US20050019436A1 - Injectable capsaicin - Google Patents

Injectable capsaicin Download PDF

Info

Publication number
US20050019436A1
US20050019436A1 US10/742,621 US74262103A US2005019436A1 US 20050019436 A1 US20050019436 A1 US 20050019436A1 US 74262103 A US74262103 A US 74262103A US 2005019436 A1 US2005019436 A1 US 2005019436A1
Authority
US
United States
Prior art keywords
pain
capsaicin
dose
capsaicinoid
site
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
US10/742,621
Other languages
English (en)
Inventor
Ronald Burch
Richard Carter
Jeff Lazar
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.)
SOFINNOVA VENTURE PARTNERS VII LP
Anesiva Inc
Original Assignee
AlgoRx Pharmaceuticals Inc
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=32685309&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20050019436(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to US10/742,621 priority Critical patent/US20050019436A1/en
Application filed by AlgoRx Pharmaceuticals Inc filed Critical AlgoRx Pharmaceuticals Inc
Assigned to ALGORX PHARMACEUTICALS, INC. reassignment ALGORX PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BURCH, RONALD M., CARTER, RICHARD B., LAZAR, JEFFREY D.
Publication of US20050019436A1 publication Critical patent/US20050019436A1/en
Priority to US11/499,995 priority patent/US8420600B2/en
Priority to US12/077,494 priority patent/US20080260791A1/en
Assigned to ARCION THERAPEUTICS, INC. reassignment ARCION THERAPEUTICS, INC. SECURITY AGREEMENT Assignors: ALGORX PHARMACEUTICALS, INC.
Assigned to SOFINNOVA VENTURE PARTNERS, VII, L.P. reassignment SOFINNOVA VENTURE PARTNERS, VII, L.P. PATENT COLLATERAL AGENT ASSIGNMENT Assignors: CMEA VENTURES VII, L.P.
Priority to US13/862,260 priority patent/US20130303620A1/en
Priority to US15/363,475 priority patent/US20170266139A1/en
Priority to US16/737,557 priority patent/US20200375926A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/81—Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local 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
    • 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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • 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

