaneously or delayed.
• Calcium is necessary for the action of RTX and enhances its effect when present in hyperphysiological concentration.
• the concentration of calcium is preferably> 2 ⁇ mol, in particular> 4 ⁇ mol.
• Some substances have also been shown to potentiate RTX activity, such as magnesium, antioxidants, preservatives and excipients, especially sodium bisulfite (> 0.2%), NaHSOs, Ammonium compounds, such as ammonium sulfate (NH 4 ) 2 SO 4, 2-10 (-30%), Polysorbate 80 (PS80) 0.025 mg / ml.
• the salts and ions dissolved in the solution medium are preferably concentrated higher than physiologically normal (e.g., in Ringer's lactate solution).
• RTX is preferably dissolved in a biocompatible solvent and is conveniently injected in an amount that corresponds to the available space in the joint to be treated, so that it fills up slightly bulging. This achieves the advantage of an optimal local distribution of RTX. But it is also possible to inject less fluid, but then the joint must be well moved for better distribution of the substance combination.
• the volume of fluid to be injected into the intracapsular area may be from 0.1 to 150 ml.
• max. 1 ml for the shoulder joint max. 10 ml, for the knee joint max. about 30-50 ml, but preferably not more than 2ml.
• the dosage of the substance combination depends on the localization and indication.
• the dosage of the RTX depends on its absolute solubility in the chosen solvent medium. A significant influence on the dosage has the capsule thickness of the affected joint. The thicker the capsule, the higher the concentration or amount of RTX needed.
• the method for treating pain with the composition used in the invention is that Resiniferatoxin (RTX) is dissolved in a suitable biocompatible solvent and preferably a liquid volume of 0.1 to 150 ml thereof a) is injected locally into the pain-infested tissue structure of the patient or b) b) is locally dropped on the surgical wound; or c) locally injected into the intracapsular area; or locally injected into the synovial bag of a joint affected by pain.
• RTX Resiniferatoxin
• the nociceptive nerve fibers become insensitive to pain by the Resiniferatoxin (RTX) for at least 14 days, preferably at least 8 weeks made.
• Resiniferatoxin (RTX) is advantageously used in such a concentration that neurolysis occurs.
• concentration of RTX is conveniently between about 10 nanomolar (nM) to 100 microMolar ( ⁇ M).
• Neuropathic joint pain Local treatment of bone pain after bone surgery by application to the bone, e.g. after iliac crest osteotomy or hallux valgus
• the advantage of this method is that it allows for local application without local anesthetics, which allows a lower RTX concentration and thus less local side effects of RTX such as swelling or inflammation occur.
• the agent is injected into a synovial cavity which is not lined with urothelium. Injection into a synovial cavity has proven to be particularly advantageous because it provides an optimal residence time for effect delivery combined with minimal side effects such as inflammation or pain.
• the therapist placed a syringe needle into the joint space of a knee joint under facultative, simultaneous (image converter, CT, sonography, MRI, arthroscopy, etc.) or subsequent (radiographic, CT, MRI, sonography, etc.) bifddressder control and injected 20 ml of a solution of 50OnM (about 0.006mg) of Resiniferatoxin in the intracapsular space.
• 50OnM about 0.006mg
• the injected solution was similar to that of Example 1, except that 5 ml of a visible contrast agent (lopamidol at a concentration of 50 g / 100 ml) was added for the imaging procedure to be used, which spread within the joint capsule after injection and so on Location of the hypodermic needle and the distribution of RTX within the capsule documented.
• the RTX containing injected solution was resuspended immediately after injection. But it could also be withdrawn after a defined substance-dependent exposure time or not at all. The patient already felt significant relief of his symptoms 15 hours after the procedure. This lasted for over 8 months.
• the therapist inserted a thin infusion catheter into the affected joint, analogous to an epidural catheter, and injected with a perfusor a solution of 1 liter of 10Nm resiniferatoxin into the affected joint at a rate of 1-10 ml / h for 12 hours.
• a drain catheter with an optional defined drainage resistance (e.g., 20 mm Hg) to achieve fluid turnover.
• the therapist achieved a uniform infiltration of the painful joint, without large concentration peaks.
• the exposure time could be better defined.
• the therapist After implantation of a knee joint prosthesis, the therapist injected 50 ml of a solution of 10OnM (about 0.001 mg) of resiniferatoxin into the resealed joint capsule. This minimized postoperative pain.
• the therapist After implantation of a hip joint prosthesis, the therapist injected 50 ml of a solution of 10OnM (about 0.001 mg) resiniferatoxin into the periprosthetic area without capsule. This minimized postoperative pain.
• the therapist placed a syringe needle into the joint space of a knee joint under facultative, simultaneous (image converter, CT, sonography, MRI, arthroscopy etc.) or subsequent (X-ray, CT, MRI, sonography, etc.) imaging imaging and injected 9 ml of a solution of 50 nM (about 0.003 mg) of Resiniferatoxin buffered to pH 6.5 with a buffer together with saline in the intracapsular space.
• the patient felt noticeable relief of his symptoms already minutes after the procedure. This lasted for over 6 months.
• the therapist placed a syringe needle into the joint space of a knee joint under facultative, simultaneous (image converter, CT, sonography, MRI, arthroscopy etc.) or subsequent (X-ray, CT, MRI, sonography, etc.) imaging imaging and injected 9 ml of a solution of 50 nM (about 0.003 mg) of resiniferatoxin in physiological Ringer's solution containing 10 mM Ca 2+ in the intracapsular space.
• the patient felt a few minutes after the procedure significant relief of his symptoms. This lasted for over 6 months.

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• 2004
  • 2004-12-28 PL PL04802396T patent/PL1838301T3/pl unknown
  • 2004-12-28 ES ES04802396.4T patent/ES2533256T3/es not_active Expired - Lifetime
  • 2004-12-28 US US11/722,779 patent/US20080139641A1/en not_active Abandoned
  • 2004-12-28 WO PCT/CH2004/000756 patent/WO2006069451A1/de not_active Ceased
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