  • This application is directed to compositions and methods for relieving pain at a specific site, for example, associated with inflammation of joints, tendons, nerves, muscle, and other soft tissues, nerve injury and neuropathies, and pain from tumors in soft tissues or bone.
  • Capsaicin a pungent substance derived from the plants of the solanaceae family (hot chili peppers) has long been used as an experimental tool because of its selective action on the small diameter afferent nerve fibers C-fibers and A-delta fibers that are believed to signal pain. From studies in animals, capsaicin appears to trigger C-fiber membrane depolarization by opening cation channels permeable to calcium and sodium. Recently one of the receptors for capsaicin effects has been cloned. Capsaicin can be readily obtained by ethanol extraction of the fruit of capsicum frutescens or capsicum annum.
  • Capsaicin is known by the chemical name N-(4-hydroxy-3-methoxybenzyl)-8-methylnon-trans-6-enamide. Capsaicin is practically insoluble in water, but freely soluble in alcohol, ether, benzene and chloroform. Therapeutically capsaicin has been used as a topical analgesic. Capsaicin is available commercially as Capsaicin USP from Steve Weiss & Co., 315 East 68 th Street, New York, N.Y. 10021 and can also be prepared synthetically by published methods.
  • Capsaicin is listed in the pharmacopoeias of the United Kingdom, Australia, Belgium, Egypt, Germany, Hungary, Italy, Japan, Tru, Portugal, Spain, and Switzerland and has previously been listed in the United States Pharmacopoeia and the National Formulary.
  • the FDA proposed monographs on analgesic drug products for over-the-counter (OTC) human use. These include capsaicin and capsicum preparations that are regarded as safe and effective for use as OTC external analgesics.
  • Capsaicin is the only chemical entity of Capsicum recognized by the FDA.
  • Capsaicin (USP) contains not less than 110% total capsaicinoids which typically corresponds to 63% pure capsaicin. USP capsaicin is trans-capsaicin (55-60%) and also contains the precursors dihydrocapsaicin and nordihydrocapsaicin.
  • Capsaicin mediated effects include: (i) activation of nociceptors in peripheral tissues; (ii) eventual desensitization of peripheral nociceptors to one or more stimulus modalities; (iii) cellular degeneration of sensitive A-delta and C-fiber afferents; (iv) activation of neuronal proteases; (v) blockage of axonal transport; and (vi) the decrease of the absolute number of nociceptive fibers without affecting the number of non-nociceptive fibers.
  • capsaicin containing creams Zostrix, Zostrix-HP, and Axsain. These products have been examined in a broad spectrum of painful conditions including osteoarthritis. However the efficacy of topically administered capsaicin in arthritis in general has proven to be limited.
  • Pat. No. 5,665,378 (Davis, et al.) describes transdermal therapeutic formulations comprising capsaicin, a nonsteroidal anti-inflammatory agent and pamabrom for the treatment of pain.
  • U.S. Pat. No. 6,248,788 (Robbins, et al.) describes administration of 7.5% capsaicin cream in combination with marcaine epidural injections in patients suffering from long-term persistent foot pain.
  • U.S. Pat. No. 6,239,180 (Robbins) describes combining capsaicin loaded patches with local anesthesia to treat peripheral neuropathy.
  • topical capsaicin has also been described in the art to treat conditions as diverse as post mastectomy pain syndrome (Watson and Evans, Pain 51: 375-79 (1992)); painful diabetic neuropathy (Tandan et al., Diabetes Care 15: 8-13 (1992)); The Capsaicin Study Group, Arch Intern Med 151: 2225-9(1991); post-herpetic neuralgia (Watson et al., Pain 33: 333-40 (1988)), Watson et al., Clin. Ther. 15: 510-26 (1993); Bernstein et al., J.
  • capsaicin Because of the ability of capsaicin to desensitize nociceptors in peripheral tissues, its potential analgesic effects have also been assessed in various clinical trials. However, since the application of capsaicin itself frequently causes burning pain and hyperalgesia apart from the neuropathic pain being treated, patient compliance has been poor and the drop out rates during clinical trials have exceeded fifty percent. The spontaneous burning pain and hyperalgesia are believed to be due to intense activation and temporary sensitization of the peripheral nociceptors at the site of capsaicin application. This activation and sensitization occur prior to the desensitization phase. The activation phase could be a barrier to use of capsaicin because of the pain produced.
  • compositions including capsaicin or capsaicin analogues thereof with effective concentrations to cause an analgesic effect without the side effects normally associated with the use of capsaicin.
  • a method for attenuating or relieving pain at a site in a human or animal in need thereof comprising administering via injection or implantation at a discrete site in a human or animal in need thereof a dose of capsaicin in an amount effective to denervate the discrete site without eliciting an effect outside the discrete location and to attenuate pain emanating from said site, the dose ranging from about 1 ⁇ g to about 5,000 ⁇ g capsaicin or a therapeutically equivalent dose of a capsaicinoid other than capsaicin.
  • capsaicinoid is meant to encompass formulations where the drug is capsaicin, a capsaicinoid other than capsaicin, or a mixture of capsaicin with one or more other capsaicinoids (the total amount of all capsaicinoid drug being based on a therapeutically equivalent dose to dose from about 1 ⁇ g to about 5,000 ⁇ g capsaicin).
  • the dose of capsaicinoid contained in a unit dose injection/implantation is from about 1 ⁇ g to about 5000 ⁇ g of capsaicin, preferably from about 10 ⁇ g to about 3000 ⁇ g capsaicin, more preferably from about 300 ⁇ g to about 1500 ⁇ g capsaicin, or a therapeutically equivalent amount of one or more capsaicinoids.
  • the dose of capsaicin is from about 400 ⁇ g to about 1200 ⁇ g, or a therapeutically equivalent amount of one or more capsaicinoids.
  • the dose of capsaicin is preferably from about 10 ⁇ g to about 1000 ⁇ g, more preferably from about 20 ⁇ g to about 300 ⁇ g, and most preferably from about 35 ⁇ g to about 200 ⁇ g.
  • the capsaicinoid is administered in a pharmaceutically and physiologically acceptable vehicle for injection or implantation, which may optionally further include one or more additional pharmaceutical excipients.
  • the dose of capsacinoid may be injected or implanted subcutaneously, intramuscularly, itrathecally, epidurally, intraperitoneally, caudally intradermally or intracutaneously, intercostally at a single nerve, intra-articularly, intrasynovially, intraspinally, intra-arterially or into body spaces.
  • Intra-articular administration of the formulations of the invention may be, e.g., into a joint selected from the group consisting of knee, elbow, hip, sternoclavicular, temporomandibular, carpal, tarsal, wrist, ankle, intervertebral disk, ligamentum flavum and any other joint subject to pain.
  • a local anesthetic may be administered prior to or concurrently with said dose of capsaicinoid in an amount and location effective to attenuate an initial hyperalgesic effect of the administered dose of capsaicinoid.
  • the local anesthetic may be administered, e.g., by direct injection into the site where said dose of capsaicinoid is administered, or as a proximal, regional, somatic, or neuraxial block. General anesthesia may be used, if necessary.
  • the administration of capsaicinoid at the discrete site provides pain attenuation or pain relief for at least about 48 hours to about 16 weeks.
  • the invention is further directed in part to a method of treating acute traumatic pain associated with an injury, comprising injecting a capsaicinoid in a physiologically compatible vehicle through the skin of a patient in proximity to an injury, said dose of capsaicinoid being sufficient to attenuate the dull, aching pain associated with C-fibers in proximity to the injury and such that the patient continues to have sensation in proximity to the injury and without affecting sharp protective pain associated with A-delta fibers in proximity to the site, the dose of capsaicinoid being therapeutically equivalent to a dose of capsaicin in an amount from about 300 to about 1500 ⁇ g and being effective to attenuate dull, aching pain in proximity to the injury for at least about 48 hours.
  • the capsaicinoid is capsaicin itself. In more preferred embodiments, the capsaicinoid comprises trans-capsaicin. In most preferred embodiments, the capsaicinoid is at least about 97% trans-capsaicin.
  • the single injectable or implantable dose of a capsaicinoid administered at a discrete painful site in accordance with the present invention is preferably in an amount effective to a) produce a selective, highly-localized destruction or incapacitation of C-fibers and/or A-delta fibers in a discrete, localized area responsible for the initiation of pain for the purpose of reducing or eliminating pain arising from a discrete locus, and b) minimize potential adverse consequences of C-fiber and/or A-delta activation and or damage outside of the locus of pain.
  • the present invention is also directed to an injectable or implantable pharmaceutical composition for attenuating pain at a site in a human or animal in need thereof, consisting essentially of from 1 ⁇ g to 5000 ⁇ g of a capsaicinoid comprising trans-capsaicin and a pharmaceutically acceptable vehicle for injection or implantation.
  • the dose of trans-capsaicin ranges from about 10 ⁇ g to about 3000 ⁇ g, from about 300 ⁇ g to about 1500 ⁇ g, or preferably from about 400 ⁇ g to about 1200 ⁇ g.
  • injection shall mean administration of capsaicin to a discrete site through the skin of a human or animal.
  • implantation shall mean administration of capsaicin to a discrete site by embedding the dose of capsaicin into the skin, tissue, muscles, tendons, joints, or other body parts of a human or animal.
  • infiltration shall mean administration into a discrete surgical site where the surgical wound is open.
  • capsaicinoid means capsaicin, capsaicin USP and purified capsaicin, capsaicin analogues and derivatives thereof (collectively referred to as capsaicinoids in this specification and appended claims) that act at the same pharmacologic sites, e.g., VR1, as capsaicin, unless otherwise specified.
  • Acute pain shall mean any pain that presents with a rapid onset followed by a short, severe course, e.g., headache, pain associated with cancer, fractures, strains, sprains, and dislocations of bones, joints, ligaments and tendons.
  • Chronic pain shall mean pain that lasts for a long period of time or is marked by frequent recurrence, e.g., pain associated with terminal illnesses, arthritis, autoimmune diseases; or neuropathic pain caused by degenerative diseases such as diabetes mellitus or spinal degeneration, or resulting from neural remodeling following traumatic injury or surgery.
  • local anesthetic means any drug or mixture of drugs that provides local numbness and/or analgesia.
  • co-administration it is meant either the administration of a single composition containing both the capsaicin and an additional therapeutically effective agent(s), e.g., local anesthetic or phenol, or the administration of a capsaicin and the additional therapeutically effective agent(s) as separate compositions within short enough time periods that the effective result is equivalent to that obtained when both compounds are administered as a single composition.
  • an additional therapeutically effective agent(s) e.g., local anesthetic or phenol
  • FIG. 1 is a graph displaying the plasma concentration of the 10 ⁇ g, 100 ⁇ g and 300 ⁇ g doses of capsaicin administered to study subjects entered into the Osteoarthritis Safety Study exemplified in Example 1.
  • FIG. 2 is a graph displaying the percent reduction in VAS score compared to baseline in study subjects entered into the Osteoarthritis Safety Study exemplified in Example 1.
  • FIG. 3 is a graph displaying the NRS Pain Score in study subjects entered into the Osteoarthritis Efficacy Study exemplified in Example 2.
  • FIG. 4 is a graph displaying a comparison of VAS Pain Score between subjects entered into the Bunionectomy Efficacy study exemplified in Example 3.
  • FIG. 5 is a graph displaying a comparison of the percent of subjects entered in to the Bunionectomy Efficacy study exemplified in Example 3 requiring rescue medication.
  • compositions and methods disclosed herein can be used for treating pain at a specific site with an effective amount of capsaicin or capsaicin analogue, hereinafter collectively referred to as “capsaicinoids”.
  • the methods involve administration of an effective amount of capsaicinoid to a discrete site in a human or animal for relieving pain at the site.
  • the methods involve providing anesthesia to the site where the capsaicinoid is to be administered, and then administering an effective amount of capsaicinoid to the site to attenuate the pain emanating from the site, e.g., for at least about 72 hours.
  • the anesthesia can be provided directly to the site, or at a remote site that causes anesthesia at the site where the capsaicinoid is to be administered.
  • epidural regional anesthesia can be provided to patients to which the capsaicinoid is to be administered at a site located from the waist down.
  • a local anesthetic may be administered as a regional block, a proximal block, a somatic block, or a neuraxial block.
  • the anesthetic may be administered as a general anesthetic, as a spinal block, as an epidural block, or as a nerve block.
  • the local anesthetic is administered prior to administration of the capsaicinoid, such that the local anesthetic has provided temporary anesthesia to the area to be treated with the capsaicinoid.
  • local anesthetic agents examples include bupivacaine, ropivacaine, dibucaine, procaine, chloroprocaine, prilocaine, mepivacaine, etidocaine, tetracaine, lidocaine, and xylocaine, and mixtures thereof and any other art-known pharmaceutically acceptable local anesthetic.
  • the local anesthetic can be in the form of a salt, for example, the hydrochloride, bromide, acetate, citrate, carbonate or sulfate.
  • the local anesthetic agent is in the form of a free base.
  • Preferred local anesthetic agents include, e.g., bupivacaine or lidocaine.
  • the free base provides a slower initial release and avoids an early “dumping” of the local anesthetic at the injection site.
  • Other local anesthetics may act differently.
  • Local anesthetic agents typically administered systematically may also be used in those cases where the means of administration results only in a local effect, rather than systemic.
  • the dose of local anesthetic will depend on the anesthetic being administered as well as the site where the local anesthetic is administered. For example, in embodiments where the local anesthetic is administered via a regional block (e.g., an ankle block), the dose of anesthetic ranges from about 1 ml up to about 30 ml of a 0.5% solution (e.g., bupivacaine). In other embodiments a 3 mg/kg dose (maximum 200 mg) of a 2% solution (e.g., lidocaine) can be administered by intr-articular infiltration. In other embodiments the dose of local anesthetic can range between 0.5 ml to about 60 ml of a 0.25% to 5% solution.
  • a regional block e.g., an ankle block
  • the dose of anesthetic ranges from about 1 ml up to about 30 ml of a 0.5% solution (e.g., bupivacaine). In other embodiments a 3 mg/
  • phenol can be administered at the site to be treated in place of (or in addition to) a local anesthetic to anesthesize the area.
  • Phenol can preferably be administered prior to administration of the capsaicinoid, or can be co-administered with the dose of capsaicinoid.
  • co-administration it is meant either the administration of a single composition containing both the capsaicinoid and the phenol, or the administration of the capsaicinoid and the phenol as separate compositions within short enough time periods that the effective result is equivalent to that obtained when both compounds are administered as a single composition.
  • capsaicin Prior to the present invention, for example, in U.S. Pat. No. 4,313,958 (LaHann), capsaicin is described as producing analgesia when administered via “systemic administration” (i.e., intrathecal, epidural, intramuscular, intravenous, intraperitoneal and subcutaneous). Animal testing was accomplished via “stair-step dosing” which purportedly was said to reduce or eliminate some of the side affects of capsaicin. It is reported therein that capsaicin, when systemically delivered in final doses of 25 mg/kg or less prior to ultra violet radiation, prevented radiation induced hyperalgesia, but did not elevate the pain threshold above normal range. Only when larger doses of capsaicin were administered systemically, i.e.
  • capsaicin being 50 mg/kg or greater, was the pain threshold elevated.
  • LaHann hypothesized that for clinical use in humans, total doses from 0.05 mg/kg to 1,000 mg/kg were acceptable and total doses from 0.25 mg/kg to 500 mg/kg were preferred.
  • the rats weighed between 125 and 175 grams and the total administered dose of capsaicin ranged from 27 mg/kg to 102 mg/kg (or a total dose injected subcutaneously of about 3.375 mg to about 17.85 mg capsaicin).
  • U.S. Pat. No. 5,962,532 (Campbell et al) describes an injection volume of 0.1 to 20 ml and a concentration of capsaicin between 0.01 to 10% for parenteral administration, which calculates to a total dose of capsaicin of between 0.01 mg to 2,000 mg, based on volume and concentration.
  • the administration of microgram quantities of capsaicin into discrete localized areas responsible for the treatment and/or attenuation of pain recognizes significant advantages over system-wide exposure to milligram quantities in order to produce a therapeutic effect through alteration of sensory nerve function in a limited area.
  • a single dose from about 1 ⁇ g to 5,000 ⁇ g of capsaicin, or a therapeutically equivalent dose of one or more other capsaicinoids is administered via injection or implantation to produce a selective, highly-localized destruction or incapacitation of C-fiber and/or A-delta-fiber in discrete localized areas responsible for the initiation of pain for the purpose of eliminating pain arising from that locus, while minimizing potential adverse consequences of C-fiber and/or A-delta-fiber activation and/or damage outside of the locus of pain.
  • from about 10 to about 3000 micrograms of capsaicin, or a therapeutically equivalent dose of one or more other capsaicinoids is administered at the site.
  • the amount of capsaicin and/or preferably the range of capsaicin administered at the site is from about 100 to about 1000 micrograms.
  • the present invention is directed to administration of a single dose of capsaicin or other capsaicinoid(s) in an amount that is greatly reduced as compared to the dosage range previously considered useful by those skilled in the art to denervate the nerve fibers in a discrete, localized area without eliciting a systemic effect (e.g., an effect beyond that discrete, localized location).
  • Capsaicinoids with similar physiological properties, i.e., triggering C fiber membrane depolarization by opening of cation channels permeable to calcium and sodium, are known.
  • resiniferatoxin is described as a capsaicin analogue in U.S. Pat. No. 5,290,816 to Blumberg.
  • U.S. Pat. No. 4,812,446 to Brand describes other capsaicin analogues and methods for their preparation.
  • U.S. Pat. No. 4,424,205 cites capsaicin analogues. Ton et al., Brit. J. Pharm.
  • capsaicin and its analogues.
  • Capsaicin, capsaicin analogues and other capsaicinoids are also described in detail in WO 96/40079, the disclosure of which is hereby incorporated by reference.
  • Capsaicinoids are also described in EP0 149 545, the disclosure of which is also hereby incorporated by reference.
  • capsaicioids may be administered at the site in replacement of, part of, or all of the dose of capsaicin, the capsaicin analogue being administered in a therapeutically equivalent amount of capsaicin for which it is substituted.
  • the capsaicin analogue can be selected from those compounds with similar physiological properties to capsaicin as are known in the art. Resiniferatoxin qualitatively resembles capsaicin in its activity, but differs quantitatively in potency (i.e. 10 3 -10 4 fold more potent) and in relative spectrum of actions.
  • resiniferatoxin it is recommended to administer 0.1 ⁇ 10 ⁇ 3 to 5 ⁇ 10 ⁇ 2 mg/kg, preferably 0.1 ⁇ 10 ⁇ 3 to 5 ⁇ 10 ⁇ 3 mg/kg, body weight of the subject for single application, or less upon multiple application.
  • resiniferatoxin is administered in the range of 1 ⁇ 10 ⁇ 5 mg/kg to 5 ⁇ 10 ⁇ 2 mg/kg to the subject.
  • Resiniferatoxin also shows a somewhat different spectrum of action, providing greater relief of pain at a given dose. Therefore, the dose of resiniferatoxin should be at least 100 fold less than a dose of capsaicin alone.
  • the capsaicinoid utilized in the compositions and methods of the invention is capsaicin itself.
  • the capsaicin is in a purified form obtained from the chemical purification of Capsaicin USP.
  • the purified capsaicin used in the compositions and methods of the invention consists essentially of the trans isomer.
  • the trans-isomer of capsaicin has its activity at the vanilloid receptor, and this embodiment, the methods and formulation of the present invention are especially useful for treating disorders or pain that can be alleviated through activation of the vanilloid receptors via, the VR-1 mechanism.
  • Capsaicin USP contains only about 55-60% trans-capsaicin, with the remainder comprising the precursors dihydrocapsaicin and nordihydrocapsaicin
  • the formulation preferably consists essentially of trans-capsaicin, e.g., preferably having a purity of greater than about 97%, preferably greater than about 98%, more preferably greater than about 99% trans-capsaicin.
  • the trans isomer is preferably prepared in accordance with the method for synthesizing the trans isomer of capsaicin from a four step process and purified as describe in U.S. Provisional Application No. 60/461,164 filed Apr. 8, 2003, the disclosure of which is hereby incorporated by reference in its entirety. In accordance with U.S. Provisional Application No.
  • said method for synthesizing the trans isomer of capsaicin comprises a) alkylating 3-methyl butyne with halovaleric acid and/or -haloalkanic acid to obtain 8-methyl-6-nonynoic acid and/or alkynoic acid analogues thereof; b) reducing said 8-methyl-6-nonynoic acid to obtain trans-8-methyl-nonenoic acid; c) activating the 8-methyl-nonenoic acid to obtain an acid chloride; and d) acylating 4-hydroxy-3-methoxybenzylamine hydrochloride with the acid chloride to obtain trans-capsaicin.
  • step a) of the method for preparation of the capsaicin for use in the present invention comprises the steps of: i) mixing anhydrous tetrahydrofuran (THF) with hexamethylphosphoramide (HMPA) and cooling the mixture to about ⁇ 78° C. to about ⁇ 75° C.; ii) adding to the mixture of step i) 3-methyl butyne followed by a dropwise addition of a base at a temperature from about ⁇ 78° C. to about ⁇ 65° C. to obtain a second mixture; iii) warming the second mixture up to about ⁇ 30° C.
  • THF anhydrous tetrahydrofuran
  • HMPA hexamethylphosphoramide
  • a method for obtaining a crude step a) intermediate product further comprising the steps of: i) adding 3M hydrochloric acid (HCl) to a reaction mixture and extracting the reaction mixture with ethyl acetate; and ii) washing the extracted reaction mixture with brine to yield a crude product.
  • HCl 3M hydrochloric acid
  • step b) of the method for preparation of the capsaicin for use in the present invention comprises the steps of: i) dissolving said 8-methyl-6-nonynoic acid in a mixture of anhydrous tetrahydrofuran and tertiary-butyl alcohol (t-BuOH) to obtain a solution and cooling the solution to about ⁇ 55° C. to about ⁇ 40° C.; ii) condensing ammonia (NH3) to the solution to a temperature of about ⁇ 50° C. to about ⁇ 40° C.; iii) adding sodium drips piece-wise and stirring from about 30 minutes to about 2 hours at a temperature from about ⁇ 45° C.
  • t-BuOH anhydrous tetrahydrofuran and tertiary-butyl alcohol
  • Step iii) of the step b) reaction may further comprise adding piece-wise lithium and stirring from about 30 minutes to about 2 hours at a temperature from about ⁇ 65 C to about ⁇ 45 C.
  • crude step b) intermediate product further comprises the steps of: i) adding water to a reaction mixture; ii) acidifying the reaction mixture with 6N HCl to a pH of about 2 to about 3; iii) extracting the reaction mixture with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate (Na2SO4); and iv) filtering and removing solvents under vacuum to obtain a crude step b) intermediate product.
  • step c) of the method for preparation of the capsaicin for use in the present invention comprises the steps of: i) adding dropwise a thionyl halide to the 8-methyl-nonenoic acid at room temperature for about 15 minutes to about 30 minutes to form a solution; ii) heating the solution at about 50° C. to about 75 C for a period of about 1 hour; and iii) removing excess thionyl halide under vacuum at about 40 C to about 45 C to obtain a step c) intermediate product.
  • step d) of the method for preparation of the capsaicin for use in the present invention comprises the steps of: i) mixing 4-hydroxy-3-methoxy benzylamine hydrochloride and dimethylformamide (DMF); ii) adding portion-wise at room temperature to the mixture of step i) 5N sodium hydroxide (NaOH) and stirring for about 30 minutes; iii) adding acid halide in anhydrous ether dropwise at a temperature of about 0° C. to about 10° C. for about 20 minutes to about 1 hour; and, thereafter, iv) gradually warming the mixture to room temperature and stirring overnight.
  • DMF dimethylformamide
  • step d) further comprises the steps of: i) adding water to the mixture and extracting the mixture with ethyl acetate to obtain an ethyl acetate extract; ii) washing said extract with 1N HCl and, thereafter, washing with sodium bicarbonate (NaHCO3); iii) washing the solution with brine and drying over anhydrous sodium sulfate (Na2SO4); and iv) filtering and removing solvents under vacuum to obtain a crude product.
  • NaHCO3 sodium bicarbonate
  • Na2SO4 anhydrous sodium sulfate
  • the method of preparing the trans-capsaicin or capsaicin intermediate after one or more of the steps (e.g., a), b), c) and/or d)) further comprises purifying the crude product by column chromatography, flash chromatography, or the like, using silica gel and eluting with a mixture of ethyl acetate/hexane to obtain a crude trans-capsaicin product.
  • the trans-capsaicin product is subjected to purification process comprising the steps of: i) dissolving the crude trans-capsaicin product in a mixture of ether/hexane and heating the mixture to about 40° C. to about 45° C.; ii) cooling the mixture to room temperature while stirring for about 2 hours; and iii) filtering the mixture to provide a purified trans-capsaicin product.
  • the capsaicin is subjected to a further purification process also referred to as a “semi-prep purification” or “semi-preparative purification” of capsaicin.
  • a further purification process also referred to as a “semi-prep purification” or “semi-preparative purification” of capsaicin.
  • the capsaicin or previously purified capsaicin is purified via the use of a semi-preparative HPLC (high performance liquid chromatography), which preferably provides for a trans-capsaicin product having a purity of greater than about 97%, preferably greater than about 98%, more preferably greater than about 99% capsaicin.
  • HPLC high performance liquid chromatography
  • the active ingredient in the preparation comprises substantially pure trans-capsaicin (e.g. having no more than about 10% precursors or other capsaicin compounds such as cis-capsaicin).
  • the preparation includes at least about 95% pure trans-capsaicin.
  • the preparation includes at least about 99% pure trans-capsaicin. While the cis-isomer of capsaicin has activity via a number of mechanisms, VR-1 is not considered to comprise a major effect of this agent.
  • trans-isomer of capsaicin In view of the collective activity of the trans-isomer of capsaicin at the VR-1 receptor, it is contemplated that it is possible in certain embodiments of the present invention that the amount of trans-capsaicin included in the methods and formulations of the present invention will be reduced in comparison to a preparation which includes a less pure form of capsaicin (e.g., capsaicin USP).
  • a preparation which includes a less pure form of capsaicin e.g., capsaicin USP
  • the formulations and methods of the invention contemplate the use of a capsaicin agent consisting essentially of cis-capsaicin.
  • Capsaicin in either crude extract form, Capsaicin USP, or as purified capsaicin, has been comprehensively studied in a variety of tests in vitro, and in several animal species in vivo. Much of the data published can be found in the open scientific literature and in the proprietary studies discussed below (See: Examples I-XI).
  • a single dose of capsaicinoid minimizes and/or prevents systemic delivery of the capsaicin for the purposes of: a) producing a selective, highly-localized destruction or incapacitation of C-fibers and/or A-delta fibers in a discrete, localized area responsible for the initiation of pain (e.g., trigger points, intra-articular spaces, bursa) for the purpose of reducing or eliminating pain arising from a discrete locus (i.e., producing antinociception), and b) minimizing potential adverse consequences of C-fiber and/or A-delta activation and or damage outside of the locus of pain (i.e., damage to homeostatic mechanisms, such as cardiac reflex [e.g., Bezold-Jarisch reflex] or micturation reflex [e.g., urge to void] or to nerve fibers in the central nervous system).
  • cardiac reflex e.g., Bezold-Jarisch reflex
  • micturation reflex e.g., urge to void]
  • the analgesic effect preferably provides pain relief for at least about 48 to about 120 hours, preferably from about 10 to about 21 days, more preferably from about 4 to about 5 weeks, even more preferably for at least about 6 to about 8 weeks, and most preferably for at least about 16 weeks or more.
  • Delivery systems can also be used to administer capsaicin/capsaicinoid and local anesthetics that produce modality-specific blockade, as reported by Schneider, et al., Anesthesiology, 74:270-281 (1991), or possess physical-chemical attributes that make them more useful for sustained release then for single injection blockade, as reported by Masters, et al., Soc. Neurosci. Abstr., 18:200 (1992), the teachings of which are incorporated herein.
  • An example of a delivery system includes microspheres wherein the anesthetic is incorporated into a polymer matrix in a percent loading of 0.1% to 90% by weight, preferably 5% to 75% by weight.
  • the delivery systems are most preferably formed of a synthetic biodegradable polymer, although other materials may also be used to formulate the delivery systems, including proteins, polysaccharides, and non-biodegradable synthetic polymers. It is most preferable that the polymer degrade in vivo over a period of less than a year, with at least 50% of the polymer degrading within six months or less. Even more preferably, the polymer will degrade significantly within a month, with at least 50% of the polymer degrading into non-toxic residues which are removed by the body, and 100% of the capsaicinoid and anesthetic being released within a two week period. Polymers should also preferably degrade by hydrolysis by surface erosion, rather than by bulk erosion, so that release is not only sustained but also linear.
  • Polymers which meet this criteria include some of the polyanhydrides, poly(hydroxy acids) such as co-polymers of lactic acid and glycolic acid wherein the weight ratio of lactic acid to glycolic acid is no more than 4:1 (i.e., 80% or less lactic acid to 20% or more glycolic acid by weight), and polyorthoesters containing a catalyst or degradation enhancing compound, for example, containing at least 1% by weight anhydride catalyst such as maleic anhydride.
  • Other polymers include protein polymers such as gelatin and fibrin and polysaccharides such as hyaluronic acid.
  • Polylactic acid is not useful since it takes at least one year to degrade in vivo.
  • the polymers should be biocompatible. Biocompatibility is enhanced by recrystallization of either the monomers forming the polymer and/or the polymer using standard techniques.
  • compositions for manufacture of suitable delivery systems for administration of capsaicinoid alone or together with the local anesthetic are known to those skilled in the art.
  • the formulations may also be designed to deliver both the anesthetic and the capsaicinoid, either simultaneously or sequentially.
  • the local anesthetic can preferably be administered by direct injection, implantation or infiltration to the site where the capsaicinoid is to be administered, for example, by administering the local anesthetic directly in the diseased or pain producing structure or the injured nerve or the nerve that provides inervation to the painful area, or to effect a regional block of the area including the site where the capsaicin is to be administered.
  • the local anesthetic can preferably be administered by injection, implantation or infiltration of the anesthetic into the epidural space adjacent to the spine for pain originating below a patient's waist, or directly into a joint for pain originating above the patient's waist.
  • the prior administration of a proximal neural block sufficiently desensitizes C fibers to the expected pungent side effects of the subsequent capsaicinoid administration.
  • the microspheres may be injected, implanted or infiltrated through a trochar, or the pellets or slabs may be surgically placed adjacent to nerves, prior to surgery or following repair or washing of a wound.
  • the microspheres can be administered alone when they include both the capsaicin and local anesthetic or in combination with a solution including capsaicin in an amount effective to prolong nerve blockade by the anesthetic released from the microspheres.
  • the suspensions, pastes, beads, and microparticles will typically include a pharmaceutically acceptable liquid carrier for administration to a patient, for example, sterile saline, sterile water, phosphate buffered saline, or other common carriers.
  • an anesthetic such as a nerve block
  • an analgesic such as a nonsteroidal anti-inflammatory agent or narcotic analgesic (i.e., the various alkaloids of opium, such as morphine, morphine salts, and morphine analogues such as normorphine).
  • an analgesic such as a nonsteroidal anti-inflammatory agent or narcotic analgesic (i.e., the various alkaloids of opium, such as morphine, morphine salts, and morphine analogues such as normorphine).
  • the administration of the capsaicinoid can be repeated if necessary.
  • compositions and methods of the present invention can be used for treating various conditions associated with pain by providing pain relief at a specific site.
  • conditions to be treated include, but are not limited to, nociceptive pain (pain transmitted across intact neuronal pathways), neuropathic pain (pain caused by damage to neural structures), pain from nerve injury (neuromas and neuromas in continuity), pain from neuralgia (pain originating from disease and/or inflammation of nerves), pain from myalgias (pain originating from disease and/or inflammation of muscle), pain associated with painful trigger points, pain from tumors in soft tissues, pain associated with neurotransmitter-dysregulation syndromes (disruptions in quantity/quality of neurotransmitter molecules associated with signal transmission in normal nerves) and pain associated with orthopedic disorders such as conditions of the foot, knee, hip, spine, shoulders, elbow, hand, head and neck.
  • nociceptor-receptors for noxious stimuli.
  • These nociceptors are free nerve endings that terminate just below the skin as to detect cutaneous pain.
  • Nociceptors are also located in tendons and joints, for detection of somatic pain and in body organs to detect visceral pain. Pain receptors are very numerous in the skin, hence pain detection here is well defined and the source of pain can be easily localized. In tendons, joints, and body organs the pain receptors are fewer. The source of pain therefore is not readily localized. Apparently, the number of nociceptors also influences the duration of the pain felt.
  • Cutaneous pain typically is of short duration, but may be reactivated upon new impacts, while somatic and visceral pain is of longer duration. It is important to note that almost all body tissue is equipped with nociceptors. As explained above, this is an important fact, as pain has primary warning functions, for example, impinging on the well-being of the patient and thereby causing the patient to seek medical assistance.
  • Nociceptive pain includes, but is not limited to post-operative pain, cluster headaches, dental pain, surgical pain, pain resulting from severe burns, post-partum pain, angina, genitor-urinary tract pain, pain associated with sports injuries (tendonitis, bursitis, etc.) and pain associated with joint degeneration and cystitis.
  • Neuropathic pain generally involves abnormalities in the nerve itself, such as degeneration of the axon or sheath.
  • the cells of the myelin sheath and/or Schwann cells may be dysfunctional, degenerative and may die, while the axon remains unaffected.
  • the axons and cells of the myelin sheath and/or Schwann cells are involved.
  • Neuropathies may also be distinguished by the process by which they occur and their location (e.g. arising in the spinal cord and extending outward or vice versa).
  • Direct injury to the nerves as well as many systemic diseases can produce this condition including AIDS/HIV, Herpes Zoster, syphilis, diabetes, and various autoimmune diseases.
  • Neuropathic pain is often described as burning, or shooting type of pain, or tingling or itching pain and may be unrelenting in its intensity and even more debilitating than the initial injury or the disease process that induced it.
  • Neuropathies treatable by the methods of the present invention include: syndromes of acute ascending motor paralysis with variable disturbance of sensory function; syndromes of subacute sensorimotor paralysis; syndromes of acquired forms of chronic sensorimotor polyneuropathy; syndromes of determined forms of genetic chronic polyneuropathy; syndromes of recurrent or relapsing polyneuropathy; and syndromes of mononeuropathy or multiple neuropathies (Adams and Victor, Principles of Neurology, 4th ed., McGraw-Hill Information Services Company, p. 1036, 1989).
  • Syndromes of acute ascending motor paralysis are selected from the group-consisting of acute idiopathic polyneuritis, Landry-Guillain-Barre Syndrome, acute immune-mediated polyneuritis, infectious mononucleosis polyneuritis, hepatitis polyneuritis; diptheric polyneuropathy; porphyric polyneuropathy; toxic polyneuropathy (e.g., thallium); acute axonal polyneuropathy; acute panautonomic neuropathy; vaccinogenic, serogenic, paraneoplastic, polyarteretic and lupus polyneuropathy.
  • Syndromes of subacute sensorimotor paralysis are selected from the group consisting of deficiency states (e.g., beriberi, pellagra, vitamin B12); heavy metal/industrial solvent poisonings (e.g., arsenic, lead); drug overdose (e.g., isoniazid, disulfuram, vincristine, taxol, chloramphenicol); uremic polyneuropathy; diabetes; sarcoidosis; ischemic neuropathy and peripheral vascular disease; AIDS; and radiation (radiotherapy).
  • deficiency states e.g., beriberi, pellagra, vitamin B12
  • heavy metal/industrial solvent poisonings e.g., arsenic, lead
  • drug overdose e.g., isoniazid, disulfuram, vincristine, taxol, chloramphenicol
  • uremic polyneuropathy e.g., diabetes; sarcoidosis; ischemic neuropathy and peripheral vascular disease
  • Syndromes of chronic sensorimotor are selected from the group consisting of carcinoma, myeloma and other malignancies; paraproteinemias; uremia; beriberi (usually subacute), diabetes, hypo/hyperthyroidism; connective tissue disease; amyloidosis; leprosy and sepsis.
  • Genetic chronic polyneuropathies are selected from the group consisting of dominant mutilating sensory neuropathy (adult); recessive mutilating sensory neuropathy (childhood); congenital insensitivity to pain; spinocerebellar degenerations, Riley Day Syndrome; Universal Anesthesia Syndrome; polyneuropathies w/ metabolic disorder; and mixed sensorimotor-autonomic type polyneuropathies.
  • Recurrent/relapsing polyneuropathy are selected from the group consisting of idiopathic polyneuritis; porphyria; chronic inflammatory polyradiculoneuropathy; mononeuritis multiplex; beriberi/drug overdose; refsum disease and tangier disease.
  • Mono/multiple neuropathies are selected from the group consisting of pressure palsies; traumatic neuropathies (e.g., irradiationor electrical injury); serum, vaccinogenic (e.g., rabies, smallpox); herpes zoster; neoplastic infiltration; leprosy; diptheretic wound infections;,migrant sensory neuropathy; shingles and post herpetic neuralgia.
  • Neurotransmitter-dysregulation pain syndromes rather than involving abnormal or damaged nerves, result from normal nerves having disruptions in the quantity and/or quality of the various neurotransmitter molecules associated with signal transmission from one neuron to another. More specifically, sensory transmitters are released from the afferent nerve ending of one nerve cell and received by receptors at the afferent end of another nerve cell. They are chemical messengers which transmit the signal. There are numerous transmitters, including glutamate, serotonin, dopamine, norepinephrine, somatostatin, substance P, calcitonin gene-related peptide, cholecystokinin, opiates and saponins.
  • a representative neurotransmitter dysregulation syndrome that may be treated by the present invention includes fibromyalgia, which is a common condition characterized by a history of chronic generalized pain and physical exam evidence of at least 11 of 18 defined “tender point” sites in muscles and connective tissue (Wolfe et al., Arthritis Rheum 33:160-72, 1990).
  • Commonly associated conditions include irritable bowel syndrome, headache, irritable bladder syndrome (interstitial cystitis), sleep disturbance, and fatigue (Goldenberg, Current Opinion in Rheumatology 8:113-123, 1996; Moldofsky et al., Psychosom Med 37:341-51, 1975; Wolfe et al., 1990; Wolfe et al., J Rheum 23:3, 1996; Yunus et al., Semin Arthritis Rheum 11:151-71, 1981).
  • CNS central nervous system
  • Neurotransmitters are chemical messengers, amino acids, biogenic amines and neuropeptides, emitted from nerve cells that interact with receptors on other nerve cells, as well as other cell types, including muscle and immune cells.
  • Neurotransmitter imbalance which leads to increased pain experience, may include a qualitative and/or quantitative decrease in the function of such neurotransmitters as glutamate, serotonin, dopamine, norepinephrine, somatostatin, substance P, calcitonin gene-related peptide, cholecystokinin, opiates and saponins.
  • Fibromyalgia is characterized by a relative deficit of serotonin effect and relative excess of substance P effect.
  • Neurotransmitter-dysregulation pain syndromes include, but are riot limited to the following: generalized syndromes, localized syndromes; craniofascial pain; vascular disease; rectal, perineum and external genitalia pain; and local syndromes of the leg/foot.
  • Generalized syndromes are selected from the group consisting of stump pain, causalgia, reflex sympathetic dystrophy, fibromyalgia or diffuse myofascial pain and burns.
  • Localized syndromes are selected from the group consisting of trigeminal neuralgia; acute herpes zoster; panautonomic neuralgia; geniculate neuralgia (Romsay Hunt Syndrome); glossopharyngeal neuralgia; vagus nerve neuralgia and occipital neuralgia.
  • Craniofacial pain includes temporomandibular pain.
  • Suboccipital and cervical muskuloskeletal disorders are selected from the group consisting of myofascial syndrome, which includes cervical sprain cervical hyperextension (whiplash); stemocleidomastoid muscle; trapezius muscle; and stylohyoid process syndrome (Eagle's syndrome).
  • Vascular disease is selected from the group consisting of Raynaud's disease; Raynaud's phenomenon; frosbite; erythema pernio (chilblains); acrocyanosis and livedo reticularis.
  • Rectal, perineum and external genitalia pain are selected from the group consisting of iliohypogastric neuralgia; iliolinguinal nerve; genotifemoral nerve and testicular pain.
  • Local syndromes of the leg/foot are selected from the group consisting of lateral cutaneous neuropathy (neuralgia paresthetica);oobturator neuralgia; femoral neuralgia; sciatica neuralgia; interdigital neuralgia of the foot (Morton's metatarsalgia or neurma); injection neuropathy and painful legs and moving toes.
  • Pain Intensity assessment scales are typically used by those of ordinary skill in the art to evaluate analgesic choices and therapeutic effects.
  • a Visual Analogue Scale is a measurement instrument that measures a characteristic that is believed to range across a continuum of values and cannot easily be directly measured. For example, the amount of pain that a patient feels ranges across a continuum from none to an extreme amount of pain may be indirectly measured via the use of a VAS.
  • a VAS is usually a horizontal line, 100 mm in length, anchored by word descriptors at each end, for example “no pain” at one end and “very severe pain” at the other end.
  • the patient marks on the line the point that they feel represents their perception of their current state.
  • the VAS score is determined by measuring in millimeters from the left hand end of the line to the point that the patient marks.
  • the 100-mm visual analog scale (VAS) a unidimensional scale that is versatile and easy to use, has been adopted in many settings.
  • capsaicinoid formulations and methods described herein may be used to treat many conditions where the capsaicinoid can be administered via injection or implantation through the skin of the patient, including but not limited to the treatment of acute or chronic pain, nociceptive and neuropathic pain, pre- and post-operative pain, cancer pain, pain associated with neurotransmitter dysregulation syndromes and orthopedic disorders, sports-related injuries, acute traumatic pain, nociceptive pain, and neurotransmitter-dysregulation syndromes.
  • the capsaicinoid formulations and methods disclosed herein can be used for the treatment/attenuation of chronic post-herniorrhaphy pain.
  • Chronic post-herniorrhaphy pain occurs in between 5-30% of patients, with social consequences limiting some type of activity in about 10% of patients and 1-4% of patients are referred to chronic pain clinics.
  • Nerve damage is probably the most plausible pathogenic factor, but specific principles for therapy have not been evidence-based and range from usual analgesics to re-operation with mesh removal and various types of nerve sections without any demonstrated efficacy in sufficient follow-up studies with or without randomized data.
  • the dose of capsaicinoid can be administered to the site where the surgery was performed or to the immediate area surrounding the incision.
  • the capsaicinoid formulations and methods disclosed herein can be used for the treatment/attenuation of pain associated with Morton's Neuroma.
  • Morton's Neuroma is considered to be most likely a mechanically induced degenerative neuropathy which has a strong predilection for the third common digital nerve in middle-aged women. It is considered a well-defined model of neuropathic pain.
  • the usual medical treatment of Morton's neuroma includes local injection of steroids, often with lidocaine. When nonsurgical means fail to relieve patient's symptoms, surgical removal of this offending neuroma through a dorsal approach can produce dramatic relief of symptoms in approximately 80% of patients.
  • stump or amputation neuroma neuroma recurrence
  • Administration of capsaicinoid in accordance with the invention is useful for the treatment of the neuropathic pain associated with Morton's Neuroma and may reduce the re-occurrence of pain associated with stump or amputation neuroma.
  • the capsaicinoid formulations and methods disclosed herein may be utilized to treat/attenuate pain associated with orthopedic disorders.
  • Orthopedic disorders treatable via the use of the formulations and methods of the invention include but are not limited to disorders of the knee, shoulders, back, hip, spine, elbows, foot, hand and other disorders, which involve pain at a specific site or body space. Orthopedic disorders affecting these locations include, but are not limited to bursitis, tendonitis, osteoarthritis, and rheumatoid arthritis. Bursitis is the inflammation of a bursa. Bursae are saclike cavities or potential cavities that contain synovial fluid located at tissue sites where friction occurs (e.g., where tendons or muscles pass over bony prominences).
  • Bursae facilitate normal movement, minimize friction between moving parts, and may communicate with joints.
  • the bursa provides a slippery surface that has almost no friction.
  • a problem arises when a bursa becomes inflamed.
  • the bursa loses its gliding capabilities, and becomes more and more irritated when it is moved.
  • bursitis occurs, the slippery bursa sac becomes swollen and inflamed.
  • the added bulk of the swollen bursa causes more friction within already confined spaces.
  • the smooth gliding bursa becomes gritty and rough. Movement of an inflamed bursa are painful and irritating. Bursitis usually occurs in the shoulder (subacromial or subdeltoid bursitis).
  • Bursitis may be caused by trauma, chronic overuse, inflammatory arthritis (eg, gout, rheumatoid arthritis), or acute or chronic infection (eg, pyogenic organisms, particularly Staphylococcus aureus; tuberculous organisms; which now rarely cause bursitis).
  • Orthopedic disorders of the foot include, but are not limited to, heel spurs, corns, bunions, Morton's neuroma, hammertoes, ankle sprain, fractures of the ankle or metatarsals or sesamoid bone or toes, plantar fascitis and injuries to the achilles tendon.
  • Orthopedic disorders of the hand include, but are not limited to, arthritis, carpal tunnel syndrome, ganglion cysts, tendon problems such as lateral epicondylitis, medial epicondylitis, rotator cuff tendonitis, DeQuervian's tenosynovitis, and trigger finger/trigger thumb.
  • orthopedic disorders include, but are not limited to, Paget's disease, scoliosis, soft-tissue injuries such as contusions, sprains and strains, long bone fractures and various other sports injuries some of which include patellar tendonitis and lumbar strain.
  • Reaspiration and injection may be required with resistant inflammation.
  • Systemic corticosteroids prednisone 15 to 30 mg/day or equivalent for 3 days
  • Chronic bursitis is treated as acute bursitis, except that splinting and rest are less likely to be helpful.
  • Surgery is rarely needed to treat bursitis and is usually done only in the chronic cases that have not improved with traditional therapy.
  • the most common surgical treatment, if needed, is an Incision and Drainage (called an I and D) and is used only in cases of infected bursa. The surgeon first numbs the skin with an anesthetic and then opens the bursa with a scalpel. Finally, the surgeon drains the fluid present in the inflamed bursa. Sometimes it is necessary to excise the entire bursa surgically. This is indicated only if the bursal swelling causes problems.
  • the capsaicinoid may be administered via injection in a location and fashion similar to that currently utilized with respect to localized injections of corticosteroids.
  • the dose of capsaicinoid is administered by intra-articular injection into the bursa.
  • the capsaicinoid formulations and methods disclosed herein may be utilized to treat/attenuate pain associated with tendonitis (inflammation of the tendons).
  • tendonitis inflammation of the tendons.
  • tendonitis inflammation of the tendons.
  • tendonitis occurs in middle-aged or older persons as the vascularity of tendons attenuates; repetitive microtrauma may increase injury.
  • Repeated or extreme trauma (short of rupture), strain, or excessive (unaccustomed) exercise is most frequently implicated.
  • the most common cause of tendonitis is overuse.
  • individuals begin an exercise program, or increase their level of exercise, and begin to experience symptoms of tendonitis. The tendon is unaccustomed to the new level of demand, and this overuse will cause an inflammation and tendonitis.
  • Tendonitis produces pain, tenderness and stiffness near a joint which is aggravated by movement.
  • NSAIDs non-steroidal anti-inflammatory drugs.
  • NSAIDs non-steroidal anti-inflammatory drugs.
  • Symptomatic relief is provided by rest or immobilization (splint or cast) of the tendon, application of heat for chronic inflammation or cold for acute inflammation (whichever benefits the patient should be used), local analgesic drugs, and NSAIDs for 7 to 10 days.
  • rest or immobilization splint or cast
  • heat for chronic inflammation or cold for acute inflammation either benefits the patient should be used
  • local analgesic drugs and NSAIDs for 7 to 10 days.
  • a critical review of the role of various anti-inflammatory medications in tendon disorders found limited evidence of short-term pain relief and no evidence of their effectiveness in providing even medium term clinical resolution.
  • Use of corticosteroid injections provides mixed results in relief of pain and at times insufficient evidence to support their use.
  • a depot corticosteroid eg, dexamethasone acetate, methylprednisolone acetate, hydrocortisone acetate
  • an equal or double volume of 1% local anesthetic eg, lidocaine
  • the injection is made blindly or proximal to the site of maximum tenderness if the specific inflammation site cannot be identified. Particular care should be taken not to inject the tendon per se (which offers greater resistance) because it may be weakened and rupture in active persons.
  • pain associated with tendonitis of the knee, shoulders, hip, pelvis, spine, elbows, leg and foot is treated with a capsaicinoid injection undertaken in similar fashion as a localized corticosteroid injection.
  • the dose of capsaicinoid can be administered by injection into the subacromial bursa with the needle inserted into the space between the acromium and the humerus on the lateral aspect of the shoulder.
  • osteoarthritis degenerative joint disease
  • Osteoarthritis is characterized by the breakdown of the joint's cartilage.
  • Cartilage is the part of the joint that cushions the ends of bones.
  • Cartilage breakdown causes bones to rub against each other, causing pain and loss of movement.
  • osteoarthritis can range from very mild to very severe. It affects hands and weight-bearing joints such as knees, hips, feet and the back.
  • factors that can cause osteoarthritis including but not limited to age, genetics, obesity, sports-related activities, work-related activities, or accidents.
  • Treatment of osteoarthritis focuses on decreasing pain and improving joint movement, and may include: Exercises to keep joints flexible and improve muscle strength; Many different medications are used to control pain, including corticosteroids and NSAIDs, glucocorticoids injected into joints that are inflamed and not responsive to NSAIDS.
  • corticosteroids and NSAIDs glucocorticoids injected into joints that are inflamed and not responsive to NSAIDS.
  • acetaminophen may be used for mild pain without inflammation; heat/cold therapy for temporary pain relief, joint protection to prevent strain or stress on painful joints; surgery (sometimes) to relieve chronic pain in damaged joints; and weight control to prevent extra stress on weight-bearing joints.
  • Pain associated with osteoarthritis may be treated/attenuated with the capsaicinoid formulations administered, e.g., by intra-articular injection at the affected site, including but not limited to orthopedic disorders of the knee such as osteoarthritis, shin splints, medial tibial stress syndrome, bursitis, tendonitis (patellar tendinitis); tears of the anterior cruciate ligament (blown out knee), posterior cruciate ligament, medial collateral ligament and lateral collateral ligament; arthritis of the knee; meniscal cartilage tear; Runner's conditions such as iliotibial band syndrome and Pes Anserine bursitis; torn meniscus and limited cartilage defects of the knee; orthopedic disorders of the shoulders including, but not limited to, bursitis, dislocation, separation, impingement and tear of the rotator cuff, tendonitis, adhesive capsulitis (frozen shoulder) and fractures.
  • orthopedic disorders of the knee such as osteoarthritis, shin splin
  • the capsaicinoid formulations and methods disclosed herein may be used to treat/attenuate pain associated with rheumatoid arthritis.
  • Rheumatoid arthritis is a chronic, systemic, inflammatory disease that chiefly affects the synovial membranes of multiple joints in the body. Because the disease is systemic, there are many extra-articular features of the disease as well.
  • Rheumatoid Arthritis can affect many joints in the body, including the knee, ankle, elbow, and wrist. Joints that are actively involved with the disease are usually tender, swollen, and likely demonstrate reduced motion. The disease is considered an autoimmune disease that is acquired and in which genetic factors appear to play a role.
  • the capsaicinoid may be administered via intra-articular injection in a location and fashion similar to that currently utilized with respect to localized injections of corticosteroids.
  • rheumatic diseases there are several different classes of drugs utilized to treat patients with the various types of rheumatic disease which maybe used in addition to the capsaicinoid treatment described herein, including analgesics to control pain, corticosteroids, uric acid-lowering drugs, immunosuppressive drugs, nonsteroidal anti-inflammatory drugs, and disease-modifying antirheumatic drugs.
  • analgesics to control pain corticosteroids, uric acid-lowering drugs, immunosuppressive drugs, nonsteroidal anti-inflammatory drugs, and disease-modifying antirheumatic drugs.
  • the capsaicinoid formulations and methods disclosed herein may be used to treat/attenuate pain associated with back pain.
  • Back pain is the second most common reason for doctor visits in the U.S.
  • the causes of lower back pain are numerous. Some of the more common causes of lower back pain are: sudden injury to the back such as may occur in an auto accident, fall, sports, or other manner; gynecological conditions such as endometriosis, menstrual cramps, fibroid tumors, and pregnancy are sometimes the cause of lower back pain in women; and stress to the muscles, nerves, or ligaments in the lower back. Slipped discs, pinched nerves, sciatica, aging, and infections are other common causes of lower back pain.
  • Zygapophysial joints are located on the back (posterior) of the spine on each side of the vertebrae where it overlaps the neighboring vertebrae.
  • the facet joints provide stability and give the spine the ability to bend and twist. They are made up of the two surfaces of the adjacent vertebrae, which are separated by a thin layer of cartilage.
  • the joint is surrounded by a sac-like capsule and is filled with synovial fluid (a lubricating liquid that reduces the friction between the two bone surfaces when the spine moves and also nourishes the cartilage.)
  • synovial fluid a lubricating liquid that reduces the friction between the two bone surfaces when the spine moves and also nourishes the cartilage.
  • a problem (such as inflammation, irritation, swelling or arthritis) in the facet joint may cause low back pain. Diagnostic tests can show an abnormality in a facet joint, which may suggest that the facet joint is the source of the pain. However, sometimes normal study results can be present while the facet joint is still the source of pain, and abnormal results do not always implicate the facet joint.
  • an injection of local anesthetic may be utilized. If an injection of a small amount of anesthetic or numbing medication into the facet joint reduces or removes the pain, it indicates that the facet joint may be the source of the pain. This is diagnostic use of the facet joint injection. Once a facet joint is pinpointed as a source of pain, therapeutic injections of anesthetic agents and anti-inflammatory medications may give pain relief for longer periods of time. The capsaicinoid formulations may be administered in such situations to attenuate such pain.
  • Facet joint injections are performed while the patient is awake, under a local anesthetic, and able to communicate. Sometimes, the health care provider may also administer drugs to make the patient more comfortable during the procedure. The injection is usually performed while the patient is lying on his or her stomach on an X-ray table. EKG, blood pressure cuffs and blood-oxygen monitoring devices may be hooked up prior to the injection process. Once the proper site has been determined, the physician will inject the anesthetic (often lidocaine or bupivicaine) and the anti-inflammatory (usually a corticosteroid.). This process may then be repeated depending on the number of affected facet joints.
  • anesthetic often lidocaine or bupivicaine
  • the anti-inflammatory usually a corticosteroid.
  • the capsaicinoid may be administered via injection to treat back pain, e.g., in a location and fashion similar to that currently utilized with respect to localized injections of corticosteroids.
  • the capsaicinoid formulations and methods disclosed herein may be used to treat/attenuate pain associated with a heel spur, which is a projection or growth of bone where certain muscles and soft tissue structures of the foot attach to the bottom of the heel.
  • a heel spur is a projection or growth of bone where certain muscles and soft tissue structures of the foot attach to the bottom of the heel.
  • the plantar fascia a broad, ligament-like structure extending from the heel bone to the base of the toes becomes inflamed, and symptoms of heel pain begin.
  • a heel spur is likely to form. If heel pain is treated early, conservative therapy is often successful arid surgery is usually avoided. Early signs of heel pain are usually due to plantar fasciitis, the inflammation of the plantar fascia. It is probably the most common cause of heel pain seen by the podiatrist.
  • capsaicinoid When capsaicinoid is used for the treatment of plantar fascia, the dose of capsaicinoid is preferably administered by injection into the affected area. When surgery is required, the capsaicinoid is preferably administered by infiltration into the heel bone.
  • the capsaicinoid formulations and methods disclosed herein may be used to treat/attenuate pain associated with laparoscopic cholecystectomy.
  • Laparoscopic cholecystectomies have virtually replaced open surgical cholecystectomy.
  • patients undergoing laparoscopic cholecystectomies still have pain. Pain control following surgery typically includes use of opioids, especially within the first several days after surgery.
  • the administration of capsaicinoid in a patient who has undergone a laparoscopic cholecystectomy may reduce the amount of opioid consumption and postoperative pain scores associated with the procedure.
  • the dose of capsaicinoid can be administered either by injection, infiltration or both injection and infiltration.
  • the capsaicinoid may be injected directly the site of incision or to the immediate area surrounding the surgical site.
  • capsaicinoid formulations and methods disclosed herein may be used to treat/attenuate pain associated with other laparoscopic surgical procedures, as well.
  • the dose of capsaicinoid contained in a unit dose injection/implantation is from about 1 ⁇ g to about 5000 ⁇ g of capsaicin, preferably from about 10 ⁇ g to about 3000 ⁇ g capsaicin, more, preferably from about 300 ⁇ g to about 1500 ⁇ g capsaicin, or a therapeutically equivalent amount of one or more capsaicinoids.
  • the dose of capsaicin is from about 400 ⁇ g to about 1200 ⁇ g, or a therapeutically equivalent amount of one or more capsaicinoids.
  • the capsaicinoid is administered in a pharmaceutically and physiologically acceptable vehicle for injection or implantation.
  • suitable doses of capsaicin/capsaicinoid for injection or implantation for the treatment of nociceptive pain, neuropathic pain, pain from nerve injury, pain from myalgias, pain associated with painful trigger points, pain from tumors in soft tissues, pain associated with neurotransmitter-dysregulation syndromes and pain associated with orthopedic disorders range from about 1 ⁇ g to about 3000 ⁇ g of capsaicin (trans 8-methyl-N-vanillyl-6-noneamide), preferably from about 20 to about 300 micrograms, more preferably from about 35 to 200 micrograms, with 100 ⁇ g most preferred.
  • an injection of local anesthetic can be administered in proximity to the site prior to administration of the capsaicinoid, e.g., as described above and in the appended examples.
  • phenol can be used instead of or in addition to the local anesthetic.
  • the capsaicinoid is administered by injection
  • the capsaicinoid is administered to a discrete site by penetrating the outer layer of the skin with an instrument known to those skilled in the art for administering injections, e.g., a needle and syringe.
  • the dose of capsaicinoid is preferably prepared for injection/implantation by being incorporated into a pharmaceutically and physiologically acceptable vehicle for administration through the skin of the patient (e.g., human or animal).
  • a pharmaceutically and physiologically acceptable vehicle for administration through the skin of the patient (e.g., human or animal).
  • the capsaicinoid may be dissolved in oils, propyleneglycol or other solvents commonly used to prepare injectable or implantable solutions.
  • Suitable pharmaceutically acceptable vehicles preferably include aqueous vehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and any combinations or mixtures thereof.
  • aqueous vehicles preferably include Sodium Chloride Injection, Bacteriostatic Sodium Chloride Injection, Ringers Injection, Isotonic Dextrose Injection, Sterile Water Injection, Bacteriostatic Sterile Water Injection, Dextrose Lactated Ringers Injection and any combinations or mixtures thereof.
  • Nonaqueous parenteral vehicles preferably include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil, peanut oil and any combinations or mixtures thereof.
  • Antimicrobial agents in bacteriostatic or fungistatic concentrations preferably include phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, ethyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride benzethonium chloride and mixtures thereof.
  • Isotonic agents preferably include sodium chloride, dextrose and any combinations or mixtures thereof.
  • Buffers preferably include acetate, phosphate, citrate and any combinations or mixtures thereof.
  • Antioxidants preferably include ascorbic acid, sodium bisulfate and any combinations or mixtures thereof.
  • Suspending and dispersing agents preferably include sodium carboxymethylcelluose, hydroxypropyl methylcellulose, polyvinylpyrrolidone and any combinations or mixtures thereof.
  • Emulsifying agents preferably include Polysorbate 80 (Tween 80).
  • Sequestering or chelating agents of metal ions preferably include ethylenediaminetetraacetic acid.
  • Additional pharmaceutically acceptable vehicles also preferably include ethyl alcohol, polyethylene glycol, glycerin and propylene glycol for water miscible vehicles and sodium hydroxide, hydrochloric acid, citric acid or lactic acid for pH adjustment and any combinations or mixtures thereof.
  • the dose of capsaicinoid can be administered as an aqueous solution or suspension for injection or implantation.
  • Injections are separated into five distinct types, generally classified as (i) medicaments or solutions or emulsions suitable for injection; (ii) dry solids or liquid concentrates containing no buffers, diluents, or other added substances, and which upon the addition of suitable vehicles, yield solutions conforming in all aspects to the requirements for injections; (iii) preparations as described in (ii) except that they contain one or more buffers, diluents or other added substances; (iv) solids which are suspended in a suitable fluid medium and which are not to be injected intravenously or into the spinal canal; and (v) dry solids, which upon the addition of suitable vehicles, yield preparations conforming in all respects to the requirements of Sterile Suspensions (see: H. C. Ansel, Introduction to Pharmaceutical Dosage Forms, 4th Edit., 1985, pg. 238).
  • a surfactant can preferably be combined with one or more of the pharmaceutically acceptable vehicles previously described herein so that the surfactant or buffering agent prevents the initial stinging or burning discomfort associated with capsaicinoid administration, as a wetting agent, emulsifier, solubilizer and/or antimicrobial.
  • Suitable surfactants include, but are not limited to, sodium stearyl fumarate, diethanolamine cetyl sulfate, polyethylene glycol, isostearate, polyethoxylated castor oil, benzalkonium chloride, nonoxyl 10, octoxynol 9, polyoxyethylene sorbitan fatty acids (polysorbate 20, 40, 60 and 80), sodium lauryl sulfate, sorbitan esters (sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitan tristearate, sorbitan laurate, sorbitan oleate, sorbitan palmitate, sorbitan stearate, sorbitan dioleate, sorbitan sesqui-isostearate, sorbitan sesquistearate, sorbitan tri-isostearate),-lecit
  • one or more surfactants when utilized in the formulations of the invention, they may be combined, e.g., with a pharmaceutically acceptable vehicle and may be present in the final formulation, e.g., in an amount ranging from about 0.1% to about 20%, more preferably from about 0.5% to about 10%.
  • Buffering agents may also be used to provide drug stability; to control the therapeutic activity of the drug substance (Ansel, Howard C., “Introduction to Pharmaceutical Dosage Forms,” 4 th Ed., 1985); and/or to prevent the initial stinging or burning discomfort associated with capsaicin administration.
  • Suitable buffers include, but are not limited to sodium bicarbonate, sodium citrate, citric acid, sodium phosphate, pharmaceutically acceptable salts thereof and combinations thereof. When one or more buffers are utilized in the formulations of the invention, they may be combined, e.g., with a pharmaceutically acceptable vehicle and may be present in the final formulation, e.g., in an amount ranging from about 0.1% to about 20%, more preferably from about 0.5% to about 10%.
  • the pharmaceutical vehicle utilized to deliver the injectable capsaicinoid comprises about 20% PEG 300, about 10 mM histidine and about 5% sucrose in water for injection.
  • delivery systems can be used to administer a unit dose of capsaicinoid.
  • the dose of capsaicinoid can preferably be administered as injectable or implantable microparticles (microcapsules and microspheres).
  • the microparticles are preferably in a size and distribution range suitable for implantation or injection.
  • the diameter and shape of the microparticles can be manipulated to modify the release characteristics. For example, larger diameter microparticles will typically provide slower rates of release and reduced tissue penetration and smaller diameters of microparticles will produce the opposite effects, relative to microparticles of different mean diameter, but of the same composition.
  • microparticles can also modify release rates by virtue of the increased ratio of surface area to mass inherent to such alternative geometrical shapes, relative to a spherical shape.
  • the diameter of microparticles preferably range in size from about 5 microns to about 200 microns in diameter.
  • the microparticles range in diameter from about 20 to about 120 microns.
  • the dose of capsaicinoid can be administered in the form of implantable pellets, rods and slabs. Methods for manufacture of microparticles, pellets, rods and slabs are well known in the art and include solvent evaporation, phase separation and fluidized bed coating.
  • the single dose of capsaicin is preferably administered at a discrete site in an amount effective to denervate the discrete site without eliciting an effect outside the discrete location.
  • the single dose is preferably administered in a nerve directly at the site where pain relief is needed, directly into the pain producing structure, or into a nerve that provides inervation to the painful area via injection or implantation.
  • Injectable or implantable administration preferably includes, but is not limited to subcutaneous (under the skin), intramuscular (muscle), itrathecal, epidural, intraperitoneal, caudal, intradermal or intracutaneous (into the skin), intercostals at a single nerve, intra-articular (joints) or body spaces, intrasynovial (joint fluid), intraspinal (spinal column), intra-arterial (arteries) administrations and administration into other connective tissue compartments.
  • intraspinal means into or within the epidural space, the intrathecal space, the white or gray matter of the spinal cord affiliated structures such as the dorsal root and dorsal root ganglia.
  • Examples of intra-articular administration include knee, elbow, hip, sternoclavicular, tempromandibular, carpal, tarsal, wrist, ankle, intervertebral disk, ligamentum flavum and any other joints subject to arthritic conditions.
  • Examples of body spaces include pleura, peritoneium, cranium, mediastinum, pericardium, and bursae or bursal.
  • Examples of bursae include acromial, bicipitoradial, cubitoradial, deltoid, infrapatellar, ishchiadica, and other bursa known to those skilled in the art to be subject to pain.
  • the injection volume of capsaicin will depend on the localized site of administration. Suitable injection volumes to be delivered preferably range from about 0.1 to about 20 ml, more preferably from about 0.5 to about 10 ml and most preferably from about 1.0 to about 5 ml, depending on the site to be treated.
  • a single unit dose capsaicinoid injection or implantation attenuates pain at the site for at least about one month, more preferably at least about 3 months, and typically in certain embodiments from about 3 to about 6 months.
  • a single unit dose capsaicinoid injection or implantation attenuates pain at the site for at least about 3 months to at least about 4 months.
  • a single unit dose capsaicinoid injection or implantation attenuates pain at the site for at least about one week, and in certain embodiments for at least about 1 month.
  • Patients can be monitored for pain relief and increased movement, in the situation where treatment is in a joint. The treatment can be repeated as necessary to control the symptoms.
  • breakthrough pain means pain which the patient experiences despite the fact that the patient is being or was administered generally effective amounts of, e.g., capsaicin.
  • capsaicin e.g., capsaicin
  • the individual may be further administered an effective amount of an analgesic in accordance with the treatment of pain in such situations performed by those skilled in the art.
  • the analgesic may be any known to the person skilled in the art such as those selected from the group comprising gold compounds such as sodium aurothiomalate; non-steroidal anti-inflammatory drugs (NSAIDs) such as naproxen, diclofenac, flurbiprofen, ibuprofen ketoprofen, ketorolac, pharmaceutically acceptable salts thereof and the like; opioid analgesics such as codeine, dextropropoxyphene, dihydrocodeine, morphine, diamorphine, hydromorphone, hydrocodone, methadone, pethidine, oxycodone, levorphanol, fentanyl and alfentanil, para- aminophenol derivatives such as paracetamol, pharmaceutically acceptable salts thereof and the like; and salicylates such as aspirin.
  • gold compounds such as sodium aurothiomalate
  • NSAIDs non-steroidal anti-inflammatory drugs
  • opioid analgesics such as codeine, dextropropoxyphene
  • the primary objective of the study was to evaluate the safety and tolerability of intra-articular capsaicin, when co-administered with intra-articular local anesthetic, compared to placebo, in subjects with end-stage osteoarthritis of the knee, already scheduled to receive knee replacements.
  • Purified capsaicin was supplied in vials containing 5 mL of purified capsaicin at a concentrations of 500 ⁇ g/mL. Study drug was stored at a temperature between 15° C. and 25° C. Within four hours prior to injection, vehicle was used to dilute the drug to final concentrations of purified capsaicin, as follows: TABLE 1 Dose Level Concentration Total Volume of Dose 10 ⁇ g 2 ⁇ g/mL 5 mL 100 ⁇ g 20 ⁇ g/mL 5 mL 300 ⁇ g 60 ⁇ g/mL 5 mL
  • Each vial was used for one infiltration administration only and appropriately labeled.
  • the supplier of the purified capsaicin was FormaTech, Inc., 200 Bullfinch Drive, Andover, Mass. 01810.
  • the vials were supplied in bulk to the study center with each vial labeled according to the contents of the vial.
  • the Pharmacist/Study Nurse who prepared the injection, maintained the investigational product in a lockable cabinet at the required temperature, 15-25° C.
  • the study blind was maintained by the Pharmacist/Study Nurse.
  • Placebo vehicle for purified capsaicin was supplied in vials containing 5 mL.
  • Local anesthetic (Lignocaine 2%) was used for each intra-articular infiltration.
  • the study was a single center, randomized, double blind, placebo controlled, dose ranging Phase 1 study of three dose levels (10 ⁇ g, 100 ⁇ g, or 300 ⁇ g) of intra-articularly administered purified capsaicin, when co-administered with intra-articular local anesthetic, in subjects with osteoarthritis of the knee who were scheduled to undergo total knee replacement.
  • the doses of purified capsaicin used in this trial were well below (>100 fold) doses known to be toxic to animals.
  • the study was designed to include 16 evaluation subjects. Sixteen subjects were enrolled in the study; 12 were treated with ultra-purified capsaicin (4 each with 10, 100, and 300 ⁇ g doses) and 4 were treated with placebo vehicle. Sixteen subjects completed the study.
  • Patients were treated randomly and in double-blind fashion in four treatment cohorts, with each cohort having a progressively longer interval between the intra-articular administration of study medication and subsequent total knee replacement (2, 4, 7, and 14 days).
  • Four subjects, 1 in each of the 4 dose groups (placebo, 10 ⁇ g, 100 ⁇ g, and 300 ⁇ g of capsaicin), were enrolled in each treatment cohort. Gross and microscopic pathology analysis was completed for each treatment cohort before the next treatment cohort was treated.
  • Each subject had 3 study visits: a Screening Day (Day ⁇ 7 to ⁇ 1), the Treatment Day (Day 0), and a Post-Treatment Day (scheduled for Day +2, +4, +7, or +14).
  • the Treatment Day the subject was randomized, pre-treatment evaluation was performed.
  • the patients were brought into the procedure room, and a VAS pain score was taken (0 mm—no pain, 100 mm—extreme pain).
  • Once the patient had marked his or her pain on the card he/she was prepped for knee cannulation. Once the cannula was placed, the patient received by intra-articular infiltration, 3 mg/kg (maximum dose of 200 mg) of 2% lignocaine into the knee scheduled to be replaced.
  • VAS pain scores as well as verbal reports were taken immediately following administration, as welt as prior to knee replacement surgery. No subjects discontinued from the study due to adverse events.
  • capsaicin Immediately following instillation of capsaicin, some patients (0 of 4 receiving placebo, 0 of 4 receiving 10 ⁇ g capsaicin, 1 of 4 receiving 100 ⁇ g capsaicin, and 4 of 4 receiving 300 ⁇ g capsaicin) reported transient burning pain representative of capsaicin injection (onset within a few seconds to minutes and lasting less than one hour). Pain was mild but for some patients, the investigator chose to place ice packs on the treated knee until the pain resolved.
  • the subject in the 100 ⁇ g dose group and 2 of the subjects in the 300 ⁇ g dose group had burning post-administration (hyper) algesic pain alone; two subjects in the 300 ⁇ g dose group had burning pain in conjunction with other types of post-administration (hyper) algesic pain (1 subject had burning and stinging pain and the second subject had burning and toothache-like pain). All of the episodes of post-administration (hyper) algesia began immediately (within 5 minutes) after administration. All of these painful episodes were brief: the duration of this pain was 9 minutes for the subject in the 100 ⁇ g dose group, and 17, 25, 25, and 42 minutes for the subjects in the 300 ⁇ g dose group.
  • the 4 subjects in the 300 ⁇ g dose group and I subject in the 100 ⁇ g dose group required intervention for their post-injection (hyper) algesia. For all but 1 of these 5 subjects, the only intervention was ice packs.
  • One subject in the 300 ⁇ g dose group was treated with paracetamol; no subjects were treated with intravenous morphine or granisetron for post-administration (hyper) algesia.
  • Most of the concomitant medications used in the study were medications taken prior to the study that continued to be taken during the study.
  • the only concomitant non-drug treatments during the study were the ice packs used in the 5 subjects with post-adminitration (hyper) algesia.
  • VAS placebo group
  • VAS capsaicin group
  • FIG. 1 The plasma concentration over time of the three dosage ranges of capsaicin are shown in FIG. 2 .
  • Ten-mL blood samples for subsequent assay of plasma ultra-purified capsaicin concentrations were collected prior to study medication administration, at 30 minutes, 1, 2, and 4 hours after study medication injection, and immediately prior to the first administration of pre-operative medications on the Post Treatment Day.
  • the pharmacokinetic parameters of Cmax, Tmax, AUC(0 ⁇ t last ) and t1 ⁇ 2 were evaluated.
  • the AUC (0 ⁇ t last ) values for the subjects in the 100 ⁇ g dose group (366.10, 75.19, and 511.21 pg*hr/mL) were similar in magnitude to the values for the 300 ⁇ g dose group (449.01, 220.42, and 498.83 pg*hr/mL).
  • the C max values in the 100 ⁇ g dose group (292.06, 79.94, and 538.32 pg/mL) were similar in magnitude to the values in the 300 ⁇ g dose group (207.62, 251.42, and 499.88 pg/mL).
  • T max was 0.5 hours in all 6 subjects.
  • the terminal exponential half lives were brief in all subjects, with values of 0.1498, 1.1488, and 0.1014 hr in the 100 ⁇ g dose group and values of 0.3268, 0.2298, and 0.1663 in the 300 ⁇ g dose group.
  • Purified capsaicin was well tolerated at all dose levels. There was low leakage of study drug from the joint space and gross and microscopic pathology was normal. There were no treatment related signs of eryhema, edema, or hemorrhage at the site of injection, and no treatment related effects on soft tissue, cartilage, or bone upon histopathological examination. No treatment related systemic side effects were seen, and there were no treatment related effects on laboratory safety parameters or vital signs. There was no discemable effect on proprioception at the injected knee in any dose group at any time point.
  • VAS visual analogue scale
  • the primary objective of the study is to evaluate the efficacy of intra-articular capsaicin, when co-administered with intra-articular local anesthetic, compared to placebo, in subjects with end-stage osteoarthritis of the knee, already scheduled to receive knee replacements (21 and 42 days after injection of study medication).
  • Purified capsaicin is supplied in vials containing 5 mL of purified capsaicin at a concentrations of 500 ⁇ g/mL. Study drug was stored at a temperature between 15° C. and 25° C. Within four hours prior to injection, vehicle is used to dilute the drug to final concentrations of purified capsaicin, as follows: TABLE 2 Dose Level Concentration Total Volume of Dose 1000 ⁇ g 200 ⁇ g/mL 5 mL
  • Each vial is used for one infiltration administration only and appropriately labeled.
  • the supplier of the purified capsaicin is FormaTech, Inc., 200 Bullfinch Drive, Andover, Mass. 01810.
  • the vials are supplied in bulk to the study center with each vial labeled according to the contents of the vial.
  • the Pharmacist/Study Nurse who prepares the injection, maintaines the investigational product in a lockable cabinet at the required temperature, 15-25° C.
  • the study blind is maintained by the Pharmacist/Study Nurse.
  • Placebo vehicle for purified capsaicin is supplied in vials containing 5 mL.
  • Local anesthetic (Lignocaine 2%) is used for each subacromial bursa infiltration.
  • the study is a single center, randomized, double blind, placebo controlled, dose ranging Phase 2 study of capsaicin (1000 ⁇ g) administered by intra-articular infiltration, when co-administered with intra-articular local anesthetic, in subjects with osteoarthritis of the knee who are scheduled to undergo total knee replacement from three to six weeks post study drug administration, wherein the primary endpoint is pain reduction at three weeks following study drug administration.
  • the study is designed to include 12 evaluation subjects (Patients suffering a defined pain: >40 mm on VAS). Six (6) subjects will be treated with capsaicin 1000 ⁇ g and 6 subjects will be treated with placebo vehicle. Patients are treated randomly and in double-blind fashion. Gross and microscopic pathology analysis are completed for each treatment group. Each subject has 3 study visits: a Screening Day (Day ⁇ 7 to ⁇ 1), the Treatment Day (Day 0), and a Post-Treatment Day (scheduled for Day +2, +4, +7, or +14). On the Treatment Day the subject is randomized, pre-treatment evaluation is performed. The patient is brought into the procedure room, and a VAS pain score is taken (0 mm—no pain, 100 mm—extreme pain).
  • the patient marks his or her pain on the card, he/she is prepped for knee cannulation.
  • the patient receives, by intra-articular infiltration, 3 mg/kg (maximum dose of 200 mg) of 2% lignocaine into the knee scheduled to be replaced.
  • This infiltration of local anesthetic is followed in 10 minutes by an intra-articular infiltration of placebo (vehicle) or 1000 ⁇ g of purified capsaicin diluted with vehicle to a total volume of 5 mL.
  • VAS pain scores as well as verbal reports are taken immediately following administration, as well as prior to knee replacement surgery.
  • Post-Treatment Day a study evaluation is performed followed by the scheduled knee replacement, with intra-operative bone and soft tissue biopsies performed for subsequent examination.
  • patients having surgery two days following infiltration are excluded since analgesia from remaining lignocaine or residual pain from the actual procedure (large volume injection) and lysing c-fiber endings is not capable of being excluded.
  • NRS Neurodegeneration Rating Scale
  • the primary objective of the study was to evaluate the safety and tolerability of capsaicin, when co-administered by intra-articular infiltration with a local anesthetic, compared to placebo, in subjects with hallux valgus deformity, already scheduled to undergo transpositional osteotomy (bunionectomy).
  • the secondary objective of the study was to evaluate the safety, tolerability and systemic pharmacokinetics of purified capsaicin following intra-operative administration.
  • the primary efficacy endpoint was the proportion of subjects in each treatment group requiring opioid analgesia in the first 24 hours post-operatively. The proportions were compared amongst treatment groups using the Cochran-Haenszel test.
  • the median time to first usage of opioid analgesia will be estimated in both treatment groups. Pairwise comparisons will be performed to test for equality of the survival curves between the 2 treatment groups using both the log-rank and the Wilcoxon test); iv) total usage of analgesia in each treatment group (the total usage of analgesia will be compared by an analysis of variance with treatment and center as independent variables. A pairwise comparison will be performed between the treatment groups); and v) VAS assessment of pain at the site of operation in each treatment group (The VAS score at each time point will be compared by an analysis of variance with treatment and center as independent variables. A pairwise comparison will be performed between the treatment groups).
  • Safety endpoints included: i) laboratory safety parameters; ii) adverse events; and iii) purified capsaicin blood levels.
  • the efficacy analysis was performed on the data obtained ten days postoperatively.
  • the safety analysis was performed based on the safety data for the entire study, including the 6 week and 12 week follow-up periods. The blind was broken at the time the efficacy analysis was performed. However, the individual treatment assignment was available to the statistical analysis group only. All other personnel involved in the study, including the Investigator, study monitor and proprietary staff, remained blinded until the entire study was completed.
  • Purified capsaicin was supplied in vials containing 5 mL of purified capsaicin at a concentrations of 500 ⁇ g/mL. Study drug was stored at a temperature between 15° C. and 25° C. Within four hours prior to injection, vehicle was used to dilute the drug to final concentrations of purified capsaicin, as follows: TABLE 3 Dose Level Concentration Total Volume of Dose 1000 ⁇ g 250 ⁇ g/mL 4 mL
  • Each vial was used for one infiltration administration only and appropriately labeled.
  • the supplier of the purified capsaicin was FormaTech, Inc., 200 Bullfinch Drive, Andover, Mass. 01810.
  • the vials were supplied in bulk to the study center with each vial labeled according to the contents of the vial.
  • the Pharmacist/Study Nurse who prepared the injection, maintained the investigational product in a lockable cabinet at the required temperature, 15-25° C.
  • the study blind was maintained by the Pharmacist/Study Nurse.
  • Placebo vehicle for purified capsaicin was supplied in vials containing 5 mL.
  • Local anesthetic (Lignocaine 2%) was used for each infiltration.
  • the study was a single center, randomized, double blind, placebo controlled, Phase II study of the safety and efficacy of intra-operative capsaicin, when co-administered with local anaesthetic, in subjects undergoing transpositional first metatarsal osteotomy and fixation for the correction of hallux valgus deformity.
  • the dose of capsaicin used in the trial was 1000 ⁇ g.
  • the study was designed to include 40 evaluation subjects. Twenty (20) randomized to the capsaicin treatment group and twenty (20) to the placebo control group. Each subject had six (6) study visits: a Screening Day (Day ⁇ 28 to ⁇ 1), an Operation Day (Day 0), and four (4) Follow-up visits (scheduled for Days 3, 10 and weeks 6 and 12).
  • VAS assessment of pain at the operation site was performed at 1, 4, 8, 12 and 24 hours post administration. In those instances where VAS measurements coincide with blood sampling procedures, the VAS assessment was performed first. Blood samples for measurement of capsaicin concentration were obtained at 1, 2, and 4 hours post administration. The quantity of each blood sample was 10 mL. Laboratory safety assessments, e.g., haematology, biochemistry, urinalysis were performed at 24 hours post administration. Adverse events were spontaneously reported by the subject and recorded.
  • the primary objective of the study is to evaluate the safety and efficacy of and to determine the duration of effect of a single dose of capsaicin in subjects with recent onset of acute epicondylitis.
  • the primary efficacy endpoint is the assessment of pain at Day 28 (3 days) as defined by Subject evaluation of pain on movement, measured by the VAS scale at 1 hour, 3 hours, 7 days (2 days) and 28 days (3 days) post-treatment.
  • the secondary efficacy endpoints are: i) subject assessment of symptoms on movement, measured by the 5-point scale at 1 hour, 3 hours, 7 days (2 days) and 28 days (3 days) post-treatment; ii) Investigator assessment of tenderness, measured by the 5-point scale at 1 hour, 3 hours, 7 days (2 days) and 28 days (3 days) post-treatment; iii) Investigator global evaluation of improvement, measured by the 6-point scale at 1 hour, 3 hours, 7 days (2 days) and 28 days (3 days) post-treatment; and iv) subject global evaluation of improvement, measured by the 6-point scale at 1 hour, 3 hours, 7 days (2-days) and 28 days (3 days) post-treatment.
  • Purified capsaicin is supplied in vials containing 5mL of purified capsaicin at a concentrations of 500 ⁇ g/mL. Study drug is stored at a temperature between 15° C. and 25° C. Within four hours prior to injection, vehicle is used to dilute the drug to final concentrations of purified capsaicin, as follows: TABLE 5 Dose Concentration Total Volume of Dose 600 ⁇ g 300 ⁇ g/ml 2 ml
  • Each vial is used for one subcutaneous injection only and appropriately labeled.
  • the supplier of the purified capsaicin is FormaTech, Inc., 200 Bullfinch Drive, Andover, Mass. 01810.
  • the vials are supplied in bulk to the study center with each vial labeled according to the contents of the vial.
  • the Pharmacist/Study Nurse who prepares the injection, maintains the investigational product in a lockable cabinet at the required temperature, 15-25“C.
  • the study blind is maintained by the Pharmacist/Study Nurse.
  • Placebo vehicle for purified capsaicin is supplied in vials containing 5 mL.
  • Local anesthetic (Lignocaine 2%) is used for each subcutaneous injection.
  • VAS Visual Analog Scale
  • Study treatment is administered to 40 subjects (20 randomized to receive 600 ⁇ g of capsaicin and 20 randomized to receive placebo).
  • Each study subject has four (4) study visits: Baseline visit (day ⁇ 7 ⁇ 4 days); Visit 2 (Day 0); and follow-up visits at Day 7 (2 days) and at Day 28 (3 days) after the administration of study treatment.
  • a review of inclusion/exclusion criteria as well as laboratory assessments are conducted.
  • lidocaine is injected by deep subcutaneous injection into muscle and tissue 1 cm distal to the lateral/medial epicondyle and aiming towards the tender spot, 10 minutes prior to injection with study drug. Study drug is then injected and firm pressure is applied to the injection site.
  • the study subject is asked to provide an NPS value for pain immediately upon injection, and 1 and 3 hours after injection.
  • a review of adverse events is conducted.
  • Some subjects receiving capsaicin may experience a short-lived painful burning sensation post-injection. This is usually adequately controlled by the application of ice packs until the symptoms have resolved, or until a maximum of 20 minutes have passes. (which ever is shorter).
  • a bolus injection of morphine is administered, which is preceded by a single bolus injection of granisetron (3 mg).
  • rescue medication in the form of paracetamol 500 mg tablets will be provided to all subjects at Visit 2 (Day 0). Subjects will be instructed to take 2 paracetamol tablets (1 gm) every 4-6 hours up to a maximum of 4 g/day if break through pain occurs.
  • the study subject On Visit 3 (day 7 ⁇ 2 days) the study subject is evaluated as follows: First, use of concomitant medications are evaluated. Changes from Visit 2 are recorded on the study subject's CRF. A clinical evaluation of the elbow is performed utilizing the following evaluation parameters: i) subject's evaluation of pain on movement (VAS); ii) subject's assessment of symptoms on movement (5-point scale); iii) investigator's assessment of tenderness (5-point scale); iv) investigator's Global Evaluation of Improvement (6-point scale); and v) subject's Global Evaluation of Improvement (6-point scale). A review of adverse events is conducted.
  • VAS pain on movement
  • iii) investigator's assessment of tenderness (5-point scale
  • investigator's Global Evaluation of Improvement (6-point scale iv) investigator's Global Evaluation of Improvement (6-point scale
  • subject's Global Evaluation of Improvement (6-point scale A review of adverse events is conducted.
  • the primary objective of the study is to evaluate the safety and efficacy of and to determine the duration of effect of a single dose of capsaicin in subjects with recent onset of painful shoulder.
  • the primary efficacy endpoint is the assessment of pain and function at Day 28 (3 days) as defined by: i) subject evaluation of pain and disability index on movement, measured by the SPADI scale at 28 days (3 days) post-treatment.
  • the secondary efficacy endpoints are: Subject assessment of SPADI score at 1 hours, 3 hours and 7 days (2 days); ii) subject assessment of symptoms on movement, measured by the 5-point scale at 1 hour, 3 hours, 7 days (2 days) and 28 days (3 days) post-treatment; iii) Investigator assessment of tenderness, measured by the 5-point scale at 1 hour, 3 hours, 7 days (2 days) and 28 days (3 days) post-treatment; iv) Investigator assessment of restricted movement, measured by degree of active/passive abduction, presence of painful arc, active/passive flexion and % of internal/external rotation with resistance at 1 hour, 3 hours, 7 days (2 days) and 28 days (3 days) post-treatment; v) Investigator global evaluation of improvement, measured by the 6-point scale at 1 hour, 3 hours, 7 days (2 days) and 28 days (3 days) post-treatment; subject global evaluation of improvement, measured by the 6-point scale at 1 hour, 3 hours, 7 days (2 days) and 28 days (3 days) post-treatment.
  • Purified capsaicin is supplied in vials containing 5 mL of purified capsaicin at a concentrations of 500 ⁇ g/mL. Study drug is stored at a temperature between 15° C. and 25° C. Within four hours prior to injection, vehicle is used to dilute the drug to final concentrations of purified capsaicin, as follows: TABLE 6 Dose Concentration Total Volume of Dose 600 ⁇ g 300 ⁇ g/ml 2 ml
  • Each vial is used for one subcutaneous injection only and appropriately labeled.
  • the supplier of the purified capsaicin is FormaTech, Inc., 200 Bullfinch Drive, Andover, Mass. 01810.
  • the vials are supplied in bulk to the study center with each vial labeled according to the contents of the vial.
  • the Pharmacist/Study Nurse who prepares the injection, maintains the investigational product in a lockable cabinet at the required temperature, 15-25° C.
  • the study blind is maintained by the Pharmacist/Study Nurse.
  • Placebo vehicle for purified capsaicin is supplied in vials containing 5 mL.
  • Local anesthetic (Lignocaine 2%) is used for each subcutaneous injection.
  • Study treatment is administered to 54 subjects (27 randomized to receive 600 ⁇ g of capsaicin and 27 randomized to receive placebo).
  • Each study subject has four (4) study visits: Baseline visit (day ⁇ 7 ⁇ 4 days); Visit 2 (Day 0); and follow-up visits at Day 7 (2 days) and at Day 28 (3 days) after the administration of study treatment.
  • Visit 1 (day ⁇ 7 ⁇ 4 days) baseline assessments are initiated, which include medical history, physical exam, vital signs, review of concomitant medication use, shoulder pain history, clinical evaluation of the shoulder as follows: i) Shoulder Pain and Disability Index; ii) subject's assessment of symptoms on movement (5-point scale); iii) investigator's assessment of tenderness (5-point scale); and iv) investigator's measurement of restricted movement. A review of inclusion/exclusion criteria as well as laboratory assessments are also conducted.
  • Eligible study subjects are randomized to receive either capsaicin 600 ⁇ g or placebo.
  • Study drug is administered according to the following procedure: the study subject is positioned in the sitting position. Aseptic technique is observed. The skin around the site of administration is cleaned. Then up to 1.0 mL of 2% lidocaine is administered by subacromial bursa injection, 10 minutes prior to injection of the study drug. Study drug is injected into the subacromial bursa with a 22-gauge 1.5 inch needle inserted into the space between the acromium and the humerus on the lateral aspect of the shoulder. The needle is withdrawn cleanly and firm pressured is applied to the injection site.
  • the study subject will be asked to provide an NPS value for pain immediately upon injection, and 1 and 3 hours after injection.
  • Some subjects receiving capsaicin may experience a short-lived painful burning sensation post-injection. This is usually adequately controlled by the application of ice packs until the symptoms have resolved, or until a maximum of 20 minutes have passes. (which ever is shorter). However, when additional analgesic management be required, a bolus injection of morphine is administered, which is preceded by a single bolus injection of granisetron (3 mg).
  • the study subject On Visit 3 (day 7 ⁇ 2 days) the study subject is evaluated as follows: First, use of concomitant medications are evaluated. Changes from Visit 2 are recorded on the study subject's CRF. A clinical evaluation of the shoulder is performed utilizing the following evaluation parameters: i) Shoulder Pain and Disability Index; ii) subject's assessment of symptoms on movement (5-point scale); iii) investigator's assessment of tenderness (5-point scale); iv) investigator's measurement of restricted movement; v) investigator's Global Evaluation of Improvement (6-point scale); and vi) subject's Global Evaluation of Improvement (6-point scale). A review of adverse events is conducted.
  • the primary objective of the study is to determine the amount of opioid consumption and postoperative pain scores following median sternotomy for patients receiving purified capsaicin by infiltration and/or injection.
  • Eligible subjects are patients undergoing cardiac, pulmonary, or mediastinal surgery for any indication between the ages of 20-70 years. The operation is performed under general anesthesia and are closely observed in a post-anesthesia care unit as per the practice of the institution.
  • the study drug will be administered to the sternal edges, muscles (e.g., muscle edges), bone (e.g., bone edges), and tissues. All patients will receive standard of care opioid on demand for treatment of pain when transferred to the ward.
  • the dose of capsaicin is administered to the sternal edges, the muscle.
  • Pain is assessed utilizing VAS 100 mm scale—baseline, every 60 minutes beginning when the patient first is placed in a bedside chair (or ambulated) for 24 hours and then every 4 hours while awake until discharge from the hospital. Patient diaries will be used following discharge for a two-week period.
  • the primary study endpoint is the time to first request of postoperative opioid.
  • the amount of opioid rescue used is recorded every 24 hours for the first 2 weeks, patients will complete an opioid-related symptom distress (SDS) questionnaire.
  • SDS opioid-related symptom distress
  • This study will evaluate the efficacy of purified capsacin administered by injection for the treatment of chronic post-herniorhappy pain in subjects who are >6 months after open inguinal herniorrhaphy with chronic pain from the surgical area influencing some type of social activities (work, leisure or sports activities, etc.). Study subjects will receive a dose of purified capsaicin in proximity to the surgical site. Pain during rest and well-defined function in relation to factors, which may provoke pain (key end-points) are evaluated. In addition, QST assessment of the surgical area before and after therapy is conducted.
  • the primary objective of this study is to evaluate the amount of opioid consumption and postoperative pain scores following laparoscopic cholecystectomy in patients administered purified capsaicin by infiltration and/or injection. Study subjects will receive a dose of purified capsaicin in proximity to the surgical site.
  • This study includes 40 patients (20 randomized to receive capsaicin study drug and 20 randomized to receive placebo study drug) between the ages of 20-60 years old with symptomatic gallstones.
  • the operation is performed under general anesthesia and the subject is closely observed in a post-anesthesia care unit for up to 24 hours and remains in the hospital (typically for 1 to 5 days).
  • All patients receive standard of care opioid on demand for treatment of pain before discharge, and opioid (to be determined) post discharge. Pain is assessed utilizing VAS 100 mm scale—baseline, every 30 minutes till the 2nd postoperative hour then every 4 hours the following 12 hours, an at 24 hours and at days 2, 3, 4, 5, 6 and 7.
  • Patient diaries are used following discharge.
  • Study subject will receive a, dose of purified capsaicin 1000-3000 ⁇ g divided over the 4 part wounds-infiltrated along the cut muscle edges.
  • the primary study endpoint is the time to first request of postoperative analgesia
  • the amount of opioid rescue is every 24 hours for first 3 days, patients complete an opioid-related symptom distress (SDS) questionnaire.
  • the primary objective of the study is to determine the short and intermediate term benefit of purified capsaicin administration by injection in subjects with Morton's Neuroma.
  • Study subjects will receive a dose of purified capsaicin at the site, and baseline pain is assessed utilizing a patient diary based on a 100 mm VAS scale. For inclusion in the trial, mean pain score for the 5 days prior to randomization must be greater than 40 mm.
  • the endpoint of the study is pain measured on a 100 mm VAS, as assessed in the patient diary. Pain scores are averaged on a weekly basis for the 8 weeks following injection. Patients will continue to be followed long-term (minimum 4 months).
  • the primary objective of the study is to evaluate the amount of opioid consumption and postoperative pain scores following knee replacement surgery for patients receiving administration of purified capsaicin by infiltration.
  • This study includes 80 patients (20 patients are randomized to receive placebo, 20 randomized to receive capsaicin 300 ⁇ g, 20 randomized to receive capsaicin 1000 ⁇ g, and 20 randomized to receive capsaicin 2000 ⁇ g).
  • Eligible subjects are patients who undergoing knee replacement surgery between the ages of 20-70 years old.
  • the knee replacement operation is performed under general anesthesia and is closely observed in a post-anesthesia care unit as per the practice of the institution. All patients receive standard of care opioid on demand for treatment of pain once transferred to the ward.
  • the volume of capsaicin administered into the wound opening during closure ranges from about 5 ml to about 10 ml.
  • Pain is assessed utilizing VAS 100 mm scale—baseline, every 60 minutes beginning when the patient first is placed on mechanical flexion/extension for 24 hours and then every 4 hours while awake until discharge from the hospital. Patient diaries are used following discharge for a two-week period.
  • Mastectomy results in significant pain and requires substantial doses of opioids postoperatively.
  • Analgesic techniques that provide good pain control while minimizing opioid side effects are thus highly desirable.
  • the primary objective of the study determines the amount of opioid consumption and postoperative pain scores following mastectomy for patients receiving capsaicin.
  • the study includes 80 patients (20 patients are randomized to receive placebo, 20 randomized to receive capsaicin 300 ⁇ g, 20 randomized to receive capsaicin 1000 ⁇ g, and 20 randomized to receive capsaicin 2000 ⁇ g).
  • Eligible patients include patients undergoing mastectomy between the ages of 20-70 years old. The operation is performed under general anesthesia and is closely observed in a post-anesthesia care unit as per the practice of the institution. All patients receive standard of care opioid on demand for treatment of pain once transferred to the ward.
  • the dose of study drug is administered by infiltration in a volume from about 5 ml to about 10 ml within the wound cavity during closure.
  • Pain is assessed utilizing VAS 100 mm scale—baseline, every 60 minutes beginning when the patient first is placed on mechanical flexion/extension for 24 hours and then every 4 hours while awake until discharge from the hospital. Patient diaries are used following discharge for a two-week period.
  • the primary endpoint is time to first request of postoperative opioid. Opioid rescue occurs every 24 hours for the first 2 weeks, patients complete an opioid-related symptom distress (SDS) questionnaire.
  • SDS opioid-related symptom distress

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Neurosurgery (AREA)
  • Rheumatology (AREA)
  • Anesthesiology (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Mycology (AREA)
  • Dermatology (AREA)
  • Botany (AREA)
  • Medical Informatics (AREA)
  • Microbiology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Biotechnology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Immunology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
US10/742,621 2002-12-18 2003-12-18 Injectable capsaicin Abandoned US20050019436A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US10/742,621 US20050019436A1 (en) 2002-12-18 2003-12-18 Injectable capsaicin
US11/499,995 US8420600B2 (en) 2002-12-18 2006-08-07 Injectable capsaicin
US12/077,494 US20080260791A1 (en) 2002-12-18 2008-03-18 Injectable capsaicin
US13/862,260 US20130303620A1 (en) 2002-12-18 2013-04-12 Injectable Capsaicin
US15/363,475 US20170266139A1 (en) 2002-12-18 2016-11-29 Injectable resiniferatoxin
US16/737,557 US20200375926A1 (en) 2002-12-18 2020-01-08 Injectable resiniferatoxin

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US43445302P 2002-12-18 2002-12-18
US46116403P 2003-04-08 2003-04-08
US10/742,621 US20050019436A1 (en) 2002-12-18 2003-12-18 Injectable capsaicin

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US11/499,995 Division US8420600B2 (en) 2002-12-18 2006-08-07 Injectable capsaicin
US12/077,494 Continuation US20080260791A1 (en) 2002-12-18 2008-03-18 Injectable capsaicin

Publications (1)

Publication Number Publication Date
US20050019436A1 true US20050019436A1 (en) 2005-01-27

Family

ID=32685309

Family Applications (5)

Application Number Title Priority Date Filing Date
US10/741,195 Abandoned US20050020690A1 (en) 2002-12-18 2003-12-18 Infiltration of capsaicin into surgical sites and open wounds
US10/742,621 Abandoned US20050019436A1 (en) 2002-12-18 2003-12-18 Injectable capsaicin
US11/499,989 Active 2026-10-30 US8367733B2 (en) 2002-12-18 2006-08-07 Infiltration of capsaicin into surgical sites and open wounds
US12/077,494 Abandoned US20080260791A1 (en) 2002-12-18 2008-03-18 Injectable capsaicin
US12/077,492 Abandoned US20080262091A1 (en) 2002-12-18 2008-03-18 Infiltration of capsaicin into surgical sites and open wounds

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US10/741,195 Abandoned US20050020690A1 (en) 2002-12-18 2003-12-18 Infiltration of capsaicin into surgical sites and open wounds

Family Applications After (3)

Application Number Title Priority Date Filing Date
US11/499,989 Active 2026-10-30 US8367733B2 (en) 2002-12-18 2006-08-07 Infiltration of capsaicin into surgical sites and open wounds
US12/077,494 Abandoned US20080260791A1 (en) 2002-12-18 2008-03-18 Injectable capsaicin
US12/077,492 Abandoned US20080262091A1 (en) 2002-12-18 2008-03-18 Infiltration of capsaicin into surgical sites and open wounds

Country Status (14)

Country Link
US (5) US20050020690A1 (es)
EP (1) EP1605956B1 (es)
JP (4) JP2006513267A (es)
CN (2) CN1750839B (es)
AU (1) AU2003299691B2 (es)
BR (1) BR0316906A (es)
CA (1) CA2510181C (es)
DK (1) DK1605956T3 (es)
EA (1) EA011708B1 (es)
ES (1) ES2562025T3 (es)
MX (1) MXPA05006670A (es)
NZ (1) NZ540769A (es)
PT (1) PT1605956E (es)
WO (1) WO2004058286A1 (es)

Cited By (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040156931A1 (en) * 2002-12-18 2004-08-12 Algorx Administration of capsaicinoids
US20050020690A1 (en) * 2002-12-18 2005-01-27 Algorx Infiltration of capsaicin into surgical sites and open wounds
US20060148903A1 (en) * 2004-11-24 2006-07-06 Algorx Pharmaceuticals, Inc. Capsaicinoid gel formulation and uses thereof
US20060211982A1 (en) * 2002-12-20 2006-09-21 Steven Prestrelski Intracutaneous injection
US20070293703A1 (en) * 2003-04-08 2007-12-20 Algorx Pharmaceuticals, Inc. Preparation and purification of synthetic capsaicin
US20080058362A1 (en) * 2006-08-31 2008-03-06 Singh Chandra U Novel pharmaceutical compositions for treating chronic pain and pain associated with neuropathy
US20080153780A1 (en) * 2004-12-28 2008-06-26 Mestex Ag Use Of A Vanilloid Receptor Agonist Together With A Glycosaminoglycan Or Proteoglycan For Producing An Agent For Treating Articular Pains And Method For Applying Said Agent
US20100120912A1 (en) * 2008-10-30 2010-05-13 Trinity Laboratories Inc. Esters of capsaicinoids as dietary supplements
US20100211071A1 (en) * 2009-02-13 2010-08-19 Lettmann Jason W Methods and devices for treating hallux valgus
US20110077656A1 (en) * 2009-09-25 2011-03-31 Sand Paul M Methods and devices for treating a structural bone and joint deformity
US7943666B2 (en) * 2006-07-24 2011-05-17 Trinity Laboratories, Inc. Esters of capsaicin for treating pain
KR101129365B1 (ko) * 2009-08-07 2012-03-26 고려대학교 산학협력단 추간판 질환용 서방성 치료제 및 이의 제조방법
KR101138317B1 (ko) * 2011-08-09 2012-04-25 고려대학교 산학협력단 추간판 질환용 서방성 치료제 및 이의 제조방법
US8317808B2 (en) 2008-02-18 2012-11-27 Covidien Lp Device and method for rolling and inserting a prosthetic patch into a body cavity
US8652141B2 (en) 2010-01-21 2014-02-18 Tarsus Medical Inc. Methods and devices for treating hallux valgus
US8696719B2 (en) 2010-06-03 2014-04-15 Tarsus Medical Inc. Methods and devices for treating hallux valgus
US8697644B2 (en) 2011-03-10 2014-04-15 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of peptide drugs
WO2014075084A2 (en) 2012-11-12 2014-05-15 Api Genesis Llc Aqueous based capsaicinoid formulations and methods of manufacture and use
US8753359B2 (en) 2008-02-18 2014-06-17 Covidien Lp Device and method for deploying and attaching an implant to a biological tissue
US8758373B2 (en) 2008-02-18 2014-06-24 Covidien Lp Means and method for reversibly connecting a patch to a patch deployment device
US8808314B2 (en) 2008-02-18 2014-08-19 Covidien Lp Device and method for deploying and attaching an implant to a biological tissue
US8888811B2 (en) 2008-10-20 2014-11-18 Covidien Lp Device and method for attaching an implant to biological tissue
US8906045B2 (en) 2009-08-17 2014-12-09 Covidien Lp Articulating patch deployment device and method of use
US9018162B2 (en) 2013-02-06 2015-04-28 Xeris Pharmaceuticals, Inc. Methods for rapidly treating severe hypoglycemia
US9034002B2 (en) 2008-02-18 2015-05-19 Covidien Lp Lock bar spring and clip for implant deployment device
WO2015073577A1 (en) 2013-11-12 2015-05-21 Vizuri Health Sciences Llc Aqueous based capsaicinoid formulations and methods of manufacture and use
US9044235B2 (en) 2008-02-18 2015-06-02 Covidien Lp Magnetic clip for implant deployment device
CN104689253A (zh) * 2015-03-31 2015-06-10 都炳霞 一种治疗胆囊切除后综合症的中药组合物
US9125805B2 (en) 2012-06-27 2015-09-08 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of small molecule drugs
US9138479B2 (en) 2011-10-31 2015-09-22 Xeris Pharmaceuticals, Inc. Formulations for the treatment of diabetes
US9301826B2 (en) 2008-02-18 2016-04-05 Covidien Lp Lock bar spring and clip for implant deployment device
US9351976B2 (en) 2011-03-18 2016-05-31 Alkermes Pharma Ireland Limited Pharmaceutical compositions comprising sorbitan esters
US9393002B2 (en) 2008-02-18 2016-07-19 Covidien Lp Clip for implant deployment device
US9393093B2 (en) 2008-02-18 2016-07-19 Covidien Lp Clip for implant deployment device
US9398944B2 (en) 2008-02-18 2016-07-26 Covidien Lp Lock bar spring and clip for implant deployment device
US9649364B2 (en) 2015-09-25 2017-05-16 Xeris Pharmaceuticals, Inc. Methods for producing stable therapeutic formulations in aprotic polar solvents
US9687527B2 (en) 2010-07-19 2017-06-27 The Regents Of The University Of Colorado, A Body Corporate Stable glucagon formulations for the treatment of hypoglycemia
WO2017127628A1 (en) * 2016-01-22 2017-07-27 Centrexion Therapeutics Corporation Capsaicn sequential dosing method for treatment of morton's neuroma pain
US9833240B2 (en) 2008-02-18 2017-12-05 Covidien Lp Lock bar spring and clip for implant deployment device
US9861699B2 (en) 2012-09-19 2018-01-09 Alkermes Pharma Ireland Limited Pharmaceutical compositions having improved storage stability
US9993556B2 (en) 2012-03-19 2018-06-12 Alkermes Pharma Ireland Limited Pharmaceutical compositions comprising fatty glycerol esters
US9999424B2 (en) 2009-08-17 2018-06-19 Covidien Lp Means and method for reversibly connecting an implant to a deployment device
US9999670B2 (en) 2012-03-19 2018-06-19 Alkermes Pharma Ireland Limited Pharmaceutical compositions comprising benzyl alcohol
US10004807B2 (en) 2012-03-19 2018-06-26 Alkermes Pharma Ireland Limited Pharmaceutical compositions comprising fatty acid esters
CN108273027A (zh) * 2018-04-02 2018-07-13 史兰 一种治疗膝骨关节炎的药膏
US10085980B2 (en) 2014-03-20 2018-10-02 Alkermes Pharma Ireland Limited Aripiprazole formulations having increased injection speeds
US20190076396A1 (en) * 2017-09-11 2019-03-14 Sorrento Therapeutics, Inc. Formulation of resiniferatoxin
KR20190101368A (ko) * 2016-11-02 2019-08-30 센트렉시온 테라퓨틱스 코포레이션 안정한 수성의 캡사이신 주사 가능한 제형 및 이의 의학적 용도
US11020403B2 (en) 2017-06-02 2021-06-01 Xeris Pharmaceuticals, Inc. Precipitation resistant small molecule drug formulations
US11129940B2 (en) 2014-08-06 2021-09-28 Xeris Pharmaceuticals, Inc. Syringes, kits, and methods for intracutaneous and/or subcutaneous injection of pastes
US11273158B2 (en) 2018-03-05 2022-03-15 Alkermes Pharma Ireland Limited Aripiprazole dosing strategy
US11590205B2 (en) 2015-09-25 2023-02-28 Xeris Pharmaceuticals, Inc. Methods for producing stable therapeutic glucagon formulations in aprotic polar solvents
US11992470B2 (en) 2022-03-22 2024-05-28 Centrexion Therapeutics Corporation Stable aqueous capsaicin injectable formulations and medical uses thereof

Families Citing this family (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE502004011941D1 (de) * 2004-12-22 2011-01-05 Mestex Ag Mischung eines vanilloidrezeptoragonisten mit einer nervenregenerationshemmenden substanz, ihre verwendung für die herstellung eines schmerzmittels und verfahren zur applikation dieses mittels
ES2533256T3 (es) 2004-12-28 2015-04-08 Mestex Ag Uso de resiniferatoxina (RTX) para la fabricación de un medicamento para el tratamiento del dolor
WO2008099615A1 (ja) 2007-02-16 2008-08-21 Aska Pharmaceutical Co., Ltd. 微粒子油性懸濁液を含む医薬組成物
WO2008136012A1 (en) * 2007-05-03 2008-11-13 Rajesh Shah Oral medicinal preparations
US8158682B2 (en) * 2008-09-12 2012-04-17 Vallinex, Inc. Instillation administration of capsaicinoids for the treatment of pain
WO2010030258A1 (en) * 2008-09-12 2010-03-18 Anesiva, Inc. Instillation administration of capsaicinoids for the treatment of pain
US8980223B2 (en) * 2009-05-07 2015-03-17 University Of Cincinnati Methods of preventing ischemic injury using peripheral nociceptive stimulation
WO2013012892A2 (en) 2011-07-19 2013-01-24 The Board Of Trustees Of The Leland Stanford Junior University Treatments for diabetes mellitus and obesity
CN102600232A (zh) * 2012-04-10 2012-07-25 何平清 一种治疗骨折、断筋的中草药
EP2818162A1 (en) * 2013-06-28 2014-12-31 Encubator AB A composition for use in the treatment of intervertebral disc-related pain
JP6563954B2 (ja) 2014-04-15 2019-08-21 ヴィズリ・ヘルス・サイエンスィズ・エルエルシー 痛みの緩和のための局所組成物、製造および使用
EP3785700A1 (en) 2014-04-21 2021-03-03 Heron Therapeutics, Inc. Compositions of a polyorthoester and an organic acid excipient
CN104338039A (zh) * 2014-10-29 2015-02-11 黄显娥 一种治疗慢性尿路感染的中药
CN104383217B (zh) * 2014-11-05 2018-06-12 刘永秋 一种用于治疗脚气的中药组合物及其制备方法
WO2016077749A1 (en) * 2014-11-13 2016-05-19 Centrexion Therapeutics Corporation Capsaicinoids for use in treating acral lick granuloma
US9359316B1 (en) 2014-11-25 2016-06-07 Concentric Analgesics, Inc. Prodrugs of phenolic TRPV1 agonists
US11634384B2 (en) 2014-11-25 2023-04-25 Concentric Analgesics, Inc. Prodrugs of phenolic TRPV1 agonists
WO2017020125A1 (en) 2015-07-31 2017-02-09 Delivra Inc. Transdermal formulations for delivery of capsaicinoids
ITUB20153879A1 (it) * 2015-09-24 2017-03-24 Professional Dietetics Spa Composizioni per il trattamento del dolore in pazienti sottoposti ad artroplastica elettiva
WO2017112693A1 (en) * 2015-12-22 2017-06-29 The Arizona Board Of Regents On Behalf Of The University Of Arizona Compositions and methods for treatment, amelioration, and prevention of anesthesia-induced hypothermia
CN105497517A (zh) * 2015-12-31 2016-04-20 陈彬 一种治疗气血两虚型产后腹痛的中药组合物及其制备方法
CN105582310A (zh) * 2015-12-31 2016-05-18 陈彬 一种治疗瘀滞子宫型产后腹痛的中药组合物及其制备方法
CN105560860A (zh) * 2016-01-03 2016-05-11 陈彬 一种治疗气血瘀滞型跟痛症的中药组合物及其制备方法
CN105477269A (zh) * 2016-01-03 2016-04-13 陈彬 一种治疗肾气亏虚型跟痛症的中药组合物及其制备方法
CN105477502A (zh) * 2016-01-03 2016-04-13 陈彬 一种治疗寒湿痹阻型跟痛症的中药组合物及其制备方法
JP2019516773A (ja) 2016-05-25 2019-06-20 コンセントリック アナルジジックス，インク． 改善された局所麻酔のための局所麻酔薬及び血管収縮薬と組み合わせたフェノールｔｒｐｖ１アゴニストのプロドラッグ
CN107281444B (zh) * 2017-06-23 2021-03-02 南充市中医医院 一种止痛的药物组合物及其制备方法和用途
AU2018302342A1 (en) 2017-07-20 2020-02-06 Centrexion Therapeutics Corporation Methods and compositions for treatment of pain using capsaicin
CN113166051A (zh) 2018-07-27 2021-07-23 同心镇痛药物公司 酚类trpv1激动剂的聚乙二醇化前药
US11254659B1 (en) 2019-01-18 2022-02-22 Centrexion Therapeutics Corporation Capsaicinoid prodrug compounds and their use in treating medical conditions
US11447444B1 (en) 2019-01-18 2022-09-20 Centrexion Therapeutics Corporation Capsaicinoid prodrug compounds and their use in treating medical conditions
BR112022018608A2 (pt) 2020-03-17 2022-11-08 Gruenenthal Gmbh Aplicação tópica repetida de emplastro de capsaicina para o tratamento de não-respondedores iniciais
MX2022012219A (es) 2020-04-03 2022-10-27 Gruenenthal Gmbh Regimen para la aplicacion topica repetida del parche de capsaicina.
RU2755206C1 (ru) 2020-05-20 2021-09-14 Федеральное государственное бюджетное учреждение науки Тихоокеанский институт биоорганической химии им. Г.Б. Елякова Дальневосточного отделения Российской академии наук (ТИБОХ ДВО РАН) Средство пролонгированного анальгетического действия и лекарственный препарат на его основе

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5560910A (en) * 1994-08-26 1996-10-01 Crandall; Wilson T. Topical anti-inflammatory composition and method
US5874420A (en) * 1995-12-26 1999-02-23 Allegheny University Of The Health Sciences Process for regulating vagal tone
US5994407A (en) * 1999-06-16 1999-11-30 Cuilty-Siller; Carlos Procedure to prepare a solution with capsaicin
US6248744B1 (en) * 1998-02-24 2001-06-19 Wake Forest University Method for the treatment of pain, including chronic and female specific pain
US6277386B1 (en) * 1998-02-25 2001-08-21 Basf Aktiengesellschaft Cosmetic
US20040204356A1 (en) * 2002-12-06 2004-10-14 Volkmar Guenzler-Pukall Treatment of diabetes

Family Cites Families (83)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4097607A (en) * 1976-12-10 1978-06-27 Larson Kenneth A Deterrent composition, method of using same, and article coated thereby
US4486450B1 (en) * 1980-07-14 1998-07-28 Joel E Bernstein Method of treating psoriatic skin and composition
US4313958A (en) * 1980-10-24 1982-02-02 The Procter & Gamble Company Method of producing analgesia
US4401663A (en) * 1981-06-30 1983-08-30 The Procter & Gamble Company Novel sulfonamide derivatives
US4460602A (en) 1981-06-30 1984-07-17 The Procter & Gamble Company Urea derivatives
US4443473A (en) * 1981-06-30 1984-04-17 The Procter & Gamble Company Carbamate derivatives
US4424205A (en) 1982-03-18 1984-01-03 The Procter & Gamble Company Hydroxyphenylacetamides having analgesic and anti-irritant activity
US4742054A (en) * 1982-11-23 1988-05-03 Naftchi Nosrat E Treatment of mammals suffering from damage to the central nervous system
US4536404A (en) * 1983-06-16 1985-08-20 Dermatological Enterprises, Ltd. Method and composition for treating post-herpetic neuralgia
US4532139A (en) * 1983-07-14 1985-07-30 The Procter & Gamble Company Compounds and compositions useful for producing analgesia
US4493848A (en) * 1983-07-14 1985-01-15 The Procter & Gamble Company Compositions and methods useful for producing analgesia
US4599342A (en) 1984-01-16 1986-07-08 The Procter & Gamble Company Pharmaceutical products providing enhanced analgesia
US4681897A (en) * 1984-01-16 1987-07-21 The Procter & Gamble Company Pharmaceutical products providing enhanced analgesia
US4702916A (en) * 1985-12-03 1987-10-27 Warner-Lambert Company Analgesic stick compositions
US4801587A (en) * 1987-03-02 1989-01-31 Gene Voss Impotence ointment
US5099030A (en) 1987-03-09 1992-03-24 The Procter & Gamble Company Novel compounds, pharmaceutical compositions, and methods for treating inflammation and pain
US4939149A (en) * 1988-10-24 1990-07-03 The United States Of America As Represented By The Department Of Health And Human Services Resiniferatoxin and analogues thereof to cause sensory afferent C-fiber and thermoregulatory desensitization
US5008289A (en) * 1988-12-02 1991-04-16 Galenpharma, Inc. Composition for treating nasal disorders and headaches
US4997853A (en) * 1988-12-02 1991-03-05 Galenpharma, Inc. Method and compositions utilizing capsaicin as an external analgesic
WO1990014083A1 (en) 1989-05-15 1990-11-29 Afferon Corporation Composition and method for neural desensitization
US5021450A (en) * 1989-05-30 1991-06-04 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services New class of compounds having a variable spectrum of activities for capsaicin-like responses, compositions and uses thereof
US5188837A (en) * 1989-11-13 1993-02-23 Nova Pharmaceutical Corporation Lipsopheres for controlled delivery of substances
US5063060A (en) * 1989-12-19 1991-11-05 Cisco Limited Partnership Compositions and method for treating painful, inflammatory or allergic disorders
US5447947A (en) * 1990-02-26 1995-09-05 Arc 1 Compositions and methods of treatment of sympathetically maintained pain
US5094782A (en) * 1990-12-24 1992-03-10 National Science Council Of Republic Of China Synthesis of capsacin derivatives and their use as an analgesic drug and vessel dilation drug
JP3540246B2 (ja) 1991-10-14 2004-07-07 ライオン株式会社 外用消炎鎮痛用貼付剤
US5431914A (en) * 1992-04-17 1995-07-11 Adekunle; Michael Method of treating an internal condition by external application of capsaicin without the need for systemic absorption
US5178879A (en) * 1992-04-17 1993-01-12 Michael Adekunle Capsaicin gel
US5985860A (en) * 1992-06-03 1999-11-16 Toppo; Frank System for transdermal delivery of pain relieving substances
US6063381A (en) * 1993-05-19 2000-05-16 Staggs; Jeff J. Therapeutic uses of pungent botanicals and their related compounds
US5910512A (en) * 1994-04-18 1999-06-08 Healthline Laboratories, Inc. Topical analgesic using water soluble capsaicin
US5660830A (en) * 1994-09-14 1997-08-26 Anderson; Cleve Richard Solubilizing counter-irritants and concurrently extracting capsaicin from the same specific peppers
US5665378A (en) * 1994-09-30 1997-09-09 Davis; Roosevelt Transdermal therapeutic formulation
US5762963A (en) 1995-06-07 1998-06-09 Emory University Method and compositions for controlling oral and pharyngeal pain using capsaicinoids
US5788982A (en) * 1995-06-16 1998-08-04 Nadoolman; Wolffe Method and composition for treating oral pain using capsaicin
US5849761A (en) * 1995-09-12 1998-12-15 Regents Of The University Of California Peripherally active anti-hyperalgesic opiates
US6248788B1 (en) * 1996-11-06 2001-06-19 The Regents Of The University Of California Therapeutic method with capsaicin and capasicin analogs
US6239180B1 (en) * 1995-11-08 2001-05-29 The Regents Of The University Of California Transdermal therapeutic device and method with capsaicin and capsaicin analogs
BR9509985A (pt) * 1995-12-12 1998-11-03 Omeros Med Sys Inc Solução para irrigação e método para inibição de dor inflamação e esparmo
US5869533A (en) * 1996-04-23 1999-02-09 Holt; Stephen D. Non-irritating capsaicin formulations and applicators therefor
US5854291A (en) * 1996-04-23 1998-12-29 Medical Merchandising, Inc. Pain reliever and method of use
US5856361A (en) * 1996-04-23 1999-01-05 Medical Merchandising, Inc. Pain reliever and method of use
CN1059577C (zh) 1996-07-12 2000-12-20 王庆新 皮疾胶囊、皮疾软膏
WO1998020867A1 (en) 1996-11-15 1998-05-22 The United States Of America, Represented By The Secretary, Department Of Health And Human Services Pharmaceutical compositions containing vanilloid agonists in combination with vanilloid antagonists
US6060060A (en) * 1997-01-31 2000-05-09 Bmb Patent Holding Corporation Analgesic compositions from sweet peppers and methods of use thereof
EP1201241B8 (en) * 1997-03-13 2010-10-27 James N. Campbell Compositions containing capsaicin or capsaicin analogues and an anesthetic
US6201022B1 (en) * 1997-03-27 2001-03-13 Myorx, Inc. Methods for treating neurotransmitter-mediated pain syndromes by topically administering an omega fatty acid
US5827886A (en) * 1997-05-07 1998-10-27 Thione International, Inc. Composition for relief of arthritis-induced symptoms
US6326020B1 (en) * 1997-05-16 2001-12-04 Children's Medical Center Corporation Local anesthetic formulations
WO1998053825A1 (en) 1997-05-27 1998-12-03 Algos Pharmaceutical Corporation Analgesic drug composition containing a capsaicinoid and potentiator therefor
US6632839B2 (en) * 1997-06-06 2003-10-14 Robert H. Neumann Capsicum based disinfectant and sterilizant
GB9711962D0 (en) * 1997-06-10 1997-08-06 Reckitt & Colmann Prod Ltd Therapeutically active compositions
US6248345B1 (en) * 1997-07-02 2001-06-19 Euro-Celtique, S.A. Prolonged anesthesia in joints and body spaces
GB2327041A (en) 1997-07-09 1999-01-13 Smithkline Beecham Plc Topical Analgesic Composition
US6063758A (en) * 1997-07-09 2000-05-16 Advanced Targeting Systems, Inc. Substance P-Saporin (SP-SAP) conjugates and methods of use thereof
US6007538A (en) * 1997-07-25 1999-12-28 Duke University Sternal closure device
US6204271B1 (en) * 1997-09-16 2001-03-20 Solvay Pharmaceuticals Gmbh Analgesic composition and method for using same
US5885597A (en) * 1997-10-01 1999-03-23 Medical Research Industries,Inc. Topical composition for the relief of pain
JP3211027B2 (ja) 1998-11-13 2001-09-25 丸石製薬株式会社 カプサイシン含有外用剤
JP2000247875A (ja) 1999-01-01 2000-09-12 Lion Corp 外用消炎鎮痛剤
IL127943A (en) * 1999-01-07 2010-12-30 Shlomo Magdassi Pharmaceutical and cosmetic compositions for the treatment of skin disorders
CA2267049A1 (en) * 1999-02-05 2000-08-05 Bioglan Laboratories Ltd. Pharmaceutical compositions
GB9902651D0 (en) 1999-02-05 1999-03-31 Bioglan Lab Ltd Pharmaceutical compositions
GB9904163D0 (en) 1999-02-23 1999-04-14 Bioglan Lab Ltd Pharmaceutical compositions
US6284797B1 (en) * 1999-04-12 2001-09-04 Donald A. Rhodes Topical treatment of pain and to promote healing
US6368618B1 (en) * 1999-07-01 2002-04-09 The University Of Georgia Research Foundation, Inc. Composition and method for enhanced transdermal absorption of nonsteroidal anti-inflammatory drugs
US6653352B2 (en) * 1999-09-29 2003-11-25 Medical Merchandising, Inc. Pain reliever and method of use
US6197823B1 (en) * 1999-09-29 2001-03-06 Medical Merchandising, Inc. Pain reliever and method of use
JP4560864B2 (ja) * 1999-11-30 2010-10-13 味の素株式会社 新規なカプサイシノイド様物質を含有する鎮痛剤、食品及び飼料
CA2398514A1 (en) * 2000-01-28 2001-08-02 Robert M. Abra Liposomes containing an entrapped compound in supersaturated solution
IL137381A (en) 2000-07-19 2005-06-19 Avshalom Bar Shalom Method and system for monitoring ruminant animals, particularly dairy cattle
CA2435418A1 (en) 2001-01-24 2002-08-01 Mestex Ag Use of neurotoxic substances in producing a medicament for treating joint pains
CA2442049C (en) 2001-03-22 2010-06-01 Michael J. Iadarola Selective ablation of pain-sensing neurons by administration of a vanilloid receptor agonist
US20030104085A1 (en) * 2001-12-05 2003-06-05 Yeomans David C. Methods and compositions for treating back pain
WO2003061626A1 (en) * 2002-01-18 2003-07-31 Control Delivery Systems, Inc. Polymeric gel system for the controlled delivery of codrugs
JP2006511930A (ja) 2002-06-21 2006-04-06 コンティネンタル・テーベス・アクチエンゲゼルシヤフト・ウント・コンパニー・オッフェネ・ハンデルスゲゼルシヤフト 電子式自動車制御装置用のプリント回路基板
EP1539124B1 (en) * 2002-09-05 2018-07-18 Vanderbilt Royalty Sub L.P. Compositions and kits for the removal of irritating compounds from bodily surfaces
MXPA05006670A (es) 2002-12-18 2005-10-19 Algorx Pharmaceuticals Inc Administracion de capsaicinoides.
US20050058734A1 (en) * 2002-12-18 2005-03-17 Algorx Administration of capsaicinoids
JP2006522815A (ja) * 2003-04-08 2006-10-05 アルゴルクス ファーマスーティカルズ，インク 合成カプサイシンの製造および精製
US20040224037A1 (en) * 2003-04-28 2004-11-11 Gonzalo Romero-Matos Devastating treatment against hiv/aids with capsaicin
WO2006058140A2 (en) 2004-11-24 2006-06-01 Algorx Pharmaceuticals, Inc. Capsaicinoid gel formulation and uses thereof
JP2013213382A (ja) * 2012-03-31 2013-10-17 Yukihiro Higuchi 高圧水作業用ポンプ車

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5560910A (en) * 1994-08-26 1996-10-01 Crandall; Wilson T. Topical anti-inflammatory composition and method
US5874420A (en) * 1995-12-26 1999-02-23 Allegheny University Of The Health Sciences Process for regulating vagal tone
US6248744B1 (en) * 1998-02-24 2001-06-19 Wake Forest University Method for the treatment of pain, including chronic and female specific pain
US6277386B1 (en) * 1998-02-25 2001-08-21 Basf Aktiengesellschaft Cosmetic
US5994407A (en) * 1999-06-16 1999-11-30 Cuilty-Siller; Carlos Procedure to prepare a solution with capsaicin
US20040204356A1 (en) * 2002-12-06 2004-10-14 Volkmar Guenzler-Pukall Treatment of diabetes

Cited By (96)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040186182A1 (en) * 2002-12-18 2004-09-23 Algorx Administration of capsaicinoids
US20050020690A1 (en) * 2002-12-18 2005-01-27 Algorx Infiltration of capsaicin into surgical sites and open wounds
US20050058734A1 (en) * 2002-12-18 2005-03-17 Algorx Administration of capsaicinoids
US20040156931A1 (en) * 2002-12-18 2004-08-12 Algorx Administration of capsaicinoids
US8790679B2 (en) 2002-12-20 2014-07-29 Xeris Pharmaceuticals, Inc. Intracutaneous paste composition
US20060211982A1 (en) * 2002-12-20 2006-09-21 Steven Prestrelski Intracutaneous injection
US8110209B2 (en) 2002-12-20 2012-02-07 Xeris Pharmaceuticals Inc. Intracutaneous injection
US20110060310A1 (en) * 2002-12-20 2011-03-10 Steven Prestrelski Intracutaneous injection
US9314424B2 (en) 2002-12-20 2016-04-19 Xeris Pharmaceuticals, Inc. Pastes for injection of a therapeutic agent
US20070293703A1 (en) * 2003-04-08 2007-12-20 Algorx Pharmaceuticals, Inc. Preparation and purification of synthetic capsaicin
US20060148903A1 (en) * 2004-11-24 2006-07-06 Algorx Pharmaceuticals, Inc. Capsaicinoid gel formulation and uses thereof
US20080153780A1 (en) * 2004-12-28 2008-06-26 Mestex Ag Use Of A Vanilloid Receptor Agonist Together With A Glycosaminoglycan Or Proteoglycan For Producing An Agent For Treating Articular Pains And Method For Applying Said Agent
US8703741B2 (en) * 2004-12-28 2014-04-22 Mestex Ag Method of treating articular pain using a vanilloid receptor agonist together with a glycosaminoglycan or proteoglycan
US7943666B2 (en) * 2006-07-24 2011-05-17 Trinity Laboratories, Inc. Esters of capsaicin for treating pain
US7645767B2 (en) 2006-08-31 2010-01-12 Trinity Laboratories, Inc. Pharmaceutical compositions for treating chronic pain and pain associated with neuropathy
US20080058362A1 (en) * 2006-08-31 2008-03-06 Singh Chandra U Novel pharmaceutical compositions for treating chronic pain and pain associated with neuropathy
US9393093B2 (en) 2008-02-18 2016-07-19 Covidien Lp Clip for implant deployment device
US10695155B2 (en) 2008-02-18 2020-06-30 Covidien Lp Device and method for deploying and attaching an implant to a biological tissue
US9107726B2 (en) 2008-02-18 2015-08-18 Covidien Lp Device and method for deploying and attaching an implant to a biological tissue
US8317808B2 (en) 2008-02-18 2012-11-27 Covidien Lp Device and method for rolling and inserting a prosthetic patch into a body cavity
US9398944B2 (en) 2008-02-18 2016-07-26 Covidien Lp Lock bar spring and clip for implant deployment device
US9044235B2 (en) 2008-02-18 2015-06-02 Covidien Lp Magnetic clip for implant deployment device
US10182898B2 (en) 2008-02-18 2019-01-22 Covidien Lp Clip for implant deployment device
US9393002B2 (en) 2008-02-18 2016-07-19 Covidien Lp Clip for implant deployment device
US10159554B2 (en) 2008-02-18 2018-12-25 Covidien Lp Clip for implant deployment device
US9034002B2 (en) 2008-02-18 2015-05-19 Covidien Lp Lock bar spring and clip for implant deployment device
US8753359B2 (en) 2008-02-18 2014-06-17 Covidien Lp Device and method for deploying and attaching an implant to a biological tissue
US8758373B2 (en) 2008-02-18 2014-06-24 Covidien Lp Means and method for reversibly connecting a patch to a patch deployment device
US9833240B2 (en) 2008-02-18 2017-12-05 Covidien Lp Lock bar spring and clip for implant deployment device
US9301826B2 (en) 2008-02-18 2016-04-05 Covidien Lp Lock bar spring and clip for implant deployment device
US9005241B2 (en) 2008-02-18 2015-04-14 Covidien Lp Means and method for reversibly connecting a patch to a patch deployment device
US8808314B2 (en) 2008-02-18 2014-08-19 Covidien Lp Device and method for deploying and attaching an implant to a biological tissue
US8888811B2 (en) 2008-10-20 2014-11-18 Covidien Lp Device and method for attaching an implant to biological tissue
US8987328B2 (en) 2008-10-30 2015-03-24 Trinity Laboratories, Inc. Esters of capsaicinoids as dietary supplements
US20100120912A1 (en) * 2008-10-30 2010-05-13 Trinity Laboratories Inc. Esters of capsaicinoids as dietary supplements
US8870876B2 (en) 2009-02-13 2014-10-28 Tarsus Medical Inc. Methods and devices for treating hallux valgus
US20100211071A1 (en) * 2009-02-13 2010-08-19 Lettmann Jason W Methods and devices for treating hallux valgus
US8734473B2 (en) 2009-02-18 2014-05-27 Covidien Lp Device and method for rolling and inserting a prosthetic patch into a body cavity
KR101129365B1 (ko) * 2009-08-07 2012-03-26 고려대학교 산학협력단 추간판 질환용 서방성 치료제 및 이의 제조방법
US8906045B2 (en) 2009-08-17 2014-12-09 Covidien Lp Articulating patch deployment device and method of use
US9999424B2 (en) 2009-08-17 2018-06-19 Covidien Lp Means and method for reversibly connecting an implant to a deployment device
US8277459B2 (en) 2009-09-25 2012-10-02 Tarsus Medical Inc. Methods and devices for treating a structural bone and joint deformity
US20110077656A1 (en) * 2009-09-25 2011-03-31 Sand Paul M Methods and devices for treating a structural bone and joint deformity
US8795286B2 (en) 2009-09-25 2014-08-05 Tarsus Medical Inc. Methods and devices for treating a structural bone and joint deformity
US8652141B2 (en) 2010-01-21 2014-02-18 Tarsus Medical Inc. Methods and devices for treating hallux valgus
US8696719B2 (en) 2010-06-03 2014-04-15 Tarsus Medical Inc. Methods and devices for treating hallux valgus
US9687527B2 (en) 2010-07-19 2017-06-27 The Regents Of The University Of Colorado, A Body Corporate Stable glucagon formulations for the treatment of hypoglycemia
US9302010B2 (en) 2011-03-10 2016-04-05 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of peptide drugs
US9295724B2 (en) 2011-03-10 2016-03-29 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of peptide drugs
US9339545B2 (en) 2011-03-10 2016-05-17 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of peptide drugs
US8697644B2 (en) 2011-03-10 2014-04-15 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of peptide drugs
US10987399B2 (en) 2011-03-10 2021-04-27 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of peptide drugs
US9351976B2 (en) 2011-03-18 2016-05-31 Alkermes Pharma Ireland Limited Pharmaceutical compositions comprising sorbitan esters
US10226458B2 (en) 2011-03-18 2019-03-12 Alkermes Pharma Ireland Limited Pharmaceutical compositions comprising sorbitan esters
KR101138317B1 (ko) * 2011-08-09 2012-04-25 고려대학교 산학협력단 추간판 질환용 서방성 치료제 및 이의 제조방법
US9138479B2 (en) 2011-10-31 2015-09-22 Xeris Pharmaceuticals, Inc. Formulations for the treatment of diabetes
US9999670B2 (en) 2012-03-19 2018-06-19 Alkermes Pharma Ireland Limited Pharmaceutical compositions comprising benzyl alcohol
US9993556B2 (en) 2012-03-19 2018-06-12 Alkermes Pharma Ireland Limited Pharmaceutical compositions comprising fatty glycerol esters
US10004807B2 (en) 2012-03-19 2018-06-26 Alkermes Pharma Ireland Limited Pharmaceutical compositions comprising fatty acid esters
US11446310B2 (en) 2012-06-27 2022-09-20 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of small molecule drugs
US10765683B2 (en) 2012-06-27 2020-09-08 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of small molecule drugs
US9125805B2 (en) 2012-06-27 2015-09-08 Xeris Pharmaceuticals, Inc. Stable formulations for parenteral injection of small molecule drugs
US11097006B2 (en) 2012-09-19 2021-08-24 Alkermes Pharma Ireland Limited Pharmaceutical compositions having improved storage stability
US9861699B2 (en) 2012-09-19 2018-01-09 Alkermes Pharma Ireland Limited Pharmaceutical compositions having improved storage stability
US11969469B2 (en) 2012-09-19 2024-04-30 Alkermes Pharma Ireland Limited Pharmaceutical compositions having improved storage stability
US10639376B2 (en) 2012-09-19 2020-05-05 Alkermes Pharma Ireland Limited Pharmaceutical compositions having improved storage stability
US10342877B2 (en) 2012-09-19 2019-07-09 Alkermes Pharma Ireland Limited Pharmaceutical compositions having improved storage stability
EP3446680A1 (en) 2012-11-12 2019-02-27 Vizuri Health Sciences LLC Aqueous based capsaicinoid formulations and methods of manufacture and use
WO2014075084A2 (en) 2012-11-12 2014-05-15 Api Genesis Llc Aqueous based capsaicinoid formulations and methods of manufacture and use
WO2014075084A3 (en) * 2012-11-12 2014-07-10 Api Genesis Llc Aqueous based capsaicinoid formulations, and treatment in combination with a corticosteroid
US9642894B2 (en) 2013-02-06 2017-05-09 Xeris Pharmaceuticals, Inc. Compositions for rapidly treating severe hypoglycemia
US9018162B2 (en) 2013-02-06 2015-04-28 Xeris Pharmaceuticals, Inc. Methods for rapidly treating severe hypoglycemia
WO2015073577A1 (en) 2013-11-12 2015-05-21 Vizuri Health Sciences Llc Aqueous based capsaicinoid formulations and methods of manufacture and use
US10085980B2 (en) 2014-03-20 2018-10-02 Alkermes Pharma Ireland Limited Aripiprazole formulations having increased injection speeds
US10238651B2 (en) 2014-03-20 2019-03-26 Alkermes Pharma Ireland Limited Aripiprazole formulations having increased injection speeds
US10813928B2 (en) 2014-03-20 2020-10-27 Alkermes Pharma Ireland Limited Aripiprazole formulations having increased injection speeds
US11406632B2 (en) 2014-03-20 2022-08-09 Alkermes Pharma Ireland Limited Aripiprazole formulations having increased injection speeds
US11931355B2 (en) 2014-03-20 2024-03-19 Alkermes Pharma Ireland Limited Aripiprazole formulations having increased injection speeds
US11129940B2 (en) 2014-08-06 2021-09-28 Xeris Pharmaceuticals, Inc. Syringes, kits, and methods for intracutaneous and/or subcutaneous injection of pastes
CN104689253A (zh) * 2015-03-31 2015-06-10 都炳霞 一种治疗胆囊切除后综合症的中药组合物
US11590205B2 (en) 2015-09-25 2023-02-28 Xeris Pharmaceuticals, Inc. Methods for producing stable therapeutic glucagon formulations in aprotic polar solvents
US10485850B2 (en) 2015-09-25 2019-11-26 Xeris Pharmaceuticals, Inc. Methods for producing stable therapeutic formulations in aprotic polar solvents
US9649364B2 (en) 2015-09-25 2017-05-16 Xeris Pharmaceuticals, Inc. Methods for producing stable therapeutic formulations in aprotic polar solvents
WO2017127628A1 (en) * 2016-01-22 2017-07-27 Centrexion Therapeutics Corporation Capsaicn sequential dosing method for treatment of morton's neuroma pain
JP2019506397A (ja) * 2016-01-22 2019-03-07 セントレクシオン セラピューティクス コーポレイション モートン神経腫疼痛の治療のためのカプサイシン連続投薬方法
US11344516B2 (en) 2016-11-02 2022-05-31 Centrexion Therapeutics Corporation Stable aqueous capsaicin injectable formulations and medical uses thereof
US11000490B2 (en) 2016-11-02 2021-05-11 Centrexion Therapeutics Corporation Stable aqueous capsaicin injectable formulations and medical uses thereof
KR20190101368A (ko) * 2016-11-02 2019-08-30 센트렉시온 테라퓨틱스 코포레이션 안정한 수성의 캡사이신 주사 가능한 제형 및 이의 의학적 용도
KR102657458B1 (ko) * 2016-11-02 2024-04-12 센트렉시온 테라퓨틱스 코포레이션 안정한 수성의 캡사이신 주사 가능한 제형 및 이의 의학적 용도
US11020403B2 (en) 2017-06-02 2021-06-01 Xeris Pharmaceuticals, Inc. Precipitation resistant small molecule drug formulations
US11833157B2 (en) 2017-06-02 2023-12-05 Xeris Pharmaceuticals, Inc. Precipitation resistant small molecule drug formulations
CN111315360A (zh) * 2017-09-11 2020-06-19 索伦托治疗有限公司 树脂毒素制剂
US20190076396A1 (en) * 2017-09-11 2019-03-14 Sorrento Therapeutics, Inc. Formulation of resiniferatoxin
US11273158B2 (en) 2018-03-05 2022-03-15 Alkermes Pharma Ireland Limited Aripiprazole dosing strategy
CN108273027A (zh) * 2018-04-02 2018-07-13 史兰 一种治疗膝骨关节炎的药膏
US11992470B2 (en) 2022-03-22 2024-05-28 Centrexion Therapeutics Corporation Stable aqueous capsaicin injectable formulations and medical uses thereof

Also Published As

Publication number Publication date
EP1605956A1 (en) 2005-12-21
PT1605956E (pt) 2016-03-09
JP5874154B2 (ja) 2016-03-02
US20060269628A1 (en) 2006-11-30
WO2004058286A1 (en) 2004-07-15
AU2003299691B2 (en) 2008-06-05
EA011708B1 (ru) 2009-04-28
US20080260791A1 (en) 2008-10-23
ES2562025T3 (es) 2016-03-02
AU2003299691A1 (en) 2004-07-22
EP1605956B1 (en) 2015-11-11
CA2510181A1 (en) 2004-07-15
CN1750839B (zh) 2013-11-13
JP6298798B2 (ja) 2018-03-20
MXPA05006670A (es) 2005-10-19
DK1605956T3 (en) 2016-02-15
CN1750839A (zh) 2006-03-22
JP2014055141A (ja) 2014-03-27
JP2010280668A (ja) 2010-12-16
US20050020690A1 (en) 2005-01-27
EP1605956A4 (en) 2009-04-29
EA200500986A1 (ru) 2005-12-29
JP2006513267A (ja) 2006-04-20
BR0316906A (pt) 2006-08-29
US8367733B2 (en) 2013-02-05
CA2510181C (en) 2011-03-08
JP2016047822A (ja) 2016-04-07
US20080262091A1 (en) 2008-10-23
CN102205127A (zh) 2011-10-05
NZ540769A (en) 2009-03-31

Similar Documents

Publication Publication Date Title
US20200375926A1 (en) Injectable resiniferatoxin
CA2510181C (en) Administration of capsaicinoids
US20060148903A1 (en) Capsaicinoid gel formulation and uses thereof

Legal Events

Date Code Title Description
AS Assignment

Owner name: ALGORX PHARMACEUTICALS, INC., NEW JERSEY

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BURCH, RONALD M.;CARTER, RICHARD B.;LAZAR, JEFFREY D.;REEL/FRAME:015912/0899;SIGNING DATES FROM 20041001 TO 20041004

STCB Information on status: application discontinuation

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

AS Assignment

Owner name: ARCION THERAPEUTICS, INC., MARYLAND

Free format text: SECURITY AGREEMENT;ASSIGNOR:ALGORX PHARMACEUTICALS, INC.;REEL/FRAME:022703/0645

Effective date: 20090518

AS Assignment

Owner name: SOFINNOVA VENTURE PARTNERS, VII, L.P.,CALIFORNIA

Free format text: PATENT COLLATERAL AGENT ASSIGNMENT;ASSIGNOR:CMEA VENTURES VII, L.P.;REEL/FRAME:023968/0872

Effective date: 20100222

Owner name: SOFINNOVA VENTURE PARTNERS, VII, L.P., CALIFORNIA

Free format text: PATENT COLLATERAL AGENT ASSIGNMENT;ASSIGNOR:CMEA VENTURES VII, L.P.;REEL/FRAME:023968/0872

Effective date: 20100